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Boom in Bilateral Mastectomies 103 | Sexual Concerns in Cancer Survivors

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| BRAF/MEK Inhibition in Melanoma

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VOLUME 5, ISSUE 18

NOVEMBER 15, 2014

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

The Next-to-Last Frontier in Managing Acute Promyelocytic Leukemia

ESMO Congress

IMPRESS Trial: Lung Cancer Progression on First-Line Tyrosine Kinase Inhibitor Indicates the Drug Should Be Stopped

By Martin S. Tallman, MD

By Alice Goodman

T

he IMPRESS trial found no benefit for continuing treatment with the epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor gefitinib (Iressa, discontinued in the United States) plus chemotherapy vs chemotherapy alone in patients with EGFR-mutated non–small cell lung cancer (NSCLC) who had disease progression on treatment with gefitinib. Progression was defined according to RECIST criteria in the IMPRESS trial, and not by clinical symptoms or metastatic spread.

Hotly Debated Issue “This study resolves a hotly debated issue, and the results demonstrated that EGFR tyrosine kinase inhibitors should not be continued beyond progression. The standard treatment at progression remains platinum-based chemotherapy,” stated lead author Tony S.K. Mok, MD, Professor of Clinical Oncology

at the Chinese University of Hong Kong, and the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.1 EGFR tyrosine kinase inhibitors are the standard first-line treatment for patients with EGFR-positive Tony S.K. Mok, MD NSCLC. Gefitinib is the EGFR tyrosine kinase inhibitor of choice in Asia and Europe, whereas erlotinib is used in the United States. Most patients who initially respond to first-line therapy with an EGFR tyrosine kinase inhibitor experience disease progression with “acquired resistance.” At that time, there are two options: to discontinue the EGFR tyrosine kinase inhibitor or to continue it and

Striving for Quality, Not Quantity, of Life

continued on page 71

Perspective

T

he treatment of acute promyelocytic leukemia (APL) represents one of the major triumphs in the field of hematologic malignancies. With either the vitamin A derivative all-trans retinoic acid (ATRA) combined with anthracycline-based chemotherapy or ATRA plus arsenic trioxide (Trisenox), approximately 85% to 90% of all patients can be cured of their disease if they survive induction therapy. Relapse after complete remission is achieved has become very uncommon even among high-risk patients (those with a presenting white blood cell count > 10,000/μL). Such success is due to the convergence of continued on page 86

Dr. Tallman is Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College in New York. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

A Conversation With Ezekiel J. Emanuel, MD, PhD By Jo Cavallo

A

MORE IN THIS ISSUE

dvances in science and medicine have led to humans living longer than at any other time in history. According to a new report1 on mortality from the Centers for Disease Control and Prevention’s National Center for Health Statistics, life expectancy in the United States is at an all-time high of 78.8 years, up 0.1 year since 2011. “Good news, America: We’re living longer!” read the opening line in a story in USA Today2 announcing the report’s findings. But those extra years do not necessarily add up

to quality ones. Advances in health care have not so much slowed the aging process as they have the dying process, contends Ezekiel J. Emanuel, MD, PhD, Chair, Medical Ethics & Health Policy at the University of Pennsylvania in Philadelphia, in an essay he penned in the October issue of The Atlantic.3 Titled “Why I Hope to Die at 75,” the article has set off a firestorm of controversy, including accusations by critics that Dr. Emanuel is advocating health-care rationing, death panels, and even legalized euthanasia for people living beyond 75, none of which is true. My main goal for writing the article Instead, Dr. Emanuel writes about his personal was to start a conversation about preference to refrain from the importance of quality rather taking life-sustaining medical steps once he reaches 75. than quantity of life, but I’m very While it is doubtless comfortable with lots of people not that death is a loss, living too long is also a loss, agreeing with my view. wrote Dr. Emanuel. “It —Ezekiel J. Emanuel, MD, PhD

Oncology Meetings Coverage ESMO��� 1, 42-47, 51-55, 64-67, 71-76 Quality Care Symposium������������� 3-5, 8-9 Best of ASCO���������������������� 14-15, 24-26 Breast Cancer Symposium����������������30, 34 Jeremy S. Abramson, MD, on Indolent Lymphoma�����������������������������������27 Direct From ASCO��������������������������� 78-81 Andreas du Bois, MD, PhD, on Pazopanib in Ovarian Cancer����������������� 106 Margaret Tempero, MD, on Pancreatic Cancer in 2014����������������������� 120 Hansjochen Wilke, MD, on Ramucirumab in Gastric Cancer������������ 155

continued on page 175

November is Pancreatic Cancer and Lung Cancer Awareness Month

A Harborside Press® Publication


The ASCO Post  |   NOVEMBER 15, 2014

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Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Associate Editors

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Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Joseph S. Bailes, MD Texas Oncology

Clifford A. Hudis, MD, FACP Memorial Sloan Kettering Cancer Center

Laurence H. Baker, DO University of Michigan Health System

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Hagop M. Kantarjian, MD MD Anderson Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Douglas W. Blayney, MD Stanford University Medical Center

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine Harold J. Burstein, MD Dana-Farber Cancer Institute

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Jamie Von Roenn, MD American Society of Clinical Oncology

Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

Lynn D. Wilson, MD Yale University School of Medicine

Susan Reckling, Senior Editor Susan@harborsidepress.com

Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

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Sarah McGullam, Web Editor Sarah@harborsidepress.com Michael Buckley, Art Director Michael@harborsidepress.com Terri Caivano, Layout Artist Terri@harborsidepress.com Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

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Quality Care Symposium Health-Care Policy

Overutilization a Key Target in Efforts to Control Health-Care Costs By Alice Goodman

O

verutilization of health-care interventions has become a prime target of efforts to rein in health-care costs. Overtreatment of cancer patients is associated with a number of common harms to the patient—not just financial harm to the health-care system. At the recent ASCO Quality Care Symposium

In 2012, an Institute of Medicine report called for better care at lower cost.2 The report estimated that $750 billion were wasted each year and attributed $210 billion of these dollars to unnecessary care. “The patient should be foremost in our thinking. Consider the harms and benefits of treatment, and if the harms

Doing unnecessary tests and giving unnecessary treatment create a cascade of effects. —Lisa K. Hicks, MD, MSc

in Boston, Lisa K. Hicks, MD, MSc, a staff physician at St. Michael’s Hospital and Assistant Professor of Medicine at University of Toronto, discussed drivers of overtreatment, gave an example from her practice, and listed common harmful effects.1

outweigh the benefits, the treatment should not be prescribed,” Dr. Hicks told the audience.

Multiple Causative Factors “Emanuel and Fuchs were the first to describe a ‘perfect storm’ that cre-

ates overutilization.3 The medical culture emphasizes data and thoroughness and is uncomfortable with uncertainty. Many physicians practice defensive medicine,” Dr. Hicks continued. Overutilization is driven by cultural, medical, financial, and social factors. They include an emphasis on diligence and exhaustive testing, financial incentives that encourage doing over observing, rapid pace of science and sophisticated marketing, using high tech because reimbursement is higher, rapid pace of medical science and sophisticated marketing, and direct-to-consumer marketing. Overtreatment occurs in four different settings: screening, investigations, treatment, and physician visits. “Patients receive fragmented care delivery, and their needs are often misaligned with resources. Quality metrics are needed, as are guidelines, but most guidelines focus on what to do, not on what not to do,” she emphasized. Dr. Hicks commended the Choosing Wisely campaign for getting the

buy-in from various medical societies to list five tests or procedures each year that should not be routinely used. ASCO, the American Society of Hematology, the American Society for Radiation Oncology, and other medical societies are participating in this campaign, she said. “Overutilization can cause patient harms,” she continued.

Cascade of Effects Dr. Hicks gave listeners an example from her own practice. A 30-year-old male patient was treated for mediastinal diffuse large B-cell lymphoma and achieved remission. Two years later, he had a slight increase in residual mass on a surveillance computed tomography (CT) scan, but otherwise he was feeling well and his lab tests were all normal. “I was worried so I ordered a [positron-emission tomography] scan and hoped for a normal result, but the findings were indeterminate. We elected to observe him, and he had a scan continued on page 4

Issues in Oncology

Choosing Wildly: A Patient’s Perspective on Overtreatment and Quality Care By Ronald Piana

O

ver the past decade, there has been growing concern in the oncology community about overdiagnosis and overtreatment of cancers that prove to be indolent and nonlethal, resulting in unnecessary and sometimes harmful procedures. At this year’s ASCO Quality Care Symposium in Boston, this important issue was tackled from the patient’s perspective, by cancer survivor and nationally regarded patient advocate Ellen L. Stovall in a presentation subtitled “Health Policy in an Era of Choosing Wildly Wisely.”1

Wild West of Cancer Ms. Stovall, who is Senior Health Policy Advisor at the National Coalition for Cancer Survivorship (NCCS), said that she was originally asked to speak about the Choosing Wisely program from the patient’s perspective, but she featured the substitution of wisely for wildly in her title, explaining, “I think that the way cancer care has been delivered historically is more like the Wild West than the wise way we

would like to think that patients are choosing the care they would like to receive.” Ms. Stovall noted that her organi-

as we see it from the patient advocacy view, is mainly geared toward physicians, and many in our community question whether Choosing Wisely is

Physicians need to be honest and have a frank conversation with their patients, starting with explaining whether their cancer is curable or incurable, and what the available options are. This lays the groundwork for a shared decision-making conversation that addresses the patients’ needs and values moving forward. —Ellen L. Stovall

zation’s central goal is to help foster a cancer care system that is evidencebased, quality-focused, and affordable and accessible to all. “After that, we’re addressing World Peace,” she joked. “The Choosing Wisely campaign,

designed to do less in all circumstances regarding cancer treatment,” noted Ms. Stovall. She emphasized that from a patient’s perspective it is difficult to parse out the underlying messages of campaigns like Choosing Wisely that

are designed to address overuse and also maintain high-quality care.

Personalize Patient Information Ms. Stovall cited a recent article in The New England Journal of Medicine, in which the author noted that the Choosing Wisely campaign had partnered with Consumer Reports to create educational materials for patients on low-value care, presenting accessible information on specific health services.2 “Patient-information and decision-aid approaches are promising, but their creation and use need to be supported and studied,” stressed Ms. Stovall. Within the context of Choosing Wisely, Ms. Stovall focused her attention on the delivery of high-quality cancer care, citing the 2013 Institute of Medicine (IOM) report, Delivering HighQuality Cancer Care: Charting a Course for a System in Crisis.3 “The recommendation from the IOM report that we’ve taken to heart is that the cancer care team continued on page 4


The ASCO Post  |   NOVEMBER 15, 2014

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Quality Care Symposium Overutilization a Key Target continued from page 3

6 weeks later with the same result. But he was so anxious and had chest pain, so we went on to biopsy. The good news is there was no cancer and he had reactive tissue. He is currently in remission, but he has a secondary diagnosis now of anxiety disorder with panic attacks. I think our testing may have worsened existing anxiety, and it may have precipitated panic attacks,” she acknowledged. Other harms of additional imaging studies include increased risk of secondary cancers (estimated at 0.05% lifetime per CT scan for a 30-year-old man), risks of general anesthesia, discomfort, lost time, and worsened anxiety leading to financial hardship. Types of harm from overtreatment in-

Choosing Wildly continued from page 3

should communicate and personalize all the information for their patients at key decision points along the continuum of care, using decision aids when available,” said Ms. Stovall, adding, “We also agree with the report’s recommendation that physicians should collaborate with their patients to develop a care plan that reflects their patients’ needs, values, and preferences and considers palliative and psychosocial support throughout the full course of care.”

Cancer Care Planning She then turned her focus to the NCCS perspective. “At NCCS, our main focus is on cancer care planning, both in the delivery of care and on payment reforms. We look at this in four buckets: the patient, reimbursement, providers, and our central goal, which is cancer care planning at diagnosis and major transition points during treatment and survivorship,” she explained. Ms. Stovall said that the delivery and payment reforms that are essential to attaining quality improvement in cancer care need to begin by changing the conversation. “Physicians need to be honest and have a frank conversation with their patients, starting with explaining whether their cancer is curable or incurable, and what the available options are.

clude adverse events, direct and indirect financial harm, psychological distress, social stigma, lost time (not just work, but sitting in waiting rooms), and incidental findings that lead to further investigations, each of which carries a risk of adverse events. Dr. Hicks cited a meta-analysis showing that 30% of CT scans pick up incidental findings,4 and this is likely to be higher among cancer patients, Dr. Hicks said. “Doing unnecessary tests and giving unnecessary treatment create a cascade of effects,” she noted. “I challenge you, when you go back home, to identify examples of overutilization in your own practice/hospital/provider community. Think about whether there is one test or procedure you could act on immediately. I sus-

Overutilization in Oncology ■■ Cultural, medical, financial, and social factors have converged to create a perfect storm of overutilization of health-care interventions. ■■ Overutilization causes patient and financial harms. ■■ Oncologists should follow the Choosing Wisely recommendations for cancer care and identify and reduce overutilization in their own practices.

pect you will have no difficultly coming up with a long list. Try to change one thing that week, that day,” she encouraged listeners. n

Disclosure: Dr. Hicks reported no potential conflicts of interest.

References 1. Hicks LK: Harms of care (overtreatment) and quality implications. ASCO Quality Care Symposium. Presented October 17, 2014.

This lays the groundwork for a shared decision-making conversation that addresses the patient’s needs and values moving forward,” she noted. On the subject of payment reforms, Ms. Stovall noted that payment reforms must be aligned to reflect improvement in communication, treatment decision-making, symptom management, and coordination of care. “The Center for Medicare & Medicare Innovation (CMMI) care model is the main focus of NCCS payment reforms. The current proposal by CMMI looks at lowering costs using a three-part payment structure reform and quality metrics intended for determining performance payments,” said Ms. Stovall.

patient-reported outcome measures, developed with input from patients, (3) ensure that therapeutic innovations will be rapidly incorporated into standard of care, and (4) reimburse for coordination of care, from screening through survivorship. Summing up the challenges to enhancing quality care while also addressing payment reforms, such as those she previously discussed from the IOM report, Ms. Stovall said, “Having worked with the IOM over the past 15 years, I can say from experience that putting out proposals, supporting quality care and reform legislation, and at the same time helping patients choose wisely— well, it is a tough nut to crack.”

Uphill Battle

Beyond Choosing Wisely

“We’ve also had a legislative proposal moving through six sessions of Congress that ASCO and many other cancer and patient advocacy organizations have supported. Moreover, we’ve worked with the main private payers and with ASCO and the Center for American Progress on payment reform,” said Ms. Stovall. She then enumerated the NCCS principles for payment reform, stating that any alternative payment system must: (1) include protections against underutilization or overutilization, (2) incorporate outcome, process, and

Ms. Stovall stated that the goal of NCCS and other advocacy groups is to get beyond Choosing Wisely and the narrow range of issues that it lays out for physicians and their patients to consider. “Matters related to overtreatment and undertreatment need to be addressed. Equally important, cost and value of interventions must be made transparent and factored into the doctor-patient discussion about their care. And along with a frank conversation about diagnosis and prognosis, patients’ fears about restricted access to costly treatment must be addressed

2. Institute of Medicine: Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. Washington, DC, National Academies Press, September 6, 2012. 3. Emanuel EJ, Fuchs VR: The perfect storm of overutilization. JAMA 299:2789-2791, 2008. 4. Lumbreras B, Donat L, HernándezAguado I: Incidental findings in imaging diagnostic tests: A systematic review. Br J Radiol 83:276-289, 2010.

when choosing which therapies are best suited to support their agreed-to goals of treatment,” she concluded. n

Disclosure: Ms. Stovall reported no potential conflicts of interest.

References 1. Stovall E: Patient perspective on overtreatment: Health policy in an era of choosing wildly wisely. ASCO Quality Care Symposium. Presented October 17, 2014. 2. Colla CH: Swimming against the current—What might work to reduce low-value care? N Engl J Med 371:1280-1283, 2014. 3. Levit L, Balogh E, Nass S, et al (eds): Delivering High-Quality Cancer Care: Charting a Course for a System in Crisis. Washington, DC, National Academies Press, 2013.

Choosing Wisely Campaign ASCO participates in the Choosing Wisely Campaign, which is an initiative of the American Board of Internal Medicine Foundation intended to spark conversations between providers and patients, to ensure that the right care is delivered at the right time. ASCO’s annually updated Top Five List of things physicians and patients should question is available at www.asco.org/practice-research/ top-five-list.

Coming Next Month Coverage of the 2014 Palliative Care in Oncology Symposium, Boston


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 5

Quality Care Symposium Geriatric Oncology

The ‘Silver Oncologic Tsunami’: Rise in Elderly Cancer Patients Brings New Challenges to Oncology Workforce By Alice Goodman

T

he “graying of America” poses increasing challenges for the cancer community in terms of rising numbers of cases of cancer and costs associated with geriatric care. The scope of this problem and potential solutions were explored by Andrew E. Chapman, DO, FACP, at the ASCO Quality Care Symposium in Boston.1 Dr. Chapman is Director of Regional Cancer Care and Co-Director of the Jefferson Senior Adult Oncology Center at the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.

Aging and Cancer “The ‘silver oncologic tsunami’ is coming. Demographics drive the issues. Cancer is a disease associated with aging,” he said. Factors associated with aging—telomere shortening, telomerase activity, chronic inflammation, DNA instability, and loss of im-

empowering the health-care workforce to improve health-care delivery in the geriatric setting, develop health-care delivery models focused on the elderly, develop oncology-based relevant data sets, and establish new standards of care to be able to implement the data and modeling in clinical practice.

Workforce Issues Over the next 15 years, even with nurse practitioners and physician assistants, there is a projected shortage of practitioners. On top of that, there are inadequate numbers of geriatricians. “In 2030, there will be one geriatrician for every 4,000 persons aged 75 and older,” he said.2,3 Empowering the workforce entails recognizing the needs of elderly patients. Geriatric patients pose unique challenges in terms of comorbidities, nutritional status, cognitive impairment, geriatric

Earlier palliative care is needed. Endof-life care should be a new standard. We should get these discussions out on the table early in the course of care for patients and families. —Andrew E. Chapman, DO, FACP

mune surveillance—are also thought to be implicated in cancer. “Geriatric patients have a high disease burden,” he continued. Sixty percent of all cancers occur in people aged 65 or older, and 69% of cancer-related deaths occur in the same age group.2,3 The exploding population of elderly people coupled with the rising costs of cancer care and the fragmentation of delivery of complex geriatric care creates a perfect storm. “To address this, we have developed an urgent to-do list with some basic goals,” Dr. Chapman said. They include

syndromes, polypharmacy, psychological status, and social support. “These issues are not commonly encountered in younger adult populations and raise major risks,” Dr. Chapman noted. Data are limited from clinical trials on management of elderly cancer patients. There are risks of overtreatment and undertreatment due to inadequate assessment of cognitive and functional status, he added. The health-care community needs to develop core competencies geared toward treating elderly patients and incorporate those into health-care training

Geriatric Cancer Care ■■ The elderly population is increasing and will continue to do so over the next decades, leading to increasing numbers of elderly cancer patients; a workforce shortage will make it difficult to deal with this onslaught. ■■ To meet the challenges of geriatric cancer care, the health-care community needs to address several critical issues, including workforce inadequacies, the need for deeper data on elderly patients from clinical trials, collaboration with patients and palliative care experts to develop models, and establishment of new standards of care.

and education. New models are needed to promote team-based care coordination, he continued. Possible ways to improve delivery of care include funding the National Workflow Commission and eliminating reimbursement barriers to team-based care (ie, the siloing of care and payment models).

Patient Involvement The development of deeper data sets is another goal. “We want to give elderly patients the treatment they need and want. They need to be enrolled in clinical trials, and this may require incentives for pharmaceutical companies to do these trials. One way to do this could be to lengthen drug patents so that compounds can be studied in aging populations,” he suggested. Elderly patients should be engaged in the process of developing new standards of care based on their needs, values, and preferences, Dr. Chapman said. Communication with patients should rely on giving understandable, relevant, and evidence-based information. Development of decision aids would be helpful, but this must be done in collaboration with patients and palliative care experts, he said. End-of-life care is a critical area that needs to be addressed. “Earlier palliative care is needed. End-of-life care should be a new standard. We should get these discussions out on the table early in the course of care for patients and families, emphasizing palliative care early on,”

he contended. “We need to create payment models for these discussions.” He added, “We can improve care of the elderly if we ‘right-size’ the care, make it coordinated, meet patients’ values and preferences, provide early palliative care and psychosocial support, and refer them to hospice in a timely manner. We need studies of drugs in the elderly, Medicare to negotiate drug pricing, and efficient coordinated health-care delivery system models.” Dr. Chapman concluded with a call to action for addressing cancer care in geriatric patients. “A new battle is emerging in this war on cancer, with significant moral, ethical, and financial implications. It is a battle we cannot afford to lose. We need your help,” he told the audience. n

Disclosure: Dr. Chapman reported no potential conflicts of interest.

References 1. Chapman AE: Healthcare delivery in senior adult oncology patients. ASCO Quality Care Symposium. Presented October 17, 2014. 2. Levit LA, Balogh EP, Nass SJ, et al: Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Institute of Medicine, National Academies Press, Washington, DC, 2014. 3. Hurria A, Naylor M, Cohen HJ: Improving the quality of cancer care in an aging population: Recommendations from an IOM report. JAMA 310:1795-1796, 2013.

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In the research of advanced cancers

What What if if inhibiting inhibiting the the PD-1 PD-1 helped helped restore restore immune immune

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checkpoint checkpoint pathway pathway response response to to tumor tumor cells? cells? Bristol-Myers Bristol-MyersSquibb Squibbisisresearching researchingways waysofofinhibiting inhibitingthe theinteraction interactionbetween betweenthe the PD-1 PD-1receptor receptorand andPD-L1 PD-L1and andPD-L2 PD-L2ligands, ligands,allowing allowingthe theimmune immunesystem systemtotorestore restore 3,10 3,10 T-cell T-cellattack attackon ontumor tumorcells, cells,which whichmay mayplay playaarole roleininhelping helpingthe thebody bodyfight fightcancer cancer Active T cell

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The ThePD-1 PD-1immune immunecheckpoint checkpointpathway: pathway:ananinnovative innovativetarget targetfor forcancer cancerresearch research 1-3,8 1-3,8 • By • By exploiting exploiting the the PD-1 PD-1 immune immune checkpoint checkpoint pathway, pathway, cancer cancer cells cells can can evade evade the the normal normal immune immune response response and and continue continue toto proliferate proliferate • Understanding • Understanding the the PD-1 PD-1 pathway pathway has has the the potential potential toto change change the the way way wewe approach approach certain certain cancers cancers

Learn more at www.pd1pathway.com • Experience the PD-1 checkpoint pathway through an immersive video • Hear a leading oncologist answer questions about the PD-1 checkpoint pathway • Learn more about how Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology

PD-1=programmed PD-1=programmed death death 1; PD-L1=PD-1 1; PD-L1=PD-1 ligand ligand 1; PD-L2=PD-1 1; PD-L2=PD-1 ligand ligand 2. 2. References: References: 1. Pardoll 1. Pardoll D, Drake D, Drake C. Immunotherapy C. Immunotherapy earns earns its spot its spot in the in the ranks ranks of cancer of cancer therapy. therapy. J Exp J Exp Med. Med. 2012;209(2):201-209. 2012;209(2):201-209. 2. Freeman 2. Freeman GJ, GJ, Long Long AJ, AJ, IwaiIwai Y, etY,al. etEngagement al. Engagement of the of the PD-1 PD-1 immunoinhibitory immunoinhibitory receptor receptor by abynovel a novel B7 family B7 family member member leads leads to negative to negative regulation regulation of lymphocyte of lymphocyte activation. activation. J Exp J Exp Med. Med. 2000;192(7):1027-1034. 2000;192(7):1027-1034. 3. Dong 3. Dong H, Strome H, Strome SE, SE, Salomao Salomao DR,DR, et al. etTumor-associated al. Tumor-associated B7-H1 B7-H1 promotes promotes T-cell T-cell apoptosis: apoptosis: a potential a potential mechanism mechanism of immune of immune evasion. evasion. NatNat Med. Med. 2002;8(8):793-800. 2002;8(8):793-800. 4. Hanahan 4. Hanahan D, Weinberg D, Weinberg RA.RA. Hallmarks Hallmarks of cancer: of cancer: thethe next next generation. generation. Cell.Cell. 2011;144(3):646-674. 2011;144(3):646-674. 5. Finn 5. Finn OJ. OJ. Cancer Cancer immunology. immunology. N Engl N Engl J Med. J Med. 2008;358(25):2704-2715. 2008;358(25):2704-2715. 6. Mellman 6. Mellman I, Coukos I, Coukos G, Dranoff G, Dranoff G. Cancer G. Cancer immunotherapy immunotherapy comes comes of age. of age. Nature. Nature. 2011;480(7378):480-489. 2011;480(7378):480-489. 7. Trapani 7. Trapani JA, JA, Smyth Smyth MJ.MJ. Functional Functional signifi signifi cance cance of the of the perforin/granzyme perforin/granzyme cellcell death death pathway. pathway. NatNat RevRev Immunol. Immunol. 2002;2(10):735-747. 2002;2(10):735-747. 8. Azuma 8. Azuma T, Yao T, Yao S, Zhu S, Zhu G, et G,al. etB7-H1 al. B7-H1 is aisubiquitous a ubiquitous antiapoptotic antiapoptotic receptor receptor on cancer on cancer cells. cells. Blood. Blood. 2008;111(7):3635-3643. 2008;111(7):3635-3643. 9. Latchman 9. Latchman Y, Wood Y, Wood CR, CR, Chernova Chernova T, etT,al. etPD-L2 al. PD-L2 is second is second ligand ligand for PD-1 for PD-1 andand inhibits inhibits T cell T cell activation. activation. NatNat Immunol. Immunol. 2001;2(3):261-268. 2001;2(3):261-268. 10.10. IwaiIwai Y, Ishida Y, Ishida M, Tanaka M, Tanaka Y, etY,al. etInvolvement al. Involvement of PD-L1 of PD-L1 on tumor on tumor cellscells in the in the escape escape from from hosthost immune immune system system andand tumor tumor immunotherapy immunotherapy by PD-L1 by PD-L1 blockade. blockade. ProcProc NatlNatl Acad Acad Sci U SciS U A.S2002;99(19):12293-12297. A. 2002;99(19):12293-12297.

©2014 ©2014 Bristol-Myers Bristol-Myers Squibb Squibb Company. Company. All All rights rights reserved. reserved. ONCUS14UB00597-02-01 ONCUS14UB00597-02-01 04/14 04/14 Printed Printed in USA. in USA.


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Quality Care Symposium Cost of Care

Financial Toxicity Potentially Harmful Treatment-Related Effect By Alice Goodman

I

t turns out that in addition to treatment-related toxicity, cancer patients commonly experience “financial toxicity,” a phrase that is increasingly coming into parlance in the cancer community. Patients should be assessed for financial toxicity as early as possible following diagnosis so that they can get help before they suffer its impact, according to a pre-

the cost of drugs themselves,” he said. Drug costs are wildly out of hand, with the current average cost of 1 month of chemotherapy estimated at $10,000, he continued. In addition to the very high costs of biologics and oral chemotherapy, insurance premiums are higher than in the past, and patients are being asked to pay higher copays, he explained.

Most oncologists are resistant to addressing cost, but they can intervene earlier and more aggressively to let patients know about assistance programs and other avenues of relief. —S. Yousuf Zafar, MD, MHS

sentation at the 2014 Quality Care Symposium, held recently in Boston.1 Although financial toxicity is more common than one might expect, oncologists typically do not discuss cost of treatment with patients. Moreover, they are often unaware of the actual costs of treatments they prescribe. Discussion with patients about financial concerns represents a clear unmet need, but it is a matter of debate as to who should initiate these discussions and the optimal timing.

‘Elephant in the Room’ “Financial toxicity is the elephant in the room. You can ask your patients one simple question about whether their cancer care is covered by a drug plan to get the conversation started,” said S. Yousuf Zafar, MD, MHS, a medical oncologist at Duke University Medical Center, Durham, North Carolina. In his presentation, Dr. Zafar sought to sensitize oncologists in the audience to the widespread problem of financial toxicity in cancer care. Many patients who are insured do not have adequate drug plan coverage and end up in bankruptcy. He gave an example from his practice of a patient who exhausted his savings to pay for his treatment, even though he had medical insurance and a drug plan. “Even when we do choose wisely,” he said, “patients sometimes cannot afford their medications. The average amount for drugs that a cancer patient pays per year is $4,800,” he told listeners. And many patients pay much more than that. “It would take at least 2 days to discuss why out-of-pocket costs are so high, but we can start with a well-known culprit—

He cited the following examples of spiraling costs: • Between 2007 and 2014, the price of erlotinib increased by 91%, the price of dasatinib (Sprycel) increased by 130%, and the price of imatinib (Gleevec) increased by 158%. • From 1999 to 2013, insurance premiums increased by 182% and worker’s contributions increased by almost 200%. Four-tiered formularies are now in place in many drug plans. In 2013, one out of every four patients was enrolled in four-tiered formulary drug plans. Cancer drugs mainly fall in the two highest-price tiers. “Together, these costs can result in financial toxicity for patients,” he stated.

Mounting Evidence Dr. Zafar and colleagues looked at a cohort of 254 insured cancer patients treated at an academic medical center.2 Approximately 75% applied for drug copayment assistance; 42% found their cancer treatment a significant or catastrophic burden; 46% stinted on food and clothing to pay for their medica-

tions, and 46% used their savings to defray costs. Adherence was compromised in 63%, and 24% avoided taking the drugs altogether. A separate study showed that cancer patients had a 2.65 times higher risk of bankruptcy compared with the general population in the State of Washington.3 “There is mounting evidence that increasing out-of-pocket costs impact patient well-being,” Dr. Zafar stated. Adherence to drug therapy is the first victim of financial toxicity. One study showed that higher copays led to a 42% increased likelihood of nonadherence to imatinib, he said.4 Another study showed that 45% of patients reported that they were nonadherent to save money.5 “Financial toxicity has an impact on quality care. There is a growing list of financial adverse events as a result of the care we are providing. They include delaying care, nonadherence, missed appointments, and taking fewer medications,” he continued. “We know nonadherence affects outcomes. We haven’t been able to measure yet whether it affects survival. We need to address the elephant in the room. It is time to intervene,” Dr. Zafar said.

Levels of Intervention He cited three levels of intervention: individual, interpersonal, and systemic. At the individual level, patients should be given information about the cost of health care. “One of our goals should be greater health literacy related to costs of care. Our patients do not have high health cost literacy,” Dr. Zafar said. He mentioned that one study showed that 60% of insured patients did not understand what a deductible is and noted that many patients do not understand the complexities of the Affordable Care Act. “Forty percent of patients pay more than they expect to. Some patients are not aware of copayment assistance programs or are enrolled in inadequate

Financial Toxicity in Cancer Care ■■ Costs of cancer care have spiraled out of control, and financial stress can adversely affect patients’ quality of life. ■■ Even insured patients may pay high out-of-pocket costs for cancer drugs. ■■ Financial toxicity is associated with adverse outcomes and should be assessed early in the course of cancer care. ■■ It is still debatable who should assess a patient’s financial situation and when discussions about cost should take place.

insurance plans. We need to promote greater cost literacy,” he told listeners. “On the interpersonal level, a study at our institution showed that about 50% of cancer patients wanted to talk to their oncologists about cost, but only 19% had that discussion.6 Barriers to communication include the perception that it is not the oncologist’s job to discuss cost. Of the 19% who did have the discussion with their doctor, 57% said that their out-ofpocket costs decreased as a result of the conversation. This is an exploratory finding that is hypothesis-generating, but 75% of the time, the costs were decreased without changing treatment,” he said. “Most oncologists are resistant to addressing cost, but they can intervene earlier and more aggressively to let patients know about assistance programs and other avenues of relief,” Dr. Zafar said. On a systemic level, high-risk patients should be identified before they accumulate debt. “Although this can be difficult at a large-volume center, we need to do a better job. We have some good screening tools, and we need to test them on a broader scale and begin to implement them. We also need to address price transparency, as there are data to suggest that greater price transparency can decrease cost,” he said. “We need to corral our resources in health literacy, patient engagement, and health-care delivery to start intervening in this problem of financial toxicity,” he stated. “We should consider financial toxicity a patient-reported outcome and assess this as we would other symptoms. If we did as good a job at this as on other side effects, we could improve outcomes,” Dr. Zafar stated.

Audience Comments During the question-and-answer session following Dr. Zafar’s talk, it became clear that there is no agreement about which health professional should address financial toxicity with a patient— an oncologist, a nurse, a nurse navigator, a social worker, or other clinician—and when these conversations should occur. Nevertheless, Dr. Zafar said that even if oncologists don’t initiate a discussion of drug coverage, they need to be aware of the costs of treatment. Jane Perlmutter, PhD, founder and President of Gemini Group, Ann Arbor, Michigan, and a 30-year cancer survivor and patient advocate, shared her point of view: “The benefits of cancer drugs are generally overestimated and the


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Quality Care Symposium harms are underestimated. I do think finances should be part of the discussions. It would be great if patients could

Jane Perlmutter, PhD

get information on their insurance coverage for drugs and required copays in the context of harms and benefits of drug therapy.” Jonas de Souza, MD, Assistant Professor at the University of Chicago Medicine, also believes that financial toxicity is critical to address with patients. He and his colleagues interviewed 155 cancer patients to develop a patient-reported outcome measure called COST (COmprehenstive Score for financial Toxicity)7 to evaluate fi-

al: Washington state cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. Health Affairs 6:1143-1152, 2013. 4. Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:306-311, 2013. 5. Zullig LL, Peppercorn JH, Schrag D,

et al: Financial distress, use of cost-coping strategies, and adherence to prescription medication among patients with cancer. J Oncol Pract 9(6S):60s-63s, B:8.75” 2013. 6. Zafar Y, Abernethy T:7.75”AP, Tulsky JA, et al: Financial distress,S:6.875” communication, and cancer treatment decision making: Does cost matter? ASCO Annual Meeting. Abstract 6506. Presented June 3, 2013.

7. de Souza JA, Yap BJ, Hlubocky FJ, et al: The development of a financial toxicity patient reported outcome in cancer: The COST measure. Cancer 120:3245-3253, 2014. 8. de Souza JA, Yap BJ: Relationship between financial toxicity and health-related quality of life in patients with advanced solid tumors. 2014 ASCO Quality Care Symposium. Abstract 31. Presented October 17, 2014.

KADCYLA: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

Jonas de Souza, MD

nancial toxicity in the clinical setting. To date, they have validated the tool in 50 cancer patients (of a planned 200), finding that COST can indeed measure financial toxicity and that a high degree of financial toxicity is associated with worse quality of life.8 Regarding Dr. Zafar’s presentation, Dr. de Souza said that it is important to assess financial toxicity, and several questions remain about the cost conversation with patients, including optimal timing and who should initiate the discussion. n Disclosure: Drs. Perlmutter, Zafar, and de Souza reported no potential conflicts of interest.

References 1. Zafar Y: The elephant in the room: How does financial toxicity impact cancer care delivery? Quality Care Symposium. Presented October 17, 2014. 2. Zafar SY, Peppercorn JM, Schrag D, et al: The financial toxicity of cancer treatment: A pilot study assessing out-of-pocket expenses and the insured cancer patient’s experience. Oncologist 18:381-390, 2013. 3. Ramsey S, Bough D, Kirchoff A, et

Indication KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do not substitute KADCYLA for or with trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo-fetal toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception

Please see the following pages for additional important safety information and brief summary of full Prescribing Information, including Boxed WARNINGS.


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Quality Care Symposium Studies Address Impact of Social Factors on Cancer Treatment Disparities

N

ew studies reported at ASCO’s 2014 Quality Care Symposium provided insight on the role social factors play in cancer treatment disparities, as well as effective approaches to improving the quality of care. “The research presented [here]

highlights how the conditions facing people living with cancer can affect their care, but also provides approaches to how we can overcome some of these potential disparities,” said ­Gregory A. Masters, MD, FACP, FASCO, Chair of ASCO’s Cancer Communications

Committee. “Improving the quality of care we provide is a continuous goal for oncologists.” Each of the studiesS:6.875” will be presented in more detail in an upcoming issue of The ASCO Post. They include the ­following:

• Having dependent children motivates advanced cancer patients to pursue more aggressive care: A pilot study of people with advanced cancer indicates that parental status is an important factor in treatment decisionmaking, with the majority stating that

The next era of treatment KADCYLA contains 3 components: the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker 1-3 In preclinical studies:

Trastuzumab (monoclonal antibody) Binds to HER2 at subdomain IV to suppress downstream signaling

DM1* (cytotoxic maytansinoid) Inhibits tubulin polymerization to induce cell-cycle arrest and cell death MCC* (stable linker) Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

• Maintains the HER2 suppression and anticancer activities of trastuzumab1 • Delivers cytotoxic DM1 to target HER2-expressing cells1 — Many normal cells express HER24 — Some cancer cells overexpress up to 200 times more HER2 than normal cells4 *Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.

Additional Important Safety Information

Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who Left Ventricular Dysfunction (LVD) had trastuzumab permanently discontinued due to infusion-related • Patients treated with KADCYLA are at increased risk of reactions (IRR) and/or hypersensitivity reactions; treatment with developing LVD. In EMILIA, LVD occurred in 1.8% of patients KADCYLA is not recommended for these patients. In EMILIA, the in the KADCYLA-treated group and in 3.3% in the comparator overall frequency of IRRs in patients treated with KADCYLA was 1.4% group. Permanently discontinue KADCYLA if LVEF has not • KADCYLA treatment should be interrupted in patients with severe IRRs improved or has declined further and permanently discontinued in the event of a life-threatening IRR. Pregnancy Registry Patients should be closely monitored for IRRs, especially during the • Advise patients to contact their healthcare provider immediately first infusion if they suspect they may be pregnant. Encourage women who Hemorrhage may be exposed to KADCYLA during pregnancy to enroll in the • Hemorrhagic events, sometimes fatal, have been reported in clinical MotHER Pregnancy Registry by contacting 1-800-690-6720 trials. In EMILIA, the incidence of ≥ Grade 3 hemorrhage was 1.8% Pulmonary Toxicity in the KADCYLA-treated group and 0.8% in the comparator group • Cases of interstitial lung disease (ILD), including pneumonitis, (overall incidence 32.2% and 16.4%, respectively) some leading to acute respiratory distress syndrome or fatal • In some of the observed cases the patients were also receiving outcome, have been reported in clinical trials with KADCYLA. anticoagulation therapy or antiplatelet therapy, or had In EMILIA, the overall frequency of pneumonitis was 1.2% thrombocytopenia; in others, there were no known additional risk • Treatment with KADCYLA should be permanently discontinued factors. Use caution with these agents and consider additional in patients diagnosed with ILD or pneumonitis monitoring when concomitant use is medically necessary Thrombocytopenia • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively) • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate © 2014 Genentech USA, Inc. All rights reserved. TDM0001944701 Printed in USA. (08/14)

B:1

T:1


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Quality Care Symposium being a parent motivates them to pursue life-extending treatments. • Medicare’s subsidy program improves hormone therapy adherence after breast cancer surgery and reduces racial disparities: A study of more than 23,000 women suggests that the Medicare Part D Extra Help program improves adher-

ence to hormone therapy after breast cancer surgery in all racial/ethnic groups and reduces disparities. • Oncologist participation in tumor board meetings may be associated with improved outcomes for paS:6.875” tients with lung or colorectal cancers: A new population-based study of close to 5,000 patients and 1,600

oncologists found that physician participation in weekly tumor board meetings was associated with improved survival for patients with stage IV colorectal cancer and stage IV/ extensive-stage small cell lung cancer. • Death of patients within 1 month of cancer surgery influenced by social and demographic factors: In a new

study of more than 1.1 million patients who underwent surgery for the most common or deadly cancers reports nearly 1 in 20 died within 1 month of the procedure. The risk of death was highest among patients who were not married, uninsured, non-white, male, older, less educated, poorer, or had advanced-stage cancer. n

NEARLY 6-MONTH IMPROVEMENT IN MEDIAN OVERALL SURVIVAL (OS) 100

30.9 months

80

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Superior efficacy with a single agent 1

lapatinib + capecitabine (n=496) No. of events: 182

10 0 8

10

12

14

16

18

20

22

24

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28

30

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34

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136 110

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5 4

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474 453

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418 368

349 297

293 240

242 204

197 159

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Nursing Mothers • Discontinue nursing or discontinue KADCYLA, taking into consideration the importance of the drug to the mother Adverse Reactions • The most common (frequency >25%) adverse drug reactions (ADR) across clinical trials with KADCYLA were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, constipation, and epistaxis. In EMILIA, the most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For more information on KADCYLA, visit KADCYLA.com.

B:11.5”

Neurotoxicity • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively) • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2 HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA-approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

T:10.5”

• The most common NCI-CTCAE (version 3) adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

S:9.875”

• 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P <0.0001)1

CD

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,3

AD

6

TC

4

QC

2

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0

No. at risk: KADCYLA 495 lapatinib + 496 capecitabine

References: 1. KADCYLA Prescribing Information. Genentech, Inc. July 2014. 2. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356. 3. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012;367:1783-1791 and Supplementary Appendix. 4. Hicks DG, Kulkarni S. Review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129:263-273.

PharmaGraphics

Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS.

S&H

17.5”

15.5”

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The ASCO Post  |   NOVEMBER 15, 2014

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Announcements

HHS Secretary Announces $840 Million Initiative to Improve Care, Lower Costs

H

ealth and Human Services Secretary Sylvia M. Burwell has announced an initiative that will fund successful applicants who work directly with medical providers to rethink and redesign their practices, moving from systems driven by quantity of care to

ones focused on patients’ health outcomes, and coordinated health-care systems. These applicants could include group practices, health-care systems, medical provider associations, and others. This effort will help clinicians develop strategies to share, adapt, and further

improve the quality of care they provide, while holding down costs. “The administration S:6.875” is partnering with clinicians to find better ways to deliver care, pay providers, and distribute information to improve the quality of care we receive and spend our na-

KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab Injection for intravenous use emtansine. Nevertheless, treatment with trastuzumab, the antibody Initial U.S. Approval: 2013 component of KADCYLA, during pregnancy in the postmarketing This is a brief summary of information about KADCYLA. setting has resulted in oligohydramnios, some associated with fatal Before prescribing, please see full Prescribing Information. pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. Do Not Substitute KADCYLA for or with Trastuzumab KADCYLA® (ado-trastuzumab emtansine)

WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception. (5.3, 8.1, 8.6) 1 INDICATIONS AND USAGE KADCYLA®, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients, one of which was fatal). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to noncirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension and/or cirrhosis-like pattern seen on the computed tomography (CT) scan of the liver but with normal transaminases and no other manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

tion’s dollars more wisely,” said Secretary Burwell.

$840 Million Over 4 Years Through the Transforming Clinical Practice Initiative, HHS will invest $840 million over the next 4 years to (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.8 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any Grade). In the randomized trial (Study 1), the overall frequency of peripheral neuropathy was 21.2% in the KADCYLA-treated group and If KADCYLA is used during pregnancy, or if the patient becomes 13.5% in the lapatinib plus capecitabine-treated group [see Adverse pregnant while receiving KADCYLA, apprise the patient of the Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy potential hazard to the fetus [see Use in Specific Populations (8.1)]. was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib Verify pregnancy status prior to the initiation of KADCYLA. Advise plus capecitabine-treated group. patients of the risks of embryo-fetal death and birth defects and the KADCYLA should be temporarily discontinued in patients need for contraception during and after treatment. Advise patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to to contact their healthcare provider immediately if they suspect they ≤ Grade 2. Patients should be clinically monitored on an ongoing may be pregnant. If KADCYLA is administered during pregnancy basis for signs or symptoms of neurotoxicity [see Nonclinical or if a patient becomes pregnant while receiving KADCYLA, Toxicology (13.2)]. immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during 5.9 HER2 Testing pregnancy to enroll in the MotHER Pregnancy Registry by contacting Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy 1-800-690-6720 [see Patient Counseling Information (17)]. because these are the only patients studied for whom benefit has 5.4 Pulmonary Toxicity been shown [see Indications and Usage (1), Clinical Studies (14.1)]. Cases of interstitial lung disease (ILD), including pneumonitis, some In the randomized study (Study 1), patients with breast cancer were leading to acute respiratory distress syndrome or fatal outcome have required to have evidence of HER2 overexpression defined as 3+ IHC been reported in clinical trials with KADCYLA. Pneumonitis at an by Dako Herceptest™ or evidence of overexpression defined as FISH incidence of 0.8% (7 out of 884 treated patients) has been reported, amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only with one case of grade 3 pneumonitis. Signs and symptoms include limited data were available for patients whose breast cancer was dyspnea, cough, fatigue, and pulmonary infiltrates. These events positive by FISH and 0 or 1+ by IHC. may or may not occur as sequelae of infusion reactions. In the randomized trial (Study 1), the overall frequency of pneumonitis was Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. 1.2% [see Adverse Reactions (6.1)]. Improper assay performance, including use of sub-optimally fixed Permanently discontinue treatment with KADCYLA in patients tissue, failure to utilize specified reagents, deviation from specific diagnosed with ILD or pneumonitis. assay instructions, and failure to include appropriate controls for Patients with dyspnea at rest due to complications of advanced assay validation, can lead to unreliable results. malignancy and co-morbidities may be at increased risk of 5.10 Extravasation pulmonary toxicity. In KADCYLA clinical studies, reactions secondary to extravasation 5.5 Infusion-Related Reactions, Hypersensitivity Reactions Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is not recommended for these patients.

have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous Infusion-related reactions, characterized by one or more of the infiltration during drug administration. following symptoms − flushing, chills, pyrexia, dyspnea, hypotension, 6 ADVERSE REACTIONS wheezing, bronchospasm, and tachycardia have been reported The following adverse reactions are discussed in greater detail in in clinical trials of KADCYLA. In the randomized trial (Study 1), the other sections of the label: overall frequency of IRRs in patients treated with KADCYLA was • Hepatotoxicity [See Warnings and Precautions (5.1)] 1.4% [see Adverse Reactions (6.1)]. In most patients, these reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] resolved over the course of several hours to a day after the infusion • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] was terminated. KADCYLA treatment should be interrupted in • Pulmonary Toxicity [See Warnings and Precautions (5.4)] patients with severe IRR. KADCYLA treatment should be permanently • Infusion-Related Reactions, Hypersensitivity Reactions [See discontinued in the event of a life-threatening IRR [see Dosage and Warnings and Precautions (5.5)] Administration (2.2)]. Patients should be observed closely for IRR • Thrombocytopenia [See Warnings and Precautions (5.6)] reactions, especially during the first infusion. • Neurotoxicity [See Warnings and Precautions (5.7)] One case of a serious, allergic/anaphylactic-like reaction has been 6.1 Clinical Trials Experience observed in clinical trials of single-agent KADCYLA. Medications to Because clinical trials are conducted under widely varying treat such reactions, as well as emergency equipment, should be conditions, adverse reaction rates observed in the clinical trials of available for immediate use. a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 5.6 Hemorrhage Cases of hemorrhagic events, including central nervous system, In clinical trials, KADCYLA has been evaluated as single-agent respiratory, and gastrointestinal hemorrhage, have been reported in in 884 patients with HER2-positive metastatic breast cancer. The clinical trials with Kadcyla. Some of these bleeding events resulted most common (frequency ≥ 25%) adverse drug reactions (ADRs) in fatal outcomes. In the randomized trial (Study 1), the overall seen in 884 patients treated with KADCYLA were fatigue, nausea, frequency of hemorrhage was 32.2% in the KADCYLA-treated musculoskeletal pain, hemorrhage, thrombocytopenia, headache, group and 16.4% in the lapatinib plus capecitabine-treated group. increased transaminases, constipation and epistaxis. The incidence of ≥ Grade 3 hemorrhage was 1.8% in the KADCYLA- The ADRs described in Table 6 were identified in patients with treated group and 0.8% in the lapatinib plus capecitabine-treated HER2-positive metastatic breast cancer treated in a randomized group [see Adverse Reactions (6.1)]. Although, in some of the trial (Study 1) [see Clinical Studies (14.1)]. Patients were randomized observed cases the patients were also receiving anticoagulation to receive KADCYLA or lapatinib plus capecitabine. The median therapy, antiplatelet therapy, or had thrombocytopenia, in others duration of study treatment was 7.6 months for patients in the there were no known additional risk factors. Use caution with these KADCYLA-treated group and 5.5 months and 5.3 months for patients agents and consider additional monitoring when concomitant use is treated with lapatinib and capecitabine, respectively. Two hundred medically necessary. and eleven (43.1%) patients experienced ≥ Grade 3 adverse events in the KADCYLA-treated group compared with 289 (59.2%) patients 5.7 Thrombocytopenia Thrombocytopenia, or decreased platelet count, was reported in in the lapatinib plus capecitabine-treated group. Dose adjustments for KADCYLA were permitted [see Dosage and Administration clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade 3; 283 of 884 treated patients with any Grade). The majority of these (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the nadir adverse event, compared with 41 patients (8.4%) who discontinued occurring by day 8 and generally improving to Grade 0 or 1 (≥ 75,000 /mm3) lapatinib, and 51 patients (10.5%) who discontinued capecitabine by the next scheduled dose. In clinical trials of KADCYLA, the due to an adverse event. The most common adverse events leading incidence and severity of thrombocytopenia were higher in Asian to KADCYLA withdrawal were thrombocytopenia and increased transaminases. Eighty patients (16.3%) treated with KADCYLA had patients. Independent of race, the incidence of severe hemorrhagic adverse events leading to dose reductions. The most frequent events in patients treated with KADCYLA was low. adverse events leading to dose reduction of KADCYLA (in ≥ 1% of In the randomized trial (Study 1), the overall frequency of patients) included thrombocytopenia, increased transaminases, thrombocytopenia was 31.2% in the KADCYLA-treated group and and peripheral neuropathy. Adverse events that led to dose delays 3.3% in the lapatinib plus capecitabine-treated group [see Adverse occurred in 116 (23.7%) of KADCYLA treated patients. The most Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was frequent adverse events leading to a dose delay of KADCYLA (in 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, capecitabine-treated group. In Asian patients, the incidence of fatigue, increased transaminases and pyrexia. ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated Table 6 reports the ADRs that occurred in patients in the KADCYLAgroup and 1.3% in the lapatinib plus capecitabine-treated group. treated group (n=490) of the randomized trial (Study 1). Selected

Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose [see Dosage and Administration (2.2)]. KADCYLA has not been studied in patients with platelet counts <100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer 5.3 Embryo-Fetal Toxicity 3 KADCYLA can cause fetal harm when administered to a pregnant KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm ) woman. There are no adequate and well-controlled studies of [see Dosage and Administration (2.2)]. Patients with thrombocytopenia

laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, hemorrhage, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

B:17

T:15


Blood and Lymphatic System Disorders Neutropenia

6.7

2.0

9.0

4.3

Anemia

14.3

4.1

10.5

2.5

Thrombocytopenia

31.2

14.5

3.3

0.4

Cardiac Disorders Left ventricular dysfunction

1.8

0.2

3.3

0.4

Eye Disorders Lacrimation increased

3.3

0

2.5

0

Dry eye

3.9

0

3.1

0

Vision blurred

4.5

0

0.8

0

Conjunctivitis

3.9

0

2.3

0

Gastrointestinal Disorders Dyspepsia

9.2

0

11.5

0.4

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

0

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5

Diarrhea

24.1

1.6

79.7

20.7

Constipation

26.5

0.4

11.1

0

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration

Increased bilirubin

All Grade %

Grade 3 %

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

17

<1

0

57

2

0

Increased AST

98

7

<1

65

3

0

Increased ALT

82

5

<1

54

3

0

Decreased platelet count

83

14

3

21

<1

<1

Decreased hemoglobin

60

4

1

64

3

<1

3

<1

Decreased neutrophils

39

38

6

8.4 Pediatric Use Safety and effectiveness of KADCYLA have not been established in Hepatic failure has been observed in two patients (0.2%) with HER2- pediatric patients. positive metastatic breast cancer in clinical trials (n=884) with 8.5 Geriatric Use KADCYLA as single-agent. Of 495 patients who were randomized to KADCYLA in the randomized trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 6.2 Immunogenicity years of age and 11 patients (2%) were ≥ 75 years of age. In patients As with all therapeutic proteins, there is the potential for an immune ≥ 65 years old (n=138 across both treatment arms) the hazard ratios response to KADCYLA. for progression-free survival (PFS) and Overall Survival (OS) were A total of 836 patients from six clinical studies were tested at 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. multiple time points for anti-therapeutic antibody (ATA) responses to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients Population pharmacokinetic analysis indicates that age does not tested positive for anti-KADCYLA antibodies at one or more post- have a clinically meaningful effect on the pharmacokinetics of dose time points. The presence of KADCYLA in patient serum at ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. Decreased potassium

33

3

0

31

6

8.6 Females of Reproductive Potential KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving KADCYLA and for 6 months following Immunogenicity data are highly dependent on the sensitivity and the last dose of KADCYLA. specificity of the test methods used. Additionally, the observed If KADCYLA is administered during pregnancy or if the patient incidence of a positive result in a test method may be influenced becomes pregnant while receiving KADCYLA, immediately report by several factors, including sample handling, timing of sample exposure to the Genentech Adverse Event Line at 1-888-835-2555. collection, drug interference, concomitant medication and the Encourage women who may be exposed during pregnancy to enroll underlying disease. Therefore, comparison of the incidence of in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see antibodies to KADCYLA with the incidence of antibodies to other Patient Counseling Information (17)]. products may be misleading. Clinical significance of anti-KADCYLA 8.7 Renal Impairment antibodies is not yet known. No dedicated renal impairment trial for KADCYLA has been

3.1

0

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

ND

0

0

Portal hypertension*

0.4

0.2

0

0

0

0.8

0

0

0.2

0

9.4

0.6

3.9

0

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

8 USE IN SPECIFIC POPULATIONS

Increased transaminases

28.8

8.0

14.3

2.5

8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3)]

Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

2.7

9.4

4.7 0

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

0

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

0

0

0

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

0

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

0

Rash

11.6

0

27.5

1.8

Vascular Disorders Hemorrhage

32.2

1.8

16.4

0.8

Hypertension

5.1

1.2

2.3

0.4

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

7 DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have been conducted. In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with KADCYLA should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying KADCYLA treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse reactions.

Risk Summary KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women. No reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, two components of KADCYLA (trastuzumab and DM1) are known or suspected to cause fetal harm or death when administered to a pregnant woman. If KADCYLA is administered during pregnancy, or if a patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus. Patients should be advised to use effective contraception during treatment with KADCYLA and for 6 months following the last dose of KADCYLA.

conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse drug reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see Clinical Pharmacology (12.3)].

8.8 Hepatic Impairment In vitro studies in human liver microsomes indicates that DM1 is metabolized by CYP3A4/5. The influence of hepatic impairment on the pharmacokinetics of ado-trastuzumab emtansine conjugate has not been determined. 10 OVERDOSAGE There is no known antidote for overdose of KADCYLA. In clinical trials, overdose of KADCYLA has been reported at approximately two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal case, the patient incorrectly received KADCYLA at 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to KADCYLA were not established. 17 PATIENT COUNSELING INFORMATION • Inform patients of the possibility of severe liver injury and advise patients to immediately seek medical attention if they experience symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus, anorexia, etc. [see Warnings and Precautions (5.1)]. • Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.2)].

• Advise pregnant women and females of reproductive potential that If KADCYLA is administered during pregnancy or if a patient KADCYLA exposure can result in fetal harm, including embryo-fetal becomes pregnant while receiving KADCYLA, immediately report death or birth defects [see Warnings and Precautions (5.3), Use in exposure to the Genentech Adverse Event Line at 1-888-835-2555. Specific Populations (8.1, 8.6)]. Encourage women who may be exposed during pregnancy to enroll • Advise females of reproductive potential to use effective in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see contraception while receiving KADCYLA and for 6 months following Patient Counseling Information (17)]. the last dose of KADCYLA [See Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.6)]. Human Data In the post-marketing setting, treatment with trastuzumab during • Advise nursing mothers treated with KADCYLA to discontinue pregnancy has resulted in cases of oligohydramnios, some nursing or discontinue KADCYLA, taking into account the importance associated with fatal pulmonary hypoplasia, skeletal abnormalities of the drug to the mother [see Use in Specific Populations (8.3)]. and neonatal death. These case reports described oligohydramnios • Encourage women who are exposed to KADCYLA during pregnancy in pregnant women who received trastuzumab either alone or in to enroll in the MotHER Pregnancy Registry by contacting combination with chemotherapy. In some case reports, amniotic 1-800-690-6720 [see Warnings and Precautions (5.3) and Use in fluid index increased after trastuzumab was stopped. In one Specific Populations (8.1, 8.6)]. case, trastuzumab therapy resumed after the amniotic fluid index KADCYLA® (ado-trastuzumab emtansine) improved, and oligohydramnios recurred. Manufactured by: Animal Data 4862200 There were no reproductive and developmental toxicology studies Genentech, Inc. Initial U.S. Approval: 02/13 conducted with ado-trastuzumab emtansine. DM1, the cytotoxic A Member of the Roche Group 1 DNA Way KADCYLA is a trademark component of KADCYLA, disrupts microtubule function. DM1 is toxic South San Francisco, CA of Genentech, Inc. to rapidly dividing cells in animals and is genotoxic, suggesting it has 08/14 TDM0001661002 the potential to cause embryotoxicity and teratogenicity. In studies 94080-4990 © U.S. License No: 1048 2014 Genentech, Inc.

B:11.5”

8.2

0

CMS will award cooperative agreements to group practices, health-care systems, and others that join together to serve as trusted partners in providing clinician practices with quality improvement expertise, best practices, coaching, and assistance. These practices have successfully achieved measurable improvements in care by implementing electronic health records, coordinating among patients and their families, and performing timely monitoring and interventions of high-risk patients to prevent unnecessary hospitalization and readmissions. Practice Transformation Networks will work with a diverse range of practices, including those in rural communities and those that provide care for the medically underserved. T:10.5”

0

7.6

Practice Transformation Networks

S:9.875”

7.1

Chills

Immune System Disorders

<1

the time of ATA sampling may interfere with the ability of this assay to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.

Peripheral edema

Hepatobiliary Disorders

2

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)].

ED

Grade 3 – 4 (%)

AE/AS

All grades (%)

CW

Grade 3 – 4 (%)

KADCYLA (3.6 mg/kg)

Parameter

CD

All grades (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate %

where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

Support and Alignment Networks CMS will award cooperative agreements to networks formed by medical professional associations and others who would align their memberships, communication channels, continuing medical education credits, and other work to support the Practice Transformation Networks and clinician practices. These Support and Alignment Networks would create an infrastructure to help identify evidence-based practices and policies and disseminate them nationwide, in a scalable, sustainable approach to improved care delivery. HHS encourages all interested clinicians to participate in this initiative. For more information on the Transforming Clinical Practice Initiative, please visit: http://innovation.cms.gov/initiatives/ Transforming-Clinical-Practices/ n

AD

KADCYLA (3.6 mg/kg) n=490 Frequency rate %

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

The initiative provides opportunities for participating clinicians to collaborate and disseminate information by building upon successful models and programs, such as the Quality Improvement Organization Program, Partnership for Patients with Hospital Engagement Networks, and Accountable Care

Organizations. Through a multipronged approach to technical assistance, it will identify existing health-care delivery models that work and rapidly spread these models to other health-care providers and clinicians. “This model will support and build partnerships with doctors and other clinicians across the country to provide better care to their patients. Clinicians want to spend time with their patients, coordinate care, and improve patient outcomes, and the Centers for Medicare & Medicaid Services (CMS) wants to be a collaborative partner helping clinicians achieve those goals and spread best practices across the nation,” said Patrick Conway, MD, Deputy Administrator for Innovation and Quality and CMS Chief Medical Officer.

TC

Adverse Drug Reactions (MedDRA) System Organ Class

Table 7 Selected Laboratory Abnormalities

Building on Success

QC

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

measurable goals, such as improving clinical outcomes, reducing unnecessary testing, achieving cost savings, and avoiding unnecessary hospitalizations. The initiative is one part of a stratS:6.875” egy advanced by the Affordable Care Act to strengthen the quality of patient care and spend health-care dollars more wisely.

PG

support 150,000 clinicians. With a combination of incentives, tools, and information, the initiative will encourage doctors to team with their peers and others to move from volume-driven systems to value-based, patient-centered, and coordinated health-care services. Successful applicants will demonstrate the ability to achieve progress toward

PROD

Announcements

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Best of ASCO® Gastrointestinal Oncology

Targeted Agents Making Inroads Against Sarcoma By Charlotte Bath

“T

argeted agents have started to make inroads in sarcoma therapies, and gastrointestinal stromal tumor (GIST) is the poster child for this success,” Mark Agulnik, MD, stated in summarizing progress in GIST and other sarcomas at the Best of ASCO meeting in Chicago. Dr. Agulnik is Associate Professor, Northwestern University, Feinberg School of Medicine, Chicago. Ten-year outcomes from the phase III SWOG Intergroup Trial S00331 show that a significant subset of patients with metastatic GIST achieved durable long-term overall survival with single-agent imatinib (Gleevec). The trial was designed to study the impact of two different doses of imatinib among patients with advanced GIST, but long-term survival rates (8 or more years) among 695 eligible patients dif-

fered little—27% for those receiving 400 mg/d and 25% for those receiving 800 mg/d. GIST genotype was available in a subset of 395 patients. Among these patients, 282 (71%) had KIT exon 11 mutations, 67 (17%) had no mutation detected in KIT or PDGFRA, 32 (8%) had KIT exon 9 mutations, and 14 (4%) had other KIT or PDGFRA mutations. At 4.5 years’ median follow-up, patients with KIT exon 11 mutations had significantly better overall survival than those with no mutations (P = .011) or with KIT exon 9 mutations (P = .049). Data from 2014 show significantly worse overall survival for patients with KIT exon 9 mutations—38 months median overall survival vs 66 months for patients with KIT exon 11 mutations (P = .001) and 40 months for patients with no mutations (P = .047).

Evolving Landscape of Options Information obtained for 137 longterm survivors revealed that 49% received no additional therapy beyond imatinib. Of the 51% who did receive additional therapy, 39% received systemic therapy with the tyrosine kinase inhibitors sunitinib (Sutent, 41 patients or 30%) and sorafenib (Nexavar, 16 patients or 12%), or other agents. A total of 41 patients (30%) received surgery; 10 patients (7%) had radiofrequency ablation; and 6 patients (4%) had radiation therapy. “The landscape of therapeutic options for GIST has evolved greatly since this early large-scale trial,” Dr. Agulnik said. He mentioned that new tyrosine kinase inhibitor therapies, including regorafenib (Stivarga), have been approved for patients following disease progression on imatinib.

“Multidisciplinary management of GIST, with resection of limited sites of oligoclonal, resistant disease, is a standard option with continuation of [tyrosine kinase inhibitor] therapy to manage residual unresectable disease,” he added. “New options for management of KIT exon 9 mutant and other resistant GIST genotypes are still needed.”

Phase II Ponatinib Trial Initial analysis of a phase II trial of ponatinib (Iclusig)2 “suggests ponatinib has activity in patients with advanced GIST,” particularly patients with KIT exon 11 mutations in whom prior tyrosine kinase inhibitor therapy has failed, Dr. Agulnik reported. “Ponatinib is an oral [tyrosine kinase inhibitor] with potent activity against BCR-ABL,” he explained, and “against mutated forms of KIT and

Advances in Sarcoma Owe Much to Children’s Oncology Group By Charlotte Bath

I

mprovements over the past 3 decades in 5-year survival rates for patients with osteosarcoma and Ewing’s sarcoma owe a lot to chemotherapy clinical trials conducted by the Children’s Oncology Group (COG), Mark Agulnik, MD, acknowledged at the Best of ASCO meeting in Chicago. Dr. Agulnik is Associate Professor at Northwestern University, Feinberg School of Medicine, in Chicago. Treatment for patients with osteosarcomas is currently a “multidisciplinary team effort,” Dr. Agulnik said, including preoperative chemotherapy, limb salvage surgery, and postoperative chemotherapy. “We now have long-term follow-up,” he noted. “In the 70s, you didn’t have that,” he added. Likewise, COG studies have shown continued improvement in survival for patients with localized Ewing sarcoma, so that now more than 75% of patients have event-free survival of 10 or more years. In general, the use of adjuvant chemotherapy has resulted in “great advances” in the treatment of osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and gastrointestinal stromal tumors, Dr. Agulnik said.

Revised Staging for Soft-Tissue Sarcomas A major advance in soft-tissue sarcomas has come about through a revised American Joint Committee on Cancer staging system reflecting the importance of grade. “What has become very important is our pathology colleagues providing that information for us,” Dr.

stage III. We still don’t do well for our stage IV patients,” he noted. For those patients, the 5-year survival is < 20%. Over the years, the chemotherapy agents for soft-tissue sarcomas have changed, and treatment has been tailored according to the type of sarcoma, Dr. Agulnik stated. Currently indicated agents include dacarbazine for

The [U.S.] incidence of soft-tissue sarcomas in 2014 is about 12,000, but what is impressive is that there are more than 50 different subtypes. So histology becomes very important, and essentially we need to change our paradigm. —Mark Agulnik, MD

Agulnik said. “Without a grade, we can’t stage a patient with sarcoma. We look at grade along with size, location, and extent of disease, whether they have nodal disease or metastatic disease,” he added. “When we look at our 5-year survival, we see that a low-grade patient with completely surgically excisable disease has a 5-year survival that almost reaches 100%,” Dr. Agulnik reported. “As we go to stage II and stage III, we see that drop off by about 20% in stage II, and then we drop down to about 50% in

leiomyosarcomas, taxanes for angiosarcomas, vinca alkaloids/topotecan/ irinotecan for rhabdomyosarcomas/ Ewing sarcomas, temozolomide plus bevacizumab (Avastin) for hemangiopericytomas/solitary fibrous tumors, and methotrexate plus vinblastine/ vinorelbine for desmoid tumors. “The [U.S.] incidence of soft-tissue sarcomas in 2014 is about 12,000, but what is impressive is that there are more than 50 different subtypes. So histology becomes very important,

and essentially we need to change our paradigm. We can’t lump all sarcomas together. We need to start splitting them up, and we need to develop treatments specific to the histology,” Dr. Agulnik said.

Proliferation of Targeted Therapies Summarizing targeted therapy for bone and soft-tissue sarcomas, Dr. Agulnik said that there were “few successes, several failed attempts, some promises, and more work needed.” Among the agents that have shown some success in specific types of sarcomas are: • imatinib (Gleevec) for dermatofibrosarcoma protuberans, desmoid tumors, and pigmented villonodular synovitis • denosumab (Xgeva) for giant cell tumors of bone • bevacizumab, sunitinib (Sutent), sorafenib (Nexavar), and pazopanib (Votrient) for hemangioendotheliomas/angiosarcomas • sunitinib and cediranib (investigational) for alveolar soft-part ­sarcoma. “There are possibilities for each of the separate subtypes,” Dr. Agulnik noted, but “we need more data.” n


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 15

Best of ASCO® PDGFRA, including KIT mutations that confer resistance to approved [tyrosine kinase inhibitors].” Ponatinib has been approved for the treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) or T315I-positive Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL), and for those with CML or Philadelphia chromosome–positive ALL for whom no other tyrosine kinase inhibitor is indicated. The phase II trial initially included patients with advanced GIST in whom one or more tyrosine kinase inhibitors have failed, but the protocol was amended earlier this year to include only patients for whom all three tyrosine kinase inhibitors approved for GIST—imatinib, sunitinib, and regorafenib—have failed. The 35 enrolled patients received ponatinib at 45 mg once daily, and 14 patients have received treatment for at least 6 months and remain on therapy (1 with a partial response, 11 with stable disease, and 2 with progressive disease). The primary endpoint of clinical benefit rate (complete response plus partial response plus stable disease) was 50% at 16 weeks for patients with KIT exon 11–mutant GIST. “When we look at overall survival and progression-free survival, we see that the patients with KIT exon 11–mutated disease do better than those without the mutation,” Dr. Agulnik pointed out. Median overall survival was not reached, but at 6 months was 80% for patients with KIT exon 11 mutations and 71% for those without. Median progres-

sion-free survival was 7 months for patients with KIT exon 11 mutations and 4 months for those without. Overall, these data “provide ponatinib proof of concept in resistant GIST and warrant future investigation,” Dr. Agulnik stated. The safety profile of ponatinib in GIST appears to be consistent with that in CML, except that “myelosuppression is notably less in GIST than in leukemia studies,” Dr. Agulnik noted. Treatmentemergent serious adverse events oc-

so, predictive biomarkers may help direct the selection of optimal therapy for an individual patient. And we do know that we need new therapeutics,” he continued. “If we could identify the targets and use these therapeutics, we could make a substantial change for these patients.” More than 6,000 physicians submitted specimens from 59 countries, and these specimens were reviewed by board-certified pathologists. The median age of the patients was 55, and 62% of

While sarcoma is rare, it is a very heterogeneous tumor, and so, predictive biomarkers may help direct the selection of optimal therapy for an individual patient. —Mark Agulnik, MD

curring in two or more patients were abdominal pain (11%), and nausea, vomiting, and fatigue (6% each). The researchers reported that one patient had myocardial ischemia and one died, possibly related to ponatinib therapy.

Predictive Biomarker Profiling In an attempt to identify predictive biomarkers for potential targeted therapies, a multiplatform profiling study3 looked at more than 1,900 specimens from a variety of sarcomas, although GIST and Kaposi sarcoma were excluded. Explaining the rationale behind this study, Dr. Agulnik noted, “While sarcoma is rare, it is a very heterogeneous tumor, and

the specimens were from females, which Dr. Agulnik said was probably a reflection of the number of uterine sarcomas. Samples were analyzed using immunohistochemistry, fluorescence or chromogenic in situ hybridization (FISH/ CISH), and/or next-generation or Sanger DNA sequencing. For 256 cases, all three platforms of testing were used. The sequencing results did not reveal many mutations. The most common mutation was in TP53, which was found in 22.4% of all patients with a variety of sarcomas, Dr. Agulnik pointed out. The frequency of other mutations ranged from 1.2% to 3.2%. TOPO2A was found to be overex-

pressed in approximately 50% of sarcomas, without associated gene amplification. This overexpression was most common in angiosarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma. The study authors concluded that the utility of TOPO2A should be studied as a biomarker for sensitivity to anthracyclines, especially in relation to TP53 status in a tumor. “Profiling through protein expression, gene copy variations, and mutations identified alterations in 99% of sarcoma samples,” Dr. Agulnik reported. “Future clinical trials are needed to determine the predictive and/or prognostic nature of these findings.” n

Disclosure: Dr. Agulnik is a consultant for and receives honoraria from Novartis and GlaxoSmithKline.

References 1. Demetri GD, Rankin CJ, Benjamin RS, et al: Long-term disease control of advanced gastrointestinal stromal tumors (GIST) with imatinib (IM): 10-year outcomes from SWOG phase III intergroup trial S0033. ASCO Annual Meeting. Abstract 10508. Presented June 1, 2014. 2. Heinrich MC, von Mehren M, Demetri GD, et al: A phase 2 study of pontanib in patients (pts) with advanced gastrointestinal stromal tumors (GIST) after failure of tyrosine kinase inhibitor (TKI) therapy: Initial report. ASCO Annual Meeting. Abstract 10506. Presented June 1, 2014. 3. Movva S, Wen W, Chen W, et al: Predictive biomarker profiling of > 1,900 sarcomas: Identification of potential novel treatment modalities. ASCO Annual Meeting. Abstract 10509. Presented June 1, 2014.

Coming in Future Issues of The ASCO Post Coverage from oncology meetings, including the Quality Care Symposium, Palliative Care Symposium, Multidisciplinary Symposium in Thoracic Oncology, American Society of Hematology Annual Meeting, San Antonio Breast Cancer Symposium, and much more! Also, Journal Spotlights with commentary from experts, including Sagar Lonial, MD, on HDAC Inhibitors and Triple Therapy in Relapsed Myeloma; Maha Hussain, MD, on the ASCO/CCO Guideline in Metastatic Castration-Resistant Prostate Cancer; and Andrew Evens, DO, MSc, on CAR T-Cell Therapy in Cancer. Ongoing Series: State of the Art Cancer Care in 2014-2015: Colorectal Cancer, with John Marshall, MD; Brain Cancer, with Tracy Batchelor, MD; Palliative Care, with Diane Meier, MD, and much more. Visit The ASCO Post at ASH, booth 741, and in San Antonio, booth T1.

For more, visit The ASCO Post online at ASCOPost.com


POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (n=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (n=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A phase 2, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy


For more information visit www.pomalyst.com/hcp or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception POMALYST is only available through a restricted distribution program called POMALYST REMS™. VENOUS THROMBOEMBOLISM • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. POMALYST is only available through a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.


POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacies must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.


WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of Grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are

those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low-dose dex arms, the most common adverse reactions (≥30%), respectively, included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low-dose dex arms, the most common Grade 3/4 adverse reactions (≥15%), respectively, included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low-dose dex arms, the most common serious adverse reactions (≥5%), respectively, were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%), dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Avoid the use of strong CYP1A2 inhibitors. If medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age

were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS on following pages. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2014 Celgene Corporation 07/14 US-POM120033a(2)


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 20

Announcements

Magee-Womens Hospital of UPMC Offers Test to Predict Possibility of Breast Cancer Recurrence

M

agee-Womens Hospital of University of Pittsburgh is offering its patients the FDA-cleared breast cancer test assessing a woman’s risk of cancer recurrence by providing a risk category and

numerical score. The hospital is the first in the tri-state area (Pennsylvania, Ohio, West Virginia) to offer this test to patients. The Prosigna test assesses a woman’s probability of her breast cancer recur-

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full Prescribing Information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS™ [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep venous thrombosis (DVT) and pulmonary embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew, or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicities Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Neutropenia • ANC <500 per mcL or febrile neutropenia (fever more than or equal to 38.5°C and ANC <1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Dose Modification

• For each subsequent drop <500 per mcL • Return to more than or equal to 500 per mcL

Interrupt POMALYST treatment Resume POMALYST treatment at 1 mg less than the previous dose

Thrombocytopenia • Platelets <25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly Resume POMALYST treatment at 3 mg daily

• Platelets return to >50,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly Resume POMALYST treatment at 3 mg daily

• For each subsequent drop <25,000 per mcL • Return to more than or equal to 50,000 per mcL

Interrupt POMALYST treatment Resume POMALYST treatment at 1 mg less than previous dose

ANC, absolute neutrophil count. For other Grade 3 or 4 toxicities, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL and the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 2.3 Dose Adjustment for Strong CYP1A2 Inhibitors in the Presence of Strong CYP3A4 and P-gp Inhibitors Avoid co-administration of strong inhibitors of CYP1A2. If necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, reduce POMALYST dose by 50%. No clinical efficacy or safety data exist [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].

ments. Currently, the test is designed for postmenopausal women with hormone receptor positive breast cancer. “Our understanding of how to diagnose and treat different types of breast

Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy, and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST, and comply with REMS requirements. Further information about the POMALYST REMS program is available www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (VTEs) (venous thromboembolism) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

ring over a 10-year period. Results of the test can help a patient and her oncologist make more informed treatment decisions when used in conjunction T:7” pathologic assesswith other clinical and


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ment decision-making.” Based on the PAM50 gene signature, the Prosigna assay categorizes risk of disease recurrence over a 10-year period. The test adds significantly more information to guide treatment than clinical factors alone, including substantially more information than other risk asT:7” sessment tests currently available. n

5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%.

treatment cycles was 5. Sixty-three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty-seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%.

Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)].

Tables 2, 3, and 4 summarize all treatment-emergent adverse reactions reported for the POMALYST + Low-dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Low-dose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low-dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia (6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low-dose Dex (69/112).

5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced Grade 3/4 dizziness, and 3% of patients experienced Grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and to not take other medications that may cause dizziness or confusional state without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of Grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 5.9 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Clinical Trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low-dose Dexamethasone (Low-dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of

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Serious Adverse Reactions in ≥2 patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: Constipation (1%, 3%); Blood and lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and labyrinth disorders: Vertigo Hepatobiliary disorders: Hyperbilirubinemia Infections and infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis Investigations: Alanine aminotransferase increased Metabolism and nutritional disorders: Hyperkalemia Renal and urinary disorders: Urinary retention Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with POMALYST: Pancytopenia, tumor lysis syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 7 DRUG INTERACTIONS Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP1A2 inhibitors: Pomalidomide exposure is increased when POMALYST is co-administered with a strong CYP1A2 inhibitor (fluvoxamine) in the presence of a strong CYP3A4/5 and P-gp inhibitor (ketoconazole). Ketoconazole in the absence of a CYP1A2 inhibitor does not increase pomalidomide exposure. Avoid co-administration of strong CYP1A2 inhibitors (eg, ciprofloxacin and fluvoxamine) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. If it is medically necessary to co-administer strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp, POMALYST dose should be reduced by 50%. The effect of a CYP1A2 inhibitor in the absence of a co-administered CYP3A4 and P-gp inhibitor has not been studied. Monitor for toxicities if CYP1A2 inhibitors are to be co-administered in the absence of a co-administered CYP3A4 and P-gp inhibitor, and reduce dose if needed. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Cosmos Communications

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cancers has grown exponentially in the last 2 decades,” said David Dabbs, MD, Chief of Pathology at Magee. “This test offers our oncology team and their patients another step toward personalized medicine and we are proud to be able to offer it to patients who come to Magee, to aid in their understanding of their disease and short- and long-term treat-


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Past Drug Failures Help Create Cancer’s Next Successes

T

he Pharmaceutical Research and Manufacturers of America (PhRMA) has released a new report, “Researching Cancer Medicines: Setbacks and Stepping Stones,” which highlights the number of investigational cancer medicines that did not succeed

in clinical trials and how these so-called failures are a critical part of the drug development process. The report illustrates the challenges in bringing new medicines to patients with cancer, and explores the factors that contributed to both the approvals CYP1A2 inducers: Co-administration of POMALYST with drugs that are CYP1A2 inducers has not been studied and may reduce pomalidomide exposure. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg/day. Additional embryo-fetal toxicity included increased resorption. 8.3 Nursing Mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness of POMALYST in patients below the age of 18 years have not been established. 8.5 Geriatric Use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41% were aged 65 years and older, while 12% were aged 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients aged greater than or equal to 65 years were more likely to experience pneumonia than patients aged less than or equal to 65 years. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual

Setbacks Instrumental to Future Growth “While it may sound counterintuitive, research setbacks are instrumental to furthering efforts to better understand a disease and how to treat it. They are also an indication of the incredible contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of 12 monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes, and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males in this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindications (4)]. POMALYST is a thalidomide analogue and may cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

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Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs, and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg/kg/day) that resulted in cardiac anomalies

of new treatments and those that failed between 1998 and 2014. Three particularly difficult to treat cancers comprise the focus of the report, including melanoma, lung cancer, and brain cancer. Key findings from the report are T:7”on page 23. shown in the sidebar


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difficulty in developing medicines to treat cancer,” said PhRMA President and CEO John J. Castellani. “These setbacks serve as a reminder that to make progress, we need a public policy framework that supports drug development in combination with promising science so that we can bring important innovations to patients.”

POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program called POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements, and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS. Provide patients with the telephone number and Web site for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment [see Venous Thromboembolism (5.3)]. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia, and anemia and the need to report signs and symptoms associated with these events to their healthcare provider for further evaluation [see Hematologic Toxicities (5.4)]. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID® [see Hypersensitivity Reaction (5.5)]. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusional state with the drug, to avoid situations where dizziness or confusional state may be a problem, and not to take other medications that may cause dizziness or confusional state without adequate medical advice [see Dizziness and Confusional State (5.6)].

to see a promising new drug candidate eliminated from the pipeline, researchers take immeasurable [lessons] from every setback and build upon each one to develop effective therapies for patients,” said Mr. Castellani. Despite these challenges, America’s biopharmaceutical companies continue to invest in research to develop

PhRMA Report Shows Drug Failures Integral to Drug Development and Future Successes ■■ 96 potential treatments for melanoma did not make it through clinical trials, but paved the way for 7 approved medicines, a nearly 14:1 ratio of failures to successes.

Neuropathy Inform patients of the risk of neuropathy and to report the signs and symptoms associated with these events to their healthcare provider for further evaluation [see Neuropathy (5.7)].

■■ Ten medicines have been approved to treat lung cancer, whereas 167 other potential treatments did not make it through clinical trials.

Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown [see Risk of Second Primary Malignancies (5.8)].

■■ Only 3 new medicines have been approved to treat brain cancer, while another 75 investigational medicines were unsuccessful in the development process.

Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warning and Precautions (5.9)]. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day. • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID®, and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. Pat. http://www.celgene.com/therapies © 2005-2014 Celgene Corporation All rights reserved. POMBS.v.003 05/14

new treatments. According to a new report by PhRMA, there are 771 cancer medicines and vaccines either in clinical trials or awaiting review by the U.S. Food and Drug Administration. Of these medicines, more than 50 are for the treatment of melanoma, 98 for lung cancer, and 47 for brain cancer. n

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• Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during POMALYST therapy, during therapy interruption, and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Significant advancements in the treatment of diseases like cancer are typically the result of cumulative innovation over time, rather than a single breakthrough in treatment. Every success—and every failure—builds on previous advances to improve patients’ lives. T:7” “While it is incredibly disappointing

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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Best of ASCO® Gastrointestinal Oncology

For Selected Patients With Metastatic Colorectal Cancer, Taking a Break From Combination Chemotherapy Might Be Appropriate and Appreciated By Charlotte Bath

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wo phase III studies presented at the Best of ASCO meeting in Chicago shed more light on the role of maintenance therapy in patients with metastatic colorectal cancer undergoing first-line treatment with oxaliplatinbased chemotherapy. The two studies compared maintenance therapy with bevacizumab (Avastin) alone or combined with a fluoropyrimidine to observation. Maintenance therapy delayed progression compared to observation, without significantly altering overall survival (neither study was powered to detect a difference in overall survival). “In a lot of modern chemotherapy regimen trials, there is this trend for people going off first-line therapy for reasons other than progressive disease,” noted Emily K. Bergsland, MD, a gastrointestinal oncologist at the Helen Diller Family Comprehensive Cancer Center and Professor of Clinical Medicine at the University of California, San Francisco. “So there is this feeling that patients would like and value breaks from therapy. We certainly could imagine that breaks from therapy might be associated with decreased toxicity, decreased time on treatment, which might translate to improved quality of life, more convenience for the patient, less time in the doctor’s office, and certainly decreased drug costs,” Dr. Bergsland said. “We don’t know the precise risks of going off therapy and having a complete treatment break. What are the risks of de-escalating therapy?”

Delayed Progression Without a Clear Impact Overall Survival “Data from the last several years have suggested that [in the metastatic colorectal cancer setting] a fluoropyrimidine plus bevacizumab (Avastin) is superior to bevacizumab alone or no therapy, but it has been controversial as to what the optimal maintenance is,” Dr. Bergsland stated. In the AIO KRK 0207 noninferiority study,1 investigators from Germany considered a fluoropyrimidine/ bevacizumab as standard maintenance therapy and then assessed whether bevacizumab alone or observation would be inferior as maintenance therapy for patients with metastatic colorectal cancer. Study patients had received induction therapy with a fluoropyrimidine, oxaliplatin, and bevacizumab and had

no disease progression at 6 months. The primary endpoint was time to failure of strategy. While results showed that bevacizumab was noninferior to maintenance therapy with a fluoropyrimidine plus bevacizumab, investigators could not say the same for observation, Dr. Bergsland said. Time to first progression was 6.2 months with combination maintenance therapy, 4.8 in the bevacizumab-alone group, and 3.8 months with observation (P < .001 for observation vs bevacizumab or combination therapy). “Both of the maintenance strategies were superior to observation alone, and there did appear to be a trend toward improved diseasefree survival with the more intensive therapy,” Dr. Bergsland stated.

was second progression, which was considered equal to first progression in patients not having CAPOX-B reintroduced after first progression for any reason. “There was statistically significant improvement with combination therapy,” Dr. Bergsland said. Capecitabine/ bevacizumab “is superior to observation, 11.7 months vs 8.5. Similarly, statistically significant improvements in time to second progression” occurred regardless of the therapy patients received after their first progression, 13.9 months with combination therapy vs 11.1 months with observation (P < .001). First progression was 8.5 months with capecitabine/bevacizumab vs 4.1 months with observation (P < .001). “There was no (significant) im-

We know that on an individual basis, drug-free intervals are often really valued. I think future strategies are likely to focus on identifying biomarkers to help us select which patients benefit from maintenance therapy and which ones don’t. —Emily K. Bergsland, MD

“There was no obvious difference, though, in overall survival,” she continued. “That is important to point out,” she said, although overall survival was not the primary study endpoint. Preliminary overall survival was 23.8 months for combination maintenance, 26.2 with bevacizumab alone, and 23.1 with observation.

Capecitabine/Bevacizumab Maintenance The CAIRO3 study2 compared maintenance with capecitabine and bevacizumab vs observation in 558 patients with metastatic colorectal cancer that had not progressed after six cycles (about 4 months) of treatment with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). At first progression, CAPOX-B was reintroduced to 61% of patients in the observation arm and 47% in the treatment arm. (Patients who did not want to go back on CAPOX-B could receive another treatment.) The primary endpoint of the trial

provement in overall survival, however, whether looked at it from time from randomization or when they started induction for chemotherapy,” Dr. Bergsland added. Overall survival from time of randomization was 21.6 months with maintenance therapy vs 18.1 months for observation, and from induction was 25.9 months for those who received maintenance vs 22.4 months for those who did not. The study was not powered to detect differences in overall survival. “In a subgroup analysis, it looked like patients with synchronous disease and resected primary tumors, as well as people with complete or partial response on induction therapy are the ones who seemed to benefit the most from maintenance therapy,” Dr. Bergsland said. Quality of life also seemed to be preserved.

Optimal Timing of Breaks Is Unclear “These two studies suggest that the fluoropyrimidine delays progression

compared to observation, without a major impact on survival, recognizing the caveats of this not being the primary endpoint of the study. I would say that the role of bevacizumab alone continues to be controversial,” Dr. Bergsland noted. “Once on maintenance therapy, patients don’t necessarily restart their induction therapy at progression. That is also important. In considering a planned maintenance strategy in which you are going to stop induction treatment, you need to think about whether you got the most out of that therapy,” she said, particularly in patients who might be reluctant to restart the induction regimen at a later date. “It does appear that if you are looking for delayed progression and you want to give some sort of maintenance therapy, the strongest data support a fluoropyrimidine/bevacizumab regimen, but we have trouble at this point assessing the impact of these breaks on overall survival. The optimal timing is unclear, whether it should be a planned break after 4 or 6 months or we should treat to maximum response. We don’t know if a fluoropyrimidine alone would be okay or if we really need the bevacizumab,” Dr. Bergsland said. There are also issues of toxicity and drug costs to consider. “We know that on an individual basis, drug-free intervals are often really valued. I think future strategies will be focused on identifying biomarkers to help us select which patients stand to benefit from maintenance therapy and which ones don’t,” she commented.

Utility of Mismatch Repair Status A pooled analysis of data from 17 adjuvant trials in the ACCENT database involving 7,803 patients with stage II/III colorectal cancer found that mismatch repair status is a prognostic marker in untreated stage II/III disease, with a stronger effect in stage II.3 The study does not change the standard of care, Dr. Bergsland said, “but confirms prior recommendations that patients with stage II colon cancer and [deficient mismatch repair] do not require adjuvant therapy and that [mismatch repair] status should not guide therapy in stage III disease.” Among patients with stage II disease treated with surgery alone, 5-year recurrence-free rates were higher among


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Best of ASCO® patients with deficient mismatch repair, 89% vs 74% for those with preserved mismatch repair, as were 5-year overall survival rates, 90% vs 78%. These findings confirm prior recommendations that patients with stage II colon cancer and deficient mismatch repair do not require adjuvant therapy, Dr. Bergsland said. These patients “should not receive fluorouracil [5-FU] due to excellent prognosis.” She added that treatment of high-risk stage II colorectal cancer remains controversial. Among patients with stage III disease who have been treated with 5-FU, 5-year overall survival “favors people with defective mismatch repair,” Dr. Bergsland said—77% for patients with deficient mismatch repair vs 71% for patients with preserved mismatch repair. “This is actually one of the most interesting things about this abstract,” she said, “because it suggests that there isn’t a negative reaction between mismatch repair and 5-FU, at least in these patients. In fact, these patients do a little bit better than people with preserved mismatch repair.” Patients with stage III tumors and deficient mismatch repair “likely still benefit from 5-FU, and may benefit from the addition of oxaliplatin” (reported at the ASCO Annual Meeting by Tougeron, et

al4). The favorable prognosis of deficient mismatch repair stage III patients treated with 5-FU means that mismatch repair “should not guide therapy in these patients,” Dr. Bergsland stated. The 17 studies used microsatellite instability, immunohistochemical analysis for MLH1/MSH2/MLH6, or both processes to determine mismatch repair status. Tumors with microsatellite instability–high or an absent protein were classified as deficient mismatch repair; the remainder were mismatch repair– proficient, the investigators explained.3 Patients classified as deficient mismatch repair included 23.1% of stage II and 14.9% of stage III patients and were more likely to be female (19% vs 14% males), have higher T stage, and right-side tumor location (left 9% vs right 27%). Patients in the trials had been treated with surgery alone (571), 5-FU monotherapy (3,878), 5-FU plus oxaliplatin (2,299), or 5-FU plus irinotecan (1,055).

Locally Advanced Rectal Cancer Adding oxaliplatin as a radiosensitizer to 5-FU–based neoadjuvant chemoradiotherapy and as part of systemic adjuvant chemotherapy significantly

improved disease-free survival for patients with locally advanced rectal cancer, according to results from the phase III CAO/ARO/AIO-04 study from Germany.5 The increase in disease-free survival, however, “did not translate into a significant increase in overall survival,” Dr. Bergsland stated (overall survival was a secondary endpoint). Overall survival at 3 years was 75.9% for those receiving oxaliplatin vs 71.2% for those who did not, and at 5 years, 68.8% vs 64.3%. An improved pathologic complete response rate among patients who received oxaliplatin (17% vs 13%, P = .038) did not translate into more sphincter-sparing procedures. The goal of the trial was to integrate more effective systemic treatment following the CAO/ARO/AIO-94, which, the investigators stated, established preoperative chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy with 5-FU as standard treatment for locally advanced rectal cancer. For the CAO/ARO/AIO-04 trial, patients with clinical T3/4 or clinical node-positive rectal cancer were randomly assigned to arm 1 (n = 637) and received either preoperative 50.4 Gy plus infusional 5-FU at 1 g/m2 on days 1 to 5

and 29 to 33, followed by total mesorectal excision and four cycles of bolus 5-FU 500 mg/m2 for 5 days) or to arm 2 (n = 628) and received preoperative 50.4 Gy plus infusional 5-FU at 250 mg/m2 days 1 to 14 and 22 to 35, oxaliplatin at 50 mg/m2 on days 1, 8, 22, and 29, followed by total mesorectal excision and eight cycles of adjuvant oxaliplatin at 100 mg/ m2 on day 1, leucovorin at 400 mg/m2 on day 1, and infusional 5-FU at 2,400 mg/ m2 on days 1 to 2. At a median follow-up of 50 months, 198 patients in arm 1 had a disease-free survival–related event, as compared with 159 patients in arm 2. Disease-free survival at 3 years was 71.2% in arm 1 vs 75.9% in arm 2. Grade 3/4 late overall treatment-related toxicity occurred in 23% of patients in arm 1 and 26% in arm 2. Among patients receiving oxaliplatin, 7% experienced grade 3/4 sensory neuropathy during treatment, but this decreased to 3% at 1 year of follow-up. Other trials of oxaliplatin-based adjuvant/neoadjuvant therapy for rectal cancer have shown inconsistent results, and “the evidence does not support use of oxaliplatin as a radiosensitizer in the setting of neoadjuvant chemotherapy,” continued on page 26

‘Incredible Changes’ in the Field of Colorectal Cancer By Charlotte Bath

“O

ver the past 50 years, there have been incredible changes in the field of colorectal cancer,” Emily K. Bergsland, MD, noted in opening the colorectal cancer session at the Best of ASCO meeting in Chicago. Dr. Berg-

magnetic resonance imaging. Cobalt, used as an energy source back in the 1960s, “actually had very low penetration and consequently there was a lot of skin toxicity associated with that and poor edge definition,

Everybody is looking to continued advances in molecular profiling to better select our patients. —Emily K. Bergsland, MD

need all three components of therapy, or whether some patients could be spared the surgery, for example, and allow organ preservation, or perhaps they don’t need radiation therapy.” Whether or not all patients need adjuvant chemotherapy afterward is also being studied. “Everybody is looking to continued advances in molecular profiling to better select our patients.”

Surgical Advances sland is a gastrointestinal oncologist at the Helen Diller Family Comprehensive Cancer Center and Professor of Clinical Medicine at the University of California, San Francisco.

Evolution of Radiotherapy Among the changes in radiation oncology, “one very important one relates to the changes in imaging modalities. Fifty years ago, we had very crude ways of assessing tumors,” Dr. Bergsland noted, such as planar images, liverspleen scans, chest x-rays, and barium enemas. They have been eclipsed first by computed tomography and then by

so you got a lot of bleed over into normal tissues,” Dr. Bergsland said. With the linear accelerators now in use, there is minimal skin toxicity, she continued. “You can spare normal tissues, and this has led to techniques such as conformal radiation, intraoperative radiation therapy, and radiosurgery.” Moving forward, consideration is being given to short-course radiation, possibly over 5 days rather than a traditional 5-week course. “There is also a trend toward looking at which patients might be spared surgery,” Dr. Bergsland said. “There are a lot of questions about whether patients

Turning to advances in surgery, Dr. Bergsland said it was important to remember that “50 years ago, the majority of patients with rectal cancer had a colostomy. Now, in contrast, it is the minority of patients who have a colostomy. There have been significant advances in surgical techniques, including the ability to do a coloanal anastomosis, various new reconstruction techniques, and also techniques involved in dealing with very early-stage rectal cancer,” she said. Minimally invasive surgery for colon cancer has resulted in reduced trauma and complications and quicker recovery. The data are not as mature for

rectal cancer, Dr. Bergsland noted. Surgical mortality has decreased, “partly due to better perioperative technique and support, and improved anesthesia techniques. With modern- day liver resections, we are looking at perioperative mortalities of only around 1% to 2% in recent studies,” Dr. Bergsland observed. Future considerations for surgery involve the selection and follow-up of candidates for organ preservation, evolving guidelines for liver resection, and the role of adjuvant/neoadjuvant chemotherapy. While 50 years ago, chemotherapy basically meant fluorouracil, effective agents now include capecitabine, oxaliplatin, and irinotecan, as well as doublets and triplets. Targeted agents, nonexistent 50 years ago, now include cetuximab (Erbitux), panitumumab (Vectibix), ziv-aflibercept (Zaltrap), bevacizumab (Avastin), and regorafenib (Stivarga). The “one-size-fits-all” approach is giving way to treatment based on molecular classifications. n Disclosure: Dr. Bergsland reported no potential conflicts of interest.


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Best of ASCO® Metastatic Colorectal Cancer continued from page 25

according to Dr. Bergsland. “I don’t think this will change the standard of care that much,” Dr. Bergsland said. The addition of oxaliplatin to a fluoropyrimidine may be beneficial in the adjuvant setting, and “additional tools are needed to determine which patients are most likely to benefit from oxaliplatinbased chemotherapy.”

First-Line Treatment for Metastatic Disease An additional study reported at the Best of ASCO colorectal cancer session found that cetuximab (Erbitux) and bevacizumab produced comparable benefits when added to first-line treatment with chemotherapy for patients with meta-

static colorectal cancer. Details of that study6 were reported in the June 25, 2014, issue of The ASCO Post. n Disclosure: Dr. Bergsland reported no potential conflicts of interest.

References 1. Arnold D, Graeven U, Lerchenmuller A, et al: Maintenance strategy with fluoropyrimidines (FP) plus bevacizumab (Bev), Bev alone, or no treatment, following a standard combination of FP, oxaliplatin (Ox), and Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC): A phase III non-inferiority trial (AIO KRK 0207). ASCO Annual Meeting. Abstract 3503. Presented June 2, 2104. 2. Koopman M, Simkens L, May AM, et al: Final results and subgroup analyses of

the phase 3 CAIRO3 study: Maintenance treatment with capecitabine + bevacizumab versus observation after induction treatment with chemotherapy + bevacizumab in metastatic colorectal cancer (mCRC). ASCO Annual Meeting. Abstract 3504. Presented June 2, 2014. 3. Sargent DJ, Shi Q, Yothers G, et al: Prognostic impact of deficient mismatch repair (dMMR) in 7,803 colon cancer (CC) patients (pts): A pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. ASCO Annual Meeting. Abstract 3507. Presented June 2, 2014. 4. Tougeron D, Sickersen G, Lecomie T, et al: Impact of adjuvant chemotherapy with 5-FU or FOLFOX in colon cancers with microsatellite instability: An AGEO multicenter study. ASCO Annual Meeting.

Abstract 3508. Presented June 2, 2014. 5. Rodel C, Liersch T, Fietkau R, et al: Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: Results of the German CAO/ARO/AIO04 randomized phase III trial. ASCO Annual Meeting. Abstract 3500. Presented June 2, 2014. 6. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wildtype untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2014.

ASCO Endorses AUA/ASTRO Guideline on Adjuvant and Salvage Radiotherapy After Prostatectomy

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SCO has issued an endorsement of the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) guideline on the use of adjuvant and salvage radiotherapy after prostatectomy, which was based on a systematic review of medical literature. The ASCO endorsement was published recently in the Journal of Clinical Oncology1 and will be reviewed in detail in an upcoming issue of The ASCO Post.

In Brief The AUA/ASTRO guideline recommends that physicians discuss adjuvant radiotherapy with patients who have

adverse pathologic findings at prostatectomy (ie, seminal vesicle invasion, extensive positive surgical margins) and salvage radiotherapy with patients with detectable postoperative prostate-specific antigen (PSA) or local recurrence after prostatectomy. Patients should be informed that, while adjuvant radiotherapy reduces the risk of recurrence and disease progression, its impact on preventing metastases and extending survival is less clear.

Qualifying Statement An ASCO guideline endorsement panel determined that the guideline

recommendations, published in August 2013 in the Journal of Urology,2 are clear, thorough, and based on the most relevant scientific evidence. The Society added one qualifying statement that not all men who are candidates for adjuvant or salvage radiotherapy have the same risk of recurrence or disease progression, and thus, not all men will derive the same benefit from adjuvant radiotherapy. Those at the highest risk for recurrence after radical prostatectomy (including men with seminal vesicle invasion, Gleason score 8 to 10, extensive positive margins, and detectable postoperative PSA) are likely to derive the greatest benefit.

The guideline is available at http://www.asco.org/guidelines/­ genitourinary-cancer, along with supplementary materials. n References 1. Freedland SJ, Rumble RB, Finelli A, et al: Adjuvant and salvage radiotherapy after prostatectomy: ASCO Clinical Practice Guideline Endorsement. J Clin Oncol. November 3, 2014 (early release online). 2. Thompson IM, Valicenti RK, Albertsen P, et al: Adjuvant and salvage radiotherapy after prostatectomy: AUA/ ASTRO Guideline. J Urol 190:441-449, 2013.

The ASCO Post Wants to Hear From You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

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NCCN Congress on Hematologic Oncology

Targeted Therapies in Indolent Lymphoma: Challenging the Current Paradigm By Alice Goodman

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he use of targeted therapies in indolent non-Hodgkin lymphoma (NHL) is a burgeoning area. New targeted therapies directed at the cell surface, intracellular pathways, and the microenvironment are being studied for relapsed indolent NHL. These treatments, if validated in large randomized trials, may make it possible to avoid traditional chemotherapeutic agents in some patients. “Ongoing clinical trials are studying these newer agents as initial therapy, in combination with, or in lieu of, traditional chemotherapy. Further study is needed to refine toxicity prevention and management and to identify optimal sequencing, novel-novel combinations, and predictors of response with targeted agents. The treatment landscape is rapidly evolving, relying less on traditional chemotherapy. The future for indolent NHL patients is increasingly bright and chemotherapy-free,” said Jeremy S. Abramson, MD, Assistant Professor at Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, during a presentation at the 8th Annual National Comprehensive Cancer Network (NCCN)

EXPERT POINT OF VIEW

“U

until relapse,” explained Andrew D. Zelenetz, MD, PhD, Vice Chair of the Department of Medicine and former Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York, and Director and Chair of the NCCN Congress on Hematologic Malignancies. “The concept that we can treat continuously until disAndrew D. Zelenetz, MD, PhD Jennifer R. Brown, MD, PhD ease progression represents a paradigm shift that comes ment, remission, and retreatment at with newer drugs that are approved emergence of symptoms. Very fre- as continuous therapy in chronic lymquently, we can show that you can de- phocytic leukemia, such as ibrutinib fer therapy in asymptomatic patients and idelalisib,” he continued. p until now, our paradigm— particularly in indolent lymphoma—has been episodic treat-

etan (Zevalin) has shown potential in relapsed/refractory indolent NHL. “[Ibritumomab tiuxetan] doesn’t replace rituximab as a treatment option, but rituximab-refractory patients may respond to this agent. It was also evaluated as maintenance therapy following

The treatment landscape is rapidly evolving, relying less on traditional chemotherapy. The future for indolent NHL patients is increasingly bright and chemotherapy-free. —Jeremy S. Abramson, MD

Congress on Hematologic Oncology.1 Rituximab (Rituxan) was the first targeted therapy to advance treatment of lymphomas. Novel targets that have been identified for study include the cell surface, intracellular pathways, and the microenvironment.

Targeting the Cell Surface Mechanisms for targeting the cell surface include naked antibodies, radioimmunoconjugates, and antibody-drug conjugates, Dr. Abramson explained. Obinutuzumab (Gazyva) has been approved in untreated chronic lymphocytic leukemia, but studies have shown this agent has less activity in indolent lymphomas, he noted. On the other hand, radioimmuotherapy with yttrium-90 ibritumomab tiux-

initial chemoimmunotherapy but was inferior to rituximab in that setting,” Dr. Abramson told listeners. A third strategy is an antibody-drug conjugate (anti-CD79b conjugated to monomethyl auristatin E). Encouraging antitumor responses to this conjugate have been observed within lymphoma subtypes, including follicular lymphoma and mantle cell lymphoma. “These are early data. This is an appealing compound, and we will be hearing more about this,” Dr. Abramson stated.

Targeting Intracellular Pathways Idelalisib (Zydelig) targets the PI3K pathway. Idelalisib was studied in relapsed/refractory indolent NHL in a

phase II trial that included 125 patients refractory to both rituximab and an alkylator, with a median of four prior therapies.2 Excellent responses were observed. “This represents an unmet need— high-risk patients who are double-refractory. The caveat is that the drug has relatively uncommon toxicities including diarrhea, colitis, pneumonia, and infection, and oncologists should keep an eye out for them,” he continued. Ibrutinib (Imbruvica) is an inhibitor of Bruton’s tyrosine kinase approved for relapsed/refractory chronic lymphocytic leukemia and studied in a phase I trial in relapsed B-cell NHL.3 Thus far, results are encouraging, with an overall response rate greater than 50% and tumor volume reductions in 55% of patients. This drug is being investigated in multiple ongoing studies in lymphomas, including combinations with lenalidomide (Revlimid), rituximab, and both lenalidomide and rituximab. “Ibrutinib is experimental outside of chronic lymphocytic leukemia, small lymphocytic lymphoma, and mantle cell lymphoma. These encouraging results in refractory lymphoma patients make us expect that we will see even better results in lower-risk patients,” he said. ABT-199 (GDC-0199) targets BCL2 in indolent NHL and has been investigated in a phase I trial in relapsed/ refractory NHL.4 Experience has taught investigators that the drug should be given in a slower dosing scheme than originally used to avoid tumor lysis

Jennifer R. Brown, MD, PhD, Director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, Boston, weighed in on the discussion. “One issue related to use of targeted therapy is that if a patient on continuous therapy becomes resistant, then we wouldn’t be able to reuse that therapy later when symptoms emerge. We want to gain the longest durable benefit for our patients. It is an open question whether this is achieved by continuous therapy or breaks in therapy with treatment at disease progression,” she stated. n Disclosure: Drs. Zelenetz and Brown reported no potential conflicts of interest.

syndrome. This drug produces grade 3/4 myelosuppression in 7% to 19% of patients. Results in mantle cell lymphoma are so far the best, with some responses in follicular lymphoma, diffuse large B-cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma. “Many of the responses with ABT199 occur at higher dose levels, but there are too few patients in these groups to validate this. We need more data at higher doses and in combinations with other drugs. We will be hearing a lot more about ABT-199,” Dr. Abramson predicted.

Targeting the Microenvironment The third strategy of targeting the microenviroment is exemplified by lenalidomide. The Cancer and Leukemia Group B (CALGB) 50401 trial compared rituximab plus lenalidomide vs lenalidomide alone in patients with recurrent follicular lymphoma.5 A third arm, rituximab alone, was closed early. The combination proved highly active, with an overall response rate of 72.7% compared to 51.1% with lenalidomide alone. At a median follow-up of 1.7 years, complete response rates were 36.4% vs 13.3%, respectively. The 2-year event-free survival rate was 44% vs 27%. Two additional trials evaluated lenalidomide plus rituximab in untreated indolent NHL.6,7 Both trials used a chemotherapy-sparing approach up front. In continued on page 28


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NCCN Congress on Hematologic Oncology Targeted Therapies in ­Indolent Lymphoma continued from page 27

the first trial (from The University of Texas MD Anderson Cancer Center), overall response rate was 85%, complete response rate was 60%, and 3-year progression-free survival rate was 78%. In the second trial (from the Alliance/CALGB), overall response rate was 96%, complete repsonse rate was 71%, and 2-year progression-free survival was 89%. These encouraging results led to the

RELEVANCE study, which will enroll about 1,000 patients and compare rituximab/lenalidomide for induction and maintenance vs rituximab and chemotherapy of the investigator’s choice followed by rituximab maintenance as first-line treatment for NHL. “Two ongoing trials are looking at PD-1 blockade in indolent NHL. Both pidilizumab and nivolumab have had interesting activity in relapsed rituximabsensitive follicular lymphoma and relapsed follicular lymphoma, respectively,”

Treating Indolent Lymphoma ■■ Targeted therapies are being explored in indolent non-Hodgkin lymphoma. ■■ It may be possible to omit chemotherapy from treatment if targeted therapies are validated in this setting. ■■ Many questions remain about the best drug for the right patient, the best combinations, the best dose, and short- and long-term toxicities.

he said. Further study is needed. n

Disclosure: Dr. Abramson is a consultant for Millennium, Gilead, and Janssen.

References 1. Abramson JS: Targeted therapy in indolent lymphoma. NCCN Annual Congress on Hematologic Malignancies. Presented September 20, 2014. 2. Gopal AK, Kahl BS, deVos S, et al: PI3K delta inhibition by idelalisib in patients with relapsed/refractory indolent lymphoma. N Engl J Med 370:1008-1018, 2014. 3. Advani RH, Buggy JJ, Sharman JP, et al: Bruton’s kinase inhibitor (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31:88-94, 2013. 4. Seymour JF, Davids MS, Pagel JM, et al: ABT-199 (GDC-0199) in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia: High response

rates about patients with high risk disease features including unmutated IGHV. European Hematology Association Annual Congress. Abstract 5375. Presented June 14, 2014. 5. Leonard J, Jung S-H, Johnson JL, et al: CALGB 50401: A randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. J Clin Oncol 30(suppl):Abstract 8000, 2012. 6. Fowler NH, Neelapu SS, Hagemeister FB, et al: Lenalidomide and rituximab for untreated indolent lymphoma: Final results of a phase II study. American Society of Hematology Annual Meeting. Abstract 901. Presented December 11, 2012. 7. Martin P, Jung S-H, Johnson JL, et al: CALGB 50803 (Alliance): A phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. ASCO Annual Meeting. Abstract 8521. Presented May 30, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Heinz-Josef Lenz, MD, on Pivotal Trials in Metastatic Colorectal Cancer see page 45

Axel Grothey, MD, on Maintenance Strategies for Metastatic Colorectal Cancer see page 46

Alexandria Phan, MD, on Everolimus in Pancreatic Neuroendocrine Tumors see page 55

Stefan Sleijfer, MD, PhD, on Pazopanib in Advanced Pretreated GIST see page 64

Heinz Ludwig, MD, on Carfilzomib in Myeloma see page 65

Enriqueta Felip, MD, PhD, on Tackling NSCLC Mutations see page 66

Giorgio V. Scagliotti, MD, PhD, on Biomarkers in NSCLC see page 72

Hope S. Rugo, MD, on Sorafenib in Advanced Breast Cancer see page 75

S. Vincent Rajkumar, MD, on Treatment of Newly Diagnosed Multiple Myeloma see page 94

Visit The ASCO Post online at ASCOPost.com

November Is

Lung Cancer Awareness Month.

See pages 1, 40, 66, and 67 for lung cancer news in The ASCO Post.


As patient needs are changing— Pfizer’s assistance programs are changing too

Introducing Pfizer RxPathways™— our answer to changing patient needs For more than 25 years, Pfizer has offered an array of prescription assistance programs to help eligible patients get access to their Pfizer medicines. To meet the changing needs of today’s patients, we’ve consolidated these services into one comprehensive program. Introducing Pfizer RxPathways, formerly Pfizer Helpful Answers, our remodeled patient assistance program that helps eligible patients get access to their Pfizer medicines by offering a range of support services, including insurance counseling, co-pay help,* providing Pfizer medicines for free or at a savings, and more.

Pfizer RxPathways: filling a need for prescription assistance Visit www.PfizerRxPath.com to learn more. *This is not health insurance. Terms and conditions apply. Pfizer RxPathways™ is a joint program of Pfizer Inc. and the Pfizer Patient Assistance Foundation. Pfizer RxPathways™ is part of Pfizer’s Global Social Investments portfolio. For more information, please visit www.pfizer.com/responsibility. PRX676305-01

©2014 Pfizer Inc.

All rights reserved.

Printed in USA/August 2014


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 30

Breast Cancer Symposium Noteworthy Abstracts From the Breast Cancer Symposium Include Studies of Novel Therapies and of the Impact of Disease Subtypes on Outcomes By Caroline Helwick

M

ore than 150 oral and poster presentations were featured at the 2014 Breast Cancer Symposium, held September 4–6 in San Francisco. The multidisciplinary meeting is sponsored by ASCO, the American Society of Breast Disease, American Society of Breast Surgeons, American Society for Radiation Oncology, National Consortium of Breast Centers, Inc, and Society of Surgical Oncology. Brief summaries of some of those studies are presented here.

Proof of Principle for Breast Cancer Vaccines In the adjuvant setting, a novel HER2-derived peptide (GP2) vaccine reduced the rate of breast cancer recurrences (though nonsignificantly) and proved safe and well tolerated in a phase II study by investigators working in the vaccine arena. Elizabeth Mittendorf, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, presented the results.1 GP2 is one of a number of vaccines being developed in breast cancer, of which the HER2-derived E75 vaccine (nelipepimut-S) is furthest along in development, now in a phase III registration trial. This human leukocyte antigen (HLA)-A2/A3–restricted immunogenic peptide designed to stimulate CD8positive T cells to recognize tumor cells with any level of HER2 expression (1+, 2+, or 3+ by immunohistochemistry). The multicenter phase II randomized study included 180 women with HLAA2+ node-positive or high-risk nodenegative breast cancer with any level of HER2 expression. All patients had been rendered disease-free by standard-of-care therapy (including trastuzumab [Herceptin], where appropriate). The women

Elizabeth Mittendorf, MD, PhD

were randomly assigned to receive GP2 plus granulocyte-macrophage colonystimulating factor (GM-CSF [Leukine], an immunostimulant) or GM-CSF alone. They received 6 monthly intradermal inoculations during the primary vaccination series followed by five boosters administered every 6 months. At a median follow-up of 34 months, in the intent-to-treat population, disease-free survival rates were 88.1% for the vaccinated group vs 81.0% for the control arm, a 37% reduction in risk (P = .428). In the per-treatment comparison, 93.5% of optimally vaccinated patients were disease-free, compared to 85.0% of controls—a 57% risk reduction (P = .168). This latter comparison excluded patients who had a disease recurrence during the vaccination series or who developed a second nonbreast malignancy. Importantly, patients with the highest expression of HER2 who received the vaccine after completing trastzu­ mab, 100% were disease-free, compared with 90% of the control arm. An in vivo antigen-specific immune response was attained with vaccination. When questioned about the lack of statistical significance in these comparisons, Dr. Mittendorf noted that as a phase II trial, the study “accomplished what we wanted it to do” in that it established activity and safety and identified a

patient population in which the vaccine can be further investigated. Most toxicities were grade 1 and occurred at the same rate as in the GM-CSF–alone arm. While the current study evaluated the sequential use of trastuzumab and the vaccine, concurrent administration of the two, which may take advantage of trastuzumab’s immune-mediated mechanism of action, could be more effective in preventing recurrences, Dr. Mittendorf hypothesized. These studies are underway.

Veliparib in BRCA-Mutated Tumors Veliparib showed antitumor activity comparable to that observed in other poly(ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA1 or BRCA2 mutations in a phase I dose escalation study presented by Shalu Pahuja, MD, of the University of Pittsburgh Cancer Institute.2 She and her colleagues evaluated single-agent veliparib, at a maximum dose of 500 mg twice daily, in 70 patients with BRCA-mutated tumors (breast and elsewhere) and 28 with wild-type tumors. They found activity to be greater among patients with mutated vs wild-type disease, with responses observed in 37% of all patients with BRCA-positive tumors at the optimal dose levels, and in 50% of patients with BRCA-positive breast cancer, compared to 0% of those with wildtype ovarian cancer and 19% of those with wild-type breast cancer. The clinical benefit rates were similar for mutated ovarian cancer (34%) and breast cancer (36%). The only common grade 3 or 4 toxicity was lymphopenia (15%). The dose that will move forward in phase II trials is 400 mg twice daily. Ongoing correlative studies from

Table 1: Survival by Type of Radiation and Tumor Subtype Type of CNS radiation received Whole-brain radiotherapy Tumor subtype

Number of cases

Median OS

archival tissues and mandatory biopsy cohort includes BRCA promoter methylation, BRCA reversion mutation, and nonhomologous end-joining (NHEJ) pathway analysis and will provide early insights on potential predictors of response and resistance. Dr. Pahuja hypothesized that veliparib will combine well with che-

Stereotactic radiosurgery Number of cases

Median OS

Total cases

HER2-positive, HRnegative

30 (22%)

30 mo

10 (15%)

11 mo

40 (20%)

HER2-positive, HRpositive

29 (21%)

14 mo

12 (19%)

25 mo

41 (20%)

HER2-negative, HRpositive

39 (29%)

8 mo

28 (44%)

18 mo

67 (34%)

Triple-negative breast cancer

33 (24%)

5 mo

12 (19%)

12 mo

45 (22%)

CNS = central nervous system; HR = hormone receptor; OS = overall survival. Courtesy of Villgran VD, et al.5

Shalu Pahuja, MD

motherapy. Phase III trials evaluating veliparib in combination with chemotherapy in BRCA-mutated and triple-negative breast cancer are underway.

Tumor-Infiltrating Lymphocytes and Response Rates In a poster that earned a Merit Award at the meeting, high levels of tumor-infiltrating lymphocytes in pretreatment breast tumor biopsies, as well as low levels after neoadjuvant therapy, predicted for pathologic complete response, according to a meta-analysis from Chinese researchers.3 In the pooled analysis of 13 neoadjuvant studies involving 3,555 patients, higher number of tumor-infiltrating lymphocytes at baseline was correlated with a greater likelihood of a pathologic complete response, with an odds ratio (OR) of 3.82, reported Yan Mao, MD, of Shanghai Jiao Tong University School of Medicine in China. Tumor-infiltrating lymphocytes especially predicted for higher rates in patients with triple-negative disease (OR = 5.03) and patients with HER2-positive tumors (OR = 5.54). No significant association was seen in those with hormone receptor–positive/HER2-negative disease (OR = 2.57).

Triple-Negative Breast Cancer and Renal Cell Cancers In another poster that earned a Merit Award, Joyce Georges Habib, MD, and colleagues were the first to report a direct association between primary triple-negative breast cancer and secondary kidney cancer and an inverse assocontinued on page 34


AV NO AI W LA BL E

NEW—A LIQUID FORMULATION—TREANDA® (bendamustine HCl) Injection Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

What else is new about TREANDA? NEW CONCENTRATION

90

mg/mL

NEW DOSAGE STRENGTHS

NEW NDCs

180 mg/2 mL 63459-396-02 45 mg/0.5 mL 63459-395-02 J Code 9033

It may be necessary to update your pharmacy and/or patient medication management systems. FOR MORE INFORMATION, CALL 1-800-896-5855 OR VISIT TREANDAHCP.COM

Supplied in single-use, 2-mL vials.

Indications TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common nonhematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities for both indications (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. Please see accompanying brief summary of Full Prescribing Information on the following pages.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40120 October 2014


Brief Summary of Prescribing Information 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 1.2 Non-Hodgkin Lymphoma (NHL) TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 2.2 Dosing Instructions for NHL Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. 2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution. Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution. Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/ 0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°-86°F) and room light. Administration of TREANDA must be completed within this period. 3 DOSAGE FORMS AND STRENGTHS TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.

TREANDA® (bendamustine hydrochloride) Injection

TREANDA® (bendamustine hydrochloride) Injection

Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.1) and (2.2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection. 5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergictype reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)]. 5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of the label [See Warnings and Precautions]: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 329 patients who participated in an activelycontrolled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Nonhematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients

System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

TREANDA (N=153) All Grade Grades 3/4

Chlorambucil (N=143) All Grade Grades 3/4

121 (79) 52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

1 (<1) 1 (<1) 2 (1)

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

0

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

0

5 (3)

0

11 (7)

3 (2)

2 (1)

0

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150 Laboratory Abnormality

Chlorambucil N=141

All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. 6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.


TREANDA® (bendamustine hydrochloride) Injection

TREANDA® (bendamustine hydrochloride) Injection

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176)

Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac disorders 0 Tachycardia 13 (7) Gastrointestinal disorders 7 (4) Nausea 132 (75) 5 (3) Vomiting 71 (40) 6 (3) Diarrhea 65 (37) 1 (<1) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 2 (1) Abdominal pain 22 (13) 0 Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 1 (<1) Dry mouth 15 (9) 0 Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) General disorders and administration site conditions 19 (11) Fatigue 101 (57) 3 (2) Pyrexia 59 (34) 0 Chills 24 (14) 1 (<1) Edema peripheral 23 (13) 4 (2) Asthenia 19 (11) 1 (<1) Chest pain 11 (6) 0 Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) Infections and infestations 5 (3) Herpes zoster 18 (10) 0 Upper respiratory tract infection 18 (10) 4 (2) Urinary tract infection 17 (10) 0 Sinusitis 15 (9) 9 (5) Pneumonia 14 (8) 11 (6) Febrile neutropenia 11 (6) 2 (1) Oral candidiasis 11 (6) 0 Nasopharyngitis 11 (6) Investigations 3 (2) Weight decreased 31 (18) Metabolism and nutrition disorders 3 (2) Anorexia 40 (23) 8 (5) Dehydration 24 (14) 1 (<1) Decreased appetite 22 (13) 9 (5) Hypokalemia 15 (9) Musculoskeletal and connective tissue disorders 5 (3) Back pain 25 (14) 0 Arthralgia 11 (6) 2 (1) Pain in extremity 8 (5) 0 Bone pain 8 (5) Nervous system disorders 0 Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) Psychiatric disorders 0 Insomnia 23 (13) 1 (<1) Anxiety 14 (8) 0 Depression 10 (6) Respiratory, thoracic and mediastinal disorders Cough 1 (<1) 38 (22) Dyspnea 3 (2) 28 (16) Pharyngolaryngeal pain 1 (<1) 14 (8) Wheezing 0 8 (5) Nasal congestion 0 8 (5) Skin and subcutaneous tissue disorders Rash 1 (<1) 28 (16) Pruritus 0 11 (6) Dry skin 0 9 (5) Night sweats 0 9 (5) Hyperhidrosis 0 8 (5) Vascular disorders Hypotension 2 (1) 10 (6) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Percent of patients Hematology variable

All Grades

Grades 3/4

Lymphocytes Decreased

99

94

Leukocytes Decreased

94

56

Hemoglobin Decreased

88

11

Neutrophils Decreased

86

60

Platelets Decreased

86

25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1. 16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons. 16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°46°F). Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved. Iss. 09/2013 (Label Code: 00016287.06) TRE-40206 This brief summary is based on TRE-009 TREANDA full Prescribing Information.


The ASCO Post  |   NOVEMBER 15, 2014

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Breast Cancer Symposium Noteworthy Abstracts continued from page 30

ciation between triple-negative breast cancer and colorectal cancer.4 Dr. Habib, of Sammons Cancer Center, Texas Oncology, in Dallas, pointed out that most large databases predate HER2 testing, which precludes the ability to look for associations by breast cancer subtype. The current study was able to do so. Their retrospective database analysis of US Oncology Network practices identified 105,795 patients with breast cancer, 2,237 (2.1%) of whom were diagnosed with at least one secondary nonbreast malignancy at a mean time of 2.6 years after breast cancer diagnosis. They were most commonly non–small cell lung (n = 346), colorectal (n = 250), uterine (n = 192), ovarian (n = 130), thyroid (n = 106), and renal cell cancers (n = 73). On multivariate analysis, triplenegative breast cancer was predictive of secondary kidney cancer (OR = 2.00; P = .019) but was a negative predictor for secondary colorectal cancer (OR = .47; P = .009), age ≤ 55 (OR = .27; P < .0001), and body mass index ≤ 30 (OR = .64; P = .019). The association between triple-negative breast cancer and kidney cancer is greater than the association seen with smoking on the univariate analysis. “Triple-negative breast cancer was a strong independent risk factor for kidney cancer,” she indicated. The negative associations between age, lower body mass index, and secondary colorectal cancer have been reported in the past, but this is the first study describing a negative association between primary triple-negative cancer and secondary colorectal cancer. “The short follow-up makes it unlikely that the secondary cancer associations were caused by the antecedent breast cancer treatments,” Dr. Habib said. “The results may potentially be attributed to genetic, environmental, or lifestyle factors.”

Tumor Subtypes and Radiotherapy to the Brain Breast cancer subtype is a significant prognostic factor for survival for patients who receive whole-brain radiation therapy for brain metastases, but not for those who receive only stereotactic radiosurgery, according to a study from the University of Pittsburgh Medical Center in Pennsylvania.5 Breast cancer subtypes have an important prognostic role in metastatic disease, but whether they also have a prognostic role in patients receiving radiotherapy for brain metastases has not been known. This single-center study

investigated the association between breast cancer subtype and overall survival among 193 breast cancer patients with brain metastases treated between 1997 and 2013. Of them, 131 received whole-brain radiotherapy (with or without stereotactic radiosurgery) and 62 received only stereotactic radiosurgery. Overall survival was defined as the time from diagnosis of brain metastases to death or last follow-up. In keeping with what was expected, the stereotactic radiosurgery group generally had better survival, since patients who receive this form of radiotherapy tend to have less burden of disease. However, patients with HER2-positive/hormone receptor– negative breast cancer had substantially better outcomes when treated with wholebrain radiotherapy than with stereotactic radiosurgery. Median overall survival was 30 months vs 11 months, respectively, reported Vipin Das Villgran, MD, MMS, along with joint first author Aju Mathew, MD, and colleagues. Additionally, with whole-brain radiotherapy, median overall survival was significantly different among the

Vipin Das Villgran, MD, MMS

subtypes (P = .0003), whereas for the stereotactic radiosurgery–only group, these differences reflected a nonsignificant trend (P = .07, Table 1, page 30). Dr. Villgran suggested that the greater benefit seen with whole-brain radiotherapy in the HER2-positive/hormone receptor–negative patients may be the result of the radiation rendering the blood-brain barrier more permeable to trastuzumab.

Ipilimumab/Cryoablation and Immune Response In light of the association of tumorinfiltrating lymphocytes with favorable prognosis in early-stage breast cancer, novel immunotherapies are being evaluated for the potential to augment antitumor immunity and prevent recurrence. In a poster earning a Merit Award, favorable immunologic effects of cryoimmunotherapy were reported from a pilot study of early-stage breast cancer patients. In this multidisciplinary study led by principal investigator, Heather McArthur, MD,

News Roundup From ASCO Breast Cancer Symposium ■■ In a phase II study, the HER2-derived peptide GP2 vaccine, given as a series following standard-of-care adjuvant treatment, demonstrated safety; in women with the highest level of HER2 expression, 100% were disease-free at 3 years, compared with 90% of the control arm. ■■ Veliparib as a single agent produced responses in 37% of patients with BRCA-mutated solid tumors and in 50% with BRCA-mutated breast cancers. ■■ Tumor-infiltrating lymphocytes in tumors prior to neoadjuvant therapy were associated with a fivefold increased chance for achieving a pathologic complete response in patients with triple-negative and HER2-positive tumors, but not those with hormone receptor–positive/HER2-negative tumors. ■■ A database analysis found a significant association between triple-negative breast cancer and subsequent development of renal cell cancer; triplenegative breast cancer was inversely associated with colorectal cancer. ■■ Breast cancer subtype was a significant prognostic factor for survival for patients who received whole-brain radiation therapy for brain metastases, but not for those receiving only stereotactic radiosurgery. ■■ In women with early-stage breast cancer, the combination of preoperative cryoablation plus ipilimumab conferred higher rates of systemic immune activation, compared with either therapy alone, in an 18-patient study.

patients received preoperative ipilimumab (Yervoy) and/or cryoablation. The data came from 18 patients, 13 of whom had hormone receptor–positive disease, two with HER2-positive disease, and three with triple-negative disease. The therapies were well tolerated, with evidence of enhanced immune activation following cryoimmunotherapy, as measured by the T-cell activation marker, inducible costimulator.6 At the Breast Cancer Symposium, David Page, MD, of Memorial Sloan Kettering Cancer Center, New York, reported that the majority of patients treated with combination therapy experienced sustained increases in plasma interferon gamma (a cytokine attributed to antitumor T-cell activity), vs only two patients treated with ipilimumab alone and no patients receiving cryoablation alone.7 These potentially beneficial immune effects were observed in both hormone receptor–positive and hormone receptor–negative subtypes, as well as in tumors with low or high baseline density of tumor-infiltrating lymphocytes, suggesting that cryoimmunotherapy should be further investigated across all subtypes of early-stage breast cancer, and in patients with both high and low baseline tumor-infiltrating lymphocyte counts. n

David Page, MD

Disclosure: Drs. Mittendorf, Pahuja, Habib, Villgran, and Page reported no potential conflicts of interest.

References 1. Schneble EJ, Perez SA, Murray JL, et al: Primary analysis of the prospective, randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients. Breast Cancer Symposium. Abstract 134. Presented September 5, 2014. 2. Pahuja S, Beumer JH, Appleman LJ, et al: Outcome of BRCA 1/2 – mutated and triple-negative, BRCA wild-type breast cancer patients in a phase I study of singleagent veliparib. Breast Cancer Symposium. Abstract 135. Presented September 5, 2014. 3. Yan M, Qing Q, Yuzi Z, et al: Tumor infiltrating lymphocytes to predict response to neoadjuvant chemotherapy in breast cancer. Breast Cancer Symposium. Abstract 138. Presented September 5, 2014. 4. Habib JG, Espirito JL, Harrell RK, et al: Secondary nonbreast malignancies after primary breast cancer. Breast Cancer Symposium. Abstract 112. Presented September 4, 2014. 5. Villgran VD, Mathew A, Rosenzweig MQ, et al: Effect of tumor subtype on overall survival in brain metastatic breast cancer patients treated with cranial irradiation. Breast Cancer Symposium. Abstract 74. Presented September 4, 2014. 6. Diab A, McArthur HL, Barnett S, et al: A pilot study of preoperative, single-dose ipilimumab and/or cryoablation in women with early-stage resectable breast cancer. ASCO Annual Meeting. Abstract 1098. Presented June 2, 2014. 7. Page DP, Yuan J, Ginsberg A, et al: Tumor and systemic immune responses to preoperative cryoablation plus immune therapy with ipilimumab in early-stage breast cancer. Breast Cancer Symposium. Abstract 64. Presented September 4, 2014.


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 35

Turning the Tide Against Cancer Conference Issues in Oncology

Young Adults With Cancer: Unique Issues Highlight Importance of Patient-Centered Care By Caroline McNeil

S

uleika Jaouad, a journalist, was 22 and had just gotten her first chance to cover a major news story—the revolution underway in Tunisia—when she was diagnosed with myelodysplastic syndrome that had evolved into acute myeloid leukemia (AML). Months into her treatment, she began to write again, but this time with a strong focus on the unique challenges—psychosocial, clinical, and financial—that confront young adults with cancer. “Nine months, eight hospitalizations, and seven chemotherapy treatments later, I’m realizing that age is an inextricable component of how we experience cancer,” she wrote in one of her first columns in the series “Life, Interrupted,” published in The New York Times. Now 26 and a cancer survivor, her work is reaching not only fellow patients and the general public, but also cancer professionals. At a recent meeting in Washington, the second national conference on Turning the Tide Against

tion for Cancer Research, and Feinstein Kean Healthcare to explore two major themes: patient-centered care and how to address cost and value in ways that align with patient-centeredness. Ms. Jaouad’s insights into the world of young adults with cancer clearly underlined the importance of both issues.

Special Set of Challenges “Where cancer is concerned, it’s safe to say there’s no such thing as good timing. But having a life-threatening disease in your 20s carries a special set of psychological and social challenges,” Ms. Jaouad wrote in one of her early ­columns. “Overnight, I lost my job, apartment, the opportunity to cover the revolution in Tunisia,” she said at the meeting. “I moved back home, into my childhood room.” After a cancer diagnosis, relationships are altered, with both friends and family. In an award-winning video series, also titled “Life, Interrupted,” Ms.

Whether we’re too embarrassed or shy—or worried that a discussion about cost might affect the quality of our care—it’s clear that both doctors and patients need to do more communicating. We talk about everything else, so why shouldn’t cost be a part of that conversation? —Suleika Jaouad

Cancer Through Sustained Medical Innovation, she spoke to oncologists and policy experts about the special challenges of young adults with cancer. Twenty-somethings are oncology’s ‘tweens,’ she said. They don’t fit in the pediatric cancer world with its many dedicated centers or in the cohort of older adults who oncologists see most often. Their survival rates have improved little over the past decades compared with the rising rates in childhood and some common adult cancers. Most important, many of the issues they care most about—independence, relationships, developing careers, the long-term health effects of treatment— inform and influence their interactions with their oncologists. Turning the Tide Against Cancer was convened by the Personalized Medicine Coalition, the American Associa-

Jaouad’s mother says, “As a mother of a young adult with cancer, you have to learn to stand back…. I wanted to do everything for her; that was not what she wanted.” She and her brother, who would be her bone marrow donor if she were able to have a transplant, describe the complexity of their feelings in another video in the series. Relationships with friends became, at least initially, awkward in some cases, the subject of another column. And then there was the relationship with her doctors. Like many patients of all ages, Ms. Jaouad soon found herself immersed in a world of unfamiliar terms and concepts. “I made it my job to learn as much as I could about AML,” she said. “But it was a bigger challenge than expected. My doctor was one of the best, but I was lost in any conversation.”

Suleika Jaouad addressed the unique challenges and issues faced by young adults with cancer at the “Turning the Tide Against Cancer Conference.” Photo by Liz Roll.

The vitalness of communication became painfully clear when she learned, by using Google, that the chemotherapy she was to undergo in less than a week would make her infertile. “I don’t want to criticize, but the absence of information felt like a breach of trust,” she told the meeting. “I understood that receiving chemotherapy was the priority and that fertility preservation wasn’t always a possibility, but I wanted to be part of the conversation.”

‘Something Called a Clinical Trial’ After fertility treatments, Ms. Jaouad went ahead with chemotherapy. But it soon became clear that the standard regimen was not working, and the cancer was growing more aggressive. She then “learned about something called a clinical trial,” and despite feelings of terror at being a guinea pig, decided with her doctor to go ahead. “At a time when everything seemed so uncertain, I craved hard facts, statistics, and proof that my cancer treatments were worth the havoc they wreaked on my mental and physical health,” she wrote in her column. “My doctors had no certain answers for me. After a few sleepless nights, I hesitantly agreed to try it. After all, I had very few other options left….” The cost of treatment is another issue with a special overlay for her age group. Like many young adults with cancer, she relied on her parents’ health insurance. But she would lose that at age 26. Even with that insurance, outof-pocket costs were high, and the time

was approaching when they could get much higher. The idea of discussing finances during a doctor’s appointment made her uncomfortable, she wrote. She found that she was not alone. But she also found a study suggesting that when patients do talk to their doctors about costs, ways are often found to reduce them. “Whether we’re too embarrassed or shy—or worried that a discussion about cost might affect the quality of our care—it’s clear that both doctors and patients need to do more communicating,” she wrote. “We talk about everything else, so why shouldn’t cost be a part of that conversation?” For 4 of the 8 months, Ms. Jaouad was hospitalized with infections, including septic shock. But the decision paid off. Her condition improved enough to make it possible to receive a bone marrow transplant (BMT). And from the BMT unit, she saw her first “Life, Interrupted” column and video published in The New York Times. In one column, she explained her decision to write about the world of young adults with cancer: “Isolated in the oncology ward, I began to think about my dream to become a writer. What could I possibly write about now? Where could I travel if I was stuck to an IV pole? Maybe the story wasn’t in a faraway land but right in front of me. I hadn’t chosen this story—it had chosen me. But I decided to accept the challenge.” n Disclosure: Ms. Jaouad reported no potential conflicts of interest.


In melanomaâ&#x20AC;Ś

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Dendritic cell

References: 1. Kaufman HL, Disis ML. J Clin Invest. 2004;113:664-667. 2. Klebanoff CA, Gattinoni L, Restifo NP. Immunol Rev. 2006;211:214-224. 3. den Boer AT, van Mierlo GJD, Fransen MF, Melief CJM, Offringa R, Toes REM. J Immunol. 2004;172:6074-6079.


AS THE ANTIGEN THAT ACTIVATES IT1

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Š2014 Amgen Inc. All rights reserved. 8/14 USA-678-100568


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 38

Turning the Tide Against Cancer Conference Issues in Oncology

Tackling the Complexity of Cancer: Finding Common Ground on Value and Progress By Margot J. Fromer

T

o kick off the second national Turning the Tide Against Cancer conference, sponsored by the American Association for Cancer Research, Personalized Medicine Coalition (PMC), and Feinstein Kean Healthcare, Edward Abrahams, PhD, President of PMC, noted that U.S. health-care costs are unsustainable and threatening future innovation. Cancer care, he said, is unnecessarily expensive ($173 billion a year by 2020), made more so by poor value and inefficient research and care delivery systems. Moreover, incidence will rise as the population ages, and costs will escalate out of control—until we might

Anna Barker, PhD

trials, and asked panelists to discuss approaches to repair, especially with regard to: • Defining value in cancer treatment: what prices are fair, how value judgments are made, and how the value of treatments evolves over time

The challenge is to sustain progress against 200 diseases while at the same time reduce overall spending. This imperative exists against a need to shift to a more patient-centric, high-value system of research and care delivery. Health care must become more efficient and effective. —Edward Abrahams, PhD

not be able to afford it at all. “The challenge is to sustain progress against 200 identifiable cancers while at the same time reduce spending. This imperative exists against a need to shift to a more patient-centric, high-value system of research and care delivery. Health care must become more efficient and effective.” These problems have existed for decades now, most policymakers and caregivers acknowledge them, innumerable conferences and roundtables discuss them and posit solutions—and little changes.

Tackling Complexity Anna Barker, PhD, Co-Director, Complex Adaptive Systems Initiative, Arizona State University, and a panel moderator, paraphrased Charles Dickens by noting that in cancer research and care, this is the best of times and the worst of times. “The best because science is now the best it’s ever been, and the worst because of the burden of the disease. The number of patients is mind-numbing, the costs worse.” She added that the system is “broken,” especially with regard to clinical

• Reforming clinical research: the overburdened, bureaucratic, rigid, and complex current system in which benefits are often not worth the difficulties encountered, and studies often fail for lack of accrual • Building a comprehensive system of research and care: gaining insights from research while protecting intellectual property rights and creating accessible open databases

Value and Patient Centrism Newton F. Crenshaw, Vice President, Lilly Oncology, and a survivor of non-Hodgkin lymphoma, said that what patients want most are innovative medicines that work, that is, significant-

Newton F. Crenshaw

ly extend their lives while keeping severe toxicity at bay. This means we need accessible clinical trials. He suggested one way to reduce barriers to such trials is by developing a user (patient)-centric design because patients tend to define the value of a trial as what turns out to be good for them. Lee N. Newcomer, MD, MHA, Senior Vice President, Oncology, Genetics, and Women’s Health, UnitedHealthCare, added that patient centrism is an old concept (“We have always taken histories and done physical examinations”), but the modern version of pa-

Lee N. Newcomer, MD, MHA

tient centrism is the necessity for evidence about the various inferences we make about treatment decisions. “We need trials to test those inferences.” Nevertheless, regardless of what their physicians advise, people apply their own values to what they decide to do. For instance, he noted that UnitedHealthcare charges a $50 copay for all oral cancer drugs, but despite this relatively low out-of-pocket cost, some people don’t fill the prescription if, for a variety of reasons and beliefs, they don’t see value in the drug. He noted that the combination of insurance premiums and out-of-pocket expenses for cancer treatment now requires about 50% of total household income— and in not too many years, it could increase to 100% without intervention. Lowell E. Schnipper, MD, Theodore W. and Evelyn G. Berenson Professor, Department of Medicine, Harvard Medical School, said that it’s not easy to define value in health care because it is such an individual, highly charged concept that depends on so many factors: cost, potential outcome, toxicity, longterm implications, and the like. Nevertheless, value assessment is part of what oncologists have to do to “mediate the treacherous sea that we call cancer— and evidence is the only way.” Patient-centric care, also called in-

Lowell E. Schnipper, MD

dividualized or personalized medicine, often works to patients’ detriment. “Doctors sometimes do too many procedures (scans, biopsies, surgery, etc) and prescribe diagnostics and medicines for the sake of profit rather than for the sake of value,” he added. This happens frequently enough in oncology that ASCO has begun publishing an annually updated list of the top five commonly used practices or interventions that do not contribute to quality patient care, as part of the American Board of Internal Medicine Foundation’s Choosing Wisely initiative (www.asco.org/ practice-research/top-five-list).

Research Data Sharing Dr. Newcomer said that clinical data resulting from comparative effectiveness research must be made available to the public—what he termed “democratization” of data. “A collaborative mindset requires that we scale back the intensity of competition so prevalent now. The more data you give away, the more you get back.” Mr. Crenshaw agreed. “We have to create incentives for companies to share the mountains of data they have collected from various sources over the years.” Dr. Schnipper noted that even 2 years ago, clinical trials resulted in clinically meaningful outcomes. This is no longer the case. “Researchers are confusing statistical significance with clinical meaning. We need a higher bar for trial results.” Moreover, he said, the clinical trial system is not representative of what’s really going on out there. That is, “real” patients often do not have the same characteristics as research subjects. Moreover, there are so many hurdles for prospective subjects to clear that “It’s easier to get into Harvard than a clinical trial,” he quipped. n Disclosure: Drs. Abrahams, Barker, Schnipper, Newcomer, and Mr. Crenshaw reported no potential conflicts of interest.


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 39

Turning the Tide Against Cancer Conference Issues in Oncology

The Ohio State and Moffitt Collaborate on ORIEN: Using Big Data to Accelerate Trials With a Cancer Research ‘Expressway’ By Margot J. Fromer

T

he Ohio State University Comprehensive Cancer Center and Moffitt Cancer Center have joined forces to create the Oncology Research Information Exchange Network (ORIEN), the largest collaboration of its kind designed to accelerate discoveries in cancer research. Members of this alliance of cancer centers will agree to use a common protocol and share data, primarily for research, that ultimately will lead to evidence-based decisions for clinical care. Patients are active participants. The endeavor was launched in May 2014, said Jeff A. Walker, MBA, Senior Executive Director for Administration, Arthur G. James Cancer Hospital–Richard J. Solove Research Institute, The Ohio State University, at the Turning the Tide Against Cancer Annual Conference, held recently in Washington, DC. Mr. Walker described the three guiding principles: • Inclusiveness: Participation by member cancer centers and their respective community networks • Data accessibility: Real-time access to research data through a hybrid model of a federated and central data warehouse. ORIEN members maintain ownership of their own data but agree to share limited data and may participate in projects that require more extensive data sharing. • Partnership building: Establishment of trusted business relationships across the public-private sector to achieve long-term program sustainability He explained that since the collaboration was formally announced, “We have received requests from several other [National Cancer Institute]–designated cancer centers to join. We are actively meeting with and evaluating each center and are anticipating that we will be able to announce others joining ORIEN in the coming months.”

More Than 100,000 Patients So Far As of the end of September, ORIEN has amassed donated tissue and clinical data from 113,370 people who provided 37,570 tumor or tissue samples and 16,279 gene-expression profiles. Data generated from these specimens include CEL files (created by Affymetrix DNA microarray image analysis software), targeted exome sequencing, whole-exome sequencing, whole-genome sequencing, single-nucleotide polymorphisms/ copy-number variations (lung, breast, and colon cancer), and RNA sequencing (breast cancer, myeloma). This all contributes to a program called Total Cancer Care. It is, said Mr.

data and follows them throughout their lifetime. ORIEN thus has access to one of the world’s largest clinically annotated cancer tissue repositories in the world.

National Cancer Database Up until now, there has been no efficient way to share insights gleaned from clinical and research data and no system to match cancer patients with the most effective ways to treat them. ORIEN has the potential to become a true national cancer database. It can provide physicians with evidence of the best therapeutic options, including clinical trial treatments specific to patients’ biologic and epidemiologic pro-

This is a collaborative effort that will speed drug discovery and provide patients with even more personalized treatment options—and better outcomes. —Jeff A. Walker, MBA

Walker, “a rapid learning environment that shares de-identified data to accelerate development of targeted treatments and allows researchers and clinicians to quickly match eligible patients to clinical trials in order to conduct larger and richer analyses.” Rapid learning is the ability to access a large, shared data warehouse to ask new research questions, develop more effective and competitive grant submissions, and participate in cross-institutional collaborations and biomarker discovery projects with academic institutions and pharmaceutical companies. Total Cancer Care, established by Moffitt in 2006, also tracks patients’ molecular, clinical, and epidemiologic

files. This will increase the likelihood of treatment efficacy, speed response time, and potentially minimize side effects. Mr. Walker noted that ORIEN will build upon Moffitt’s Total Cancer Care warehouse of genotypic and phenotypic data, as well as Ohio State’s depth and breadth in translating molecular- and genetic-based discovery protocols into more effective ways to detect and treat cancers.

Business Management ORIEN will be managed by M2Gen, a wholly owned for-profit subsidiary of Moffitt that will serve as its operational and commercial provider of informatics. M2Gen is in the business of infor-

matics, data management, clinical trial matching, and biobanking. It works with the pharmaceutical industry to identify new biomarkers and to seek opportunities for drug development and delivery. To this end, it can analyze data from all participating ORIEN centers to quickly match patients with molecular and genomic target-based clinical trials. It also performs pharmacovigilance and comparative effectiveness studies. ORIEN members can earn revenue through collaborations that would not otherwise be available to single cancer centers, such as grant funding, revenue stemming from shared intellectual property, and participation in M2Genindustry projects with biopharmaceutical companies. Mr. Walker said that ORIEN’s approach to clinical trial matching will provide an opportunity for pharmaceutical companies to modernize trial recruitment and design. Through M2Gen, industry researchers will be able to match their targeted drugs to patients who participate in ORIEN for the purpose of trial efficiency and flexibility. This should enable better identification of potential candidates for drug trials. He added that ORIEN means that, for the first time, there is a true national cancer database. “This is a collaborative effort that will speed drug discovery and provide patients with even more personalized treatment options—and better outcomes. Patients will be active partners in the lifelong study of their disease.” n Disclosure: M2Gen, which is managing ORIEN, is a wholly owned for-profit subsidiary of Moffitt that will serve as its operational and commercial provider of informatics. M2Gen is in the business of informatics, data management, clinical trial matching, and biobanking. It works with the pharmaceutical industry to identify new biomarkers and to seek opportunities for drug development and delivery.

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The ASCO Post  |   NOVEMBER 15, 2014

PAGE 40

FDA Update

FDA Grants Breakthrough Therapy Designation Pembrolizumab in Advanced Non–Small Cell Lung Cancer

P

embrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, pembrolizumab releases the PD-1

pathway–mediated inhibition of the immune response, including the antitumor immune response. Pembrolizumab is currently indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) and, if BRAF V600 mutation–positive, a BRAF inhibitor.

FDA Grants Breakthrough Therapy Designation The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to the anti–PD-1

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

therapy pembrolizumab (Keytruda) for the treatment of patients with epidermal growth factor receptor (EGFR) mutation–negative, and anaplastic lymphoma kinase (ALK) rearrangement–

negative non–small cell lung cancer (NSCLC) that has progressed on or following platinum-based chemotherapy. The Breakthrough Therapy designation in advanced NSCLC is supported

by data from the ongoing phase IB KEYNOTE-001 study, updated findings of which were recently presented at the European Society of Medical Oncology (ESMO) 2014 Congress. n


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 41

FDA Update

FDA Approves Labeling With Abuse-Deterrent Features for Extended-Release Opioid Analgesic

T

he U.S. Food and Drug Administration (FDA) has approved new labeling for morphine sulfate and naltrexone hydrochloride extendedrelease capsules. The drug, marketed

as Embeda, is an opioid analgesic used to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

The drug is the third extended-release opioid analgesic to be approved with labeling describing the product’s abusedeterrent properties. The new labeling includes a claim indicating that oral

We want to change the face of EGFR-targeted therapy Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are wellestablished side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014. 4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed August 26, 2014. Copyright © 2014 Clovis Oncology. DARO-101 8/14

abuse of the drug may be reduced, though not prevented, when the drug is crushed and taken orally or snorted.

Mode of Administration: Crushed vs Intact Embeda works by releasing only the morphine in the capsule when taken properly. When crushed, the naltrexone in the drug blocks some of the euphoric effects of the morphine and can precipitate withdrawal in persons dependent on opioids. When swallowed intact, however, Embeda can still be abused or misused because the naltrexone is not expected to substantially block the euphoric effects of the morphine. It is unknown whether the abuse-deterrent properties of the agent will result in a reduction in abuse by the intravenous route until additional postmarketing data are available.

Deterring Abuse and Managing Pain Public Priorities “Preventing prescription opioid abuse and ensuring that patients have access to appropriate treatments for pain are both top public health priorities for the FDA,” said Sharon Hertz, MD, Acting Director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA’s Center for Drug Evaluation and Research. “The science behind developing prescription opioids with abuse-deterrent properties is still evolving and these properties will not completely fix the problem. But they can be part of a comprehensive approach to combat the very serious problem of prescription drug abuse in the United States.”

Embeda Part of REMS Program The FDA is requiring postmarketing studies of Embeda to further assess the effects of the abuse-deterrent features on the risk for abuse of the drug and the consequences of that abuse. In addition, Embeda is part of the Extended Release/Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS), which requires companies to make available to health-care professionals educational programs on how to safely prescribe these opioid analgesics and to provide medication guides and patient counseling documents containing information on the safe use, storage, and disposal of these agents. For more information, visit http:// www.fda.gov/downloads/Drugs/DrugSafety/UCM179172.pdf. n


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ESMO Congress Gastrointestinal Oncology

All-RAS Testing in Metastatic Colorectal Cancer: Just the First Step By Caroline Helwick

N

ow that clinicians know to “think beyond KRAS” in metastatic colorectal cancer—and test for all RAS mutations, not just those in exon 2—it seems this is still not sufficient for selecting the best drugs. At the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, a proffered paper session was devoted solely to discussing the efficacy of monoclonal antibodies in the first-line setting for patients with all-RAS wild-type colorectal cancer.

Sebastian Stintzing, MD

Updated or extended analyses of the FIRE-3 trial and Cancer and Leukemia Group B (CALGB)/SWOG 80405 provided food for thought and fodder for discussion. The two phase III trials compared treatment approaches for chemotherapy plus cetuximab (Erbitux), which targets the epidermal growth factor receptor (EGFR), or bevacizumab (Avastin), directed against the vascular endothelial growth factor (VEGF). Which strategy is optimal remains an unresolved issue.

Updated FIRE-3 All-RAS Analysis While FIRE-3 demonstrated an overall survival gain with cetuximab

added to FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan), this was a secondary endpoint. RECIST response rate was the primary endpoint and was not different between the arms. Progression-free survival also did not differ between the two regimens.1 At the ESMO meeting, Sebastian Stintzing, MD, of the University of Munich in Germany, presented an independent radiologic review of the data. The study compared cetuximab and bevacizumab in combination with FOLFIRI in 592 patients with KRAS exon 2 wild-type colorectal cancer. Extended RAS analysis was performed on, and outcome data available for, 400 patients deemed to have all-RAS wildtype disease.2 “The independent [computed tomography (CT)] review demonstrated a significantly higher objective response rate in FOLFIRI-plus-cetuximab–treated patients, compared to those receiving FOLFIRI plus bevacizumab,” Dr. Stintzing reported. Response rates were 72.0% with cetuximab vs 56.1% with bevacizumab (P = .003). FOLFIRI plus cetuximab also was associated with greater early tumor shrinkage, defined as ≥ 20% change in diameter on the first CT image (6  weeks): 68.2% vs 49.1% (P = .0005). In both treatment arms, overall survival was significantly longer in patients who obtained early tumor shrinkage. Median depth of response (percentage of maximal tumor shrinkage at the nadir, compared to baseline) was 48.9% in the cetuximab arm and 32.3% in the

bevacizumab arm (P < .0001), and this also correlated with survival, Dr. Stintzing reported.

CALGB/SWOG 80405 In patients with surgically resected colorectal cancer who demonstrate no evidence of disease, disease-free survival can exceed 5 years, according to Alan Venook, MD, of the University of California, San Francisco, who presented a subset analysis of CALGB/SWOG 80405.3 He reported the outcomes of 180 patients who underwent resection with the potential of cure, following neoad-

The overall survival of more than 30 months in both arms [of CALGB/ SWOG 80405] sets a new benchmark for patients with metastatic colorectal cancer, which was achieved across a broad clinical trials network and suggests that the results apply in a variety of practice settings. —Heinz-Josef Lenz, MD

juvant chemotherapy with cetuximab or bevacizumab plus FOLFIRI or FOLFOX (leucovorin/5-FU/oxaliplatin), per physician’s choice. Of these patients, 132 at some point after surgery were deemed as having no evidence of disease. The median overall survival for this selected population of patients was 65 months, “almost 5½ years,” Dr. Venook reported.

Pivotal Trials in Metastatic Colorectal Cancer ■■ At ESMO 2014, updated or extended analyses were presented for two randomized phase III trials comparing cetuximab and bevacizumab, both given with chemotherapy, in the first-line setting for metastatic colorectal cancer. ■■ Independent radiologic review in FIRE-3 found that patients receiving cetuximab/FOLFIRI had significantly higher rates of response and early tumor shrinkage, and significantly deeper responses, compared to patients receiving FOLFIRI plus bevacizumab. ■■ An analysis of patients in CALGB/SWOG 80405 who underwent curative resection found that patients who achieved “no evidence of disease” status had a median overall survival of 5.5 years. ■■ Testing for RAS mutations in the CALGB/SWOG 80405 population revealed that 15% of patients with KRAS wild-type disease harbored additional RAS mutations beyond exon 2. In the all-RAS wild-type sample, median progression-free survival was almost 1 year and median overall survival exceeded 30 months, with no differences between the biologic treatment arms.

numerically higher, and we don’t know why at this point,” he said. “One thing this is not due to is response rate,” he continued. Investigator-assessed responses (not yet audited) were higher with cetuximab (66% vs 57%). “This is not surprising to us in the field, and is validated by FIRE-3,” he noted. The differences were only seen among patients treated with FOLFOX, which in accordance with North American practice included three-quarters of the patients. Among the resected patients who achieved “no evidence of disease” status and were assessable, however, response

Alan Venook, MD

“It is key to note that of those rendered free of disease, 81 (60%) got cetuximab as their biologic and fewer got bevacizumab. Though we see their median overall survival is the same (67 months with bevacizumab and 64 months with cetuximab), more patients went on to potentially curative resection on cetuximab. The difference is not statistically significantly different, but

rates were greater in the bevacizumab arm (82% vs 68%), though probably similar statistically, he said. Median disease-free survival for all resected patients was 16 months; median time to recurrence after randomization was 26 months and was similar for the two arms. With the full RAS mutational analysis, the investigators observed that outcomes were much better when patients with all-RAS wild-type disease were rendered disease-free. For this group, median overall survival was 78 months, vs 48 months for patients with RAS ­mutations. “Patients with mutations in KRAS or NRAS could still be rendered diseasefree, but after that point, they did not do as well as the RAS wild-type patients,” Dr. Venook explained. “These differences are perhaps suggestive of a different biology,” he speculated. “This subset of patients reaching [no evidence of disease] does well, and some do very well,” he concluded. “They appear more likely to reach [no evidence of disease] on cetuximab-containing regimens, but ultimately their outcomes are similar.” From this dataset, the investigators will further characterize the tu-


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ESMO Congress mors’ molecular profiles, exploring the depth of response, evaluating circulating tumor DNA, developing a model of curability, determining the prognostic impact of RAS mutations, and looking for differences between extreme responders and rapid ­progressors. The answers are most likely to come,

Dr. Venook suggested, by “combining, rather than contrasting, data sets across studies, including FIRE-3.”

Exploratory Analysis Another analysis of CALGB/ SWOG 80405 explored the treatment effect in patients with all-RAS wild-type colorectal cancer as determined by ex-

GAZYVA® (obinutuzumab) Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)]. • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation. 5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

panded RAS testing using BEAMing technology (beads, emulsion, amplification, magnetics). This sensitive test identifies mutant alleles with a prevalence ≥ 1% and can detect and enumerate mutant sequences down to a 1:10,000 ratio. Outcomes were analyzed for 526 patients lacking any mutation in RAS and

Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)]. For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication as is suggested here. 5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function, and fluid balance, and administer supportive care, including dialysis as indicated.

were presented at the ESMO meeting by Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.4 Using this highly accurate technology, the researchers found that 15% of patients originally identified as having continued on page 44

• Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)] The most common adverse reactions (incidence ≥ 10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 45 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA based therapy. Table 3 Summary of Adverse Reactions Reported with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days). Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered. 5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle. 5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4b % Grades % 3–4b % Injury, Poisoning and Procedural Complications Infusion related reactions

69

21

0

0

Blood and lymphatic system disordersc

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. 5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

GAZYVA + Chlorambucil n = 240

Adverse Reactions (MedDRAa) System Organ Class

Neutropenia

40

34

18

Thrombocytopenia

15

11

7

16 3

Anemia

12

4

10

5

Leukopenia

7

5

0

0

General disorders and administration site conditions Pyrexia

10

<1

7

0

Respiratory, thoracic and mediastinal disorders Cough

10

0

7

<1

a MedDRA coded adverse reactions as reported by investigators. b c

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms. Adverse events reported under ‘Blood and lymphatic system disorders’ reflect those reported by investigator as clinically significant. Table 4 Post-Baseline Laboratory Abnormalities by CTCAE Grade with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm GAZYVA + Chlorambucil n = 240

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia Lymphopenia Leukopenia Thrombocytopenia Chemistry Hypocalcemia Hyperkalemia Hyponatremia AST (SGOT increased) Creatinine increased ALT (SGPT increased) Hypoalbuminemia Alkaline Phosphatase increased Hypokalemia

77 80 84 47

46 40 36 14

53 9 12 50

27 2 <1 11

32

3

29

<1

31

5

17

2

29

8

11

2

28

<1

12

0

28

<1

18

<1

25

<1

14

0

22 16

<1 0

14 11

<1 0

13

1

4

<1


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ESMO Congress All-RAS Testing in Colorectal Cancer continued from page 43

KRAS wild-type disease had additional RAS mutations beyond exon 2. In the all-RAS wild-type sample, median progression-free survival was 11.3 months with bevacizumab/chemotherapy and 11.4 months with cetuximab/chemo-

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused. Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, anti-histamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and < 2% thereafter [see Dosage and Administration (2)]. Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm. Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3–4 and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The number of fatal hemorrhagic events was similar between the treatment arms, with 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1. Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of pre-existing cardiac conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

therapy, and median overall survival was 31.2 and 32.0 months, respectively. As in the primary analysis,5 there was no significant advantage of one drug over the other in these comparisons. “The overall survival of more than 30 months in both arms sets a new benchmark for patients with metastatic colorectal cancer, which was achieved

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth. 8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established. 8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients < 75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

across a broad clinical trials network and suggests that the results apply in a variety of practice settings,” Dr. Lenz said. Commenting on this largest expanded RAS analysis with a head-tohead comparison in colon cancer, Dr. Lenz added, “First-line therapy should reflect the treatment goal and concern for potential side effects.”

GAZYVA® [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

GAZYVA is a trademark of Genentech, Inc. 8/14 GAZ0002214501 © 2014 Genentech, Inc.

He continued, “ With additional data such as dose intensity, treatment duration, location, tumor shrinkage, second-line therapies, and additional biomarkers for anti-EGFR and anti-VEGF therapies, we might better understand the differences between FIRE‑3 and CALGB/SWOG 80405.” n Disclosure: Dr. Stintzing has received honoraria from Amgen, Merck, Roche, Sanofi, and travel expenses from Amgen, Merck, Roche, and Sanofi. Dr. Venook has received research support from Genentech/Roche, BMS, Lilly, and Novartis. Dr. Lenz reported serving on the advisory boards of Genentech/Roche, MerckKG, EMD, and BMS.

References 1. Heinemann V, von Weikersthal LF, Decker T, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised open-label phase 3 trial. Lancet Oncol 15:1065-1075, 2014. 2. Stintzing S, Modest DP, Fischer von Weikersthal L, et al: Independent radiological evaluation of objective response rate, early tumor shrinkage, and depth of responses in FIRE-3 (AIO KRK-0306). ESMO Congress. Abstract LBA11. Presented September 29, 2014. 3. Venook A, Niedzwiecki D, Lenz H, et al: CALGB/SWOG 80405: Outcome of patients treated with curative intent. ESMO Congress. Abstract LBA10. Presented September 29, 2014. 4. Lenz H, Niedzwiecki D, Innocenti F, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FY/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with expanded ras analyses untreated metastatic adenocarcinoma of the colon or rectum. ESMO Congress. Abstract 501O. Presented September 29, 2014. 5. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. ASCO Annual Meeting. Abstract LBA3. Presented June 1, 2014.

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PAGE 45

ESMO Congress EXPERT POINT OF VIEW

D

uring a special session at the ESMO 2014 Congress, additional analyses from the FIRE-3 and Cancer and Leukemia Group B (­CALGB)/ SWOG 80405 trial were presented, and an expert panel was charged with putting the findings into context.

Role of Subsequent Treatment Andrés Cervantes, MD, PhD, of University Hospital of Valencia, Spain, said the discordant overall survival results between the trials cannot be understood without detailed information on subsequent therapies. “In particular, the proportion of patients randomized to chemotherapy plus bevacizumab [Avastin] who never got cetuximab ­ ­[Erbitux] could be of importance in interpreting these results,” he said. “In a setting where more than 80% of patients get second-line therapy, it could imply that the sequence of treatments would not be relevant for overall survival. However, if the proportion of patients missing cetuximab in the second line is higher, the sequence of treatments could be very relevant,” he indicated. Dr. Cervantes also questioned the relevance of the higher response rate with cetuximab-containing regimens, and he called on the CALGB/SWOG investigators to analyze their data with respect to depth of response and early tumor shrinkage.

and convincing. The anti-EGFR story in first-line KRAS wild-type is less convincing, but appears to provide an advantage over chemotherapy alone. The anti-EGFR story in first-line RAS wildtype is convincing as compared to chemotherapy. And the anti-EGFR story in first-line RAS wild-type is convincing, vs bevacizumab,” he said. “That was the data up to now. Now we have new data,” he said. He found the FIRE-3 data “easy to interpret” and to have “strong internal consistency,” while finding the CALGB/SWOG data less so.

came out ahead in FIRE-3, as did panitumumab (Vectibix) in the PEAK trial. “But PEAK was a phase II trial, and both FIRE-3 and PEAK failed their respective endpoints and had overall survival only as a secondary endpoint. Therefore, the evidence of a survival benefit cannot be viewed as particularly strong,” he added. “The only trial with an appropriate design was CALGB/SWOG 80405, which showed a modest improvement with cetuximab. But in all the trials, the hazard ratios were below 1.0, and we must agree there’s something there,” Dr. Arnold sug-

The proportion of patients randomized to chemotherapy plus bevacizumab who never got cetuximab could be of importance in interpreting these results. —Andrés Cervantes, MD, PhD

Chemotherapy plus a biologic is a ‘must’ in the first-line setting, though the best combination may not yet be proven. —Fortunato Ciardiello, MD, PhD

Three Questions Alberto Sobrero, MD, of San Martino Hospital, Genoa, Italy, tried to square the findings with three questions: Are the data true? Are they relevant? And are they practice changing? “I analyzed the new data in light of five stories we already have in advanced colorectal cancer, for anti-VEGF and

Alberto Sobrero, MD

anti-EGFR agents,” he said. Reviewing published data from other studies, Dr. Sobrero concluded, “The bevacizumab story in first line is very strong and convincing. The antiEGFR story in third line is very strong

Regarding both trials, Dr. Sobrero said he would “wait for the complete data before challenging these strong stories.”

Decision-Making Still Complex Dirk Arnold, MD, PhD, of the Klinik fuer Tumorbiologie, Freiburg, Germany, commented on the emerging use of the RAS mutation as a biomarker. He noted that any RAS mutation is a negative predictive biomarker that eliminates candidates for anti-EGFR antibodies. “But the question is whether signals are so strong that we could potentially … say that not only does a negative biomarker exist— RAS mutation—but wild-type RAS may be a positive predictive marker for the anti-EGFR antibodies and may indicate patients for whom an anti-­EGFR antibody is preferable,” he said. That said, how convincing are all the data taken together? The CALGB/ SWOG trial found no difference between the biologics, but cetuximab

gested. “It may be about extent of benefit. FIRE-3 may be overstating it, and ­CALGB may be understating it.” “The data are somewhat in line with the thought that patients with wild-type RAS do slightly better with an anti-­EGFR antibody, but there are many open questions,” he continued. While one might question why the outcomes were different in the two trials, one might also question whether having further information on treatment characteristics “will change our clinical view of the data. I doubt it.” Decision-making in metastatic colo­ rectal cancer “remains complex,” requiring clinical characteristics, treatment aims, and molecular information. A greater understanding of molecular subtypes and further refinement of this heterogeneous population beyond RAS testing will lead to treatment advances, he said. Meanwhile, expanded RAS testing is a prerequisite for any use of an anti-EGFR antibody, and for RAS wild-type patients,

Dirk Arnold, MD, PhD

any chemotherapy/antibody combination is appropriate. Selection should take into account clinical factors and patient preferences. “We balance all factors. That is the art of oncology,” Dr. Arnold said.

Two Good Options Fortunato Ciardiello, MD, PhD, of Second University of Naples, Italy, said the studies demonstrate that “patients with RAS wild-type cancer have two good therapeutic options that should be offered sequentially in the first and second line—FOLFOX [leucovorin, fluorouracil (5-FU), oxaliplatin] or FOLFIRI [leucovorin, 5-FU, irinotecan] plus either an anti-EGFR monoclonal antibody or bevacizumab.” He continued, “In my opinion, FOLFIRI or FOLFOX with an anti-EGFR antibody is the preferred first-line choice if tumor shrinkage is a relevant therapeutic goal.” This includes high tumor burden, symptomatic disease, potential conversion to surgical resection of liver metastases or, possibly, of the primary tumor. “Tolerability, side effects, and informed discussion with the patient could be important aspects for first-line choices,” Dr. Ciardiello suggested. He called for research on the role of maintenance and the reintroduction of chemotherapy, appropriate sequencing of bevacizumab and anti-­ EGFR antibodies, and strategies to prevent or overcome acquired resistance to these biologics. “Whereas FIRE-3 data should be considered the final results of this trial, CALGB/SWOG research is still a work in progress, and we will get important information in the near future when additional analyses are completed,” he said. Meanwhile, he concluded, “Chemotherapy plus a biologic is a ‘must’ in the first-line setting, though the best combination may not yet be proven.” n

Disclosure: Drs. Cervantes and Arnold reported no potential conflicts of interest. Dr. Sobrero has served on advisory boards and as a speaker for Roche, Merck, Sanofi, Bayer, Amgen, Celgene, and Lilly. Dr. Ciardiello has received honoraria and/or research funds from Merck Serono, Roche, AstraZeneca, Bayer, and Astellas.


The ASCO Post  |   NOVEMBER 15, 2014

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ESMO Congress Gastrointestinal Oncology

European Studies Explore Maintenance Strategies for Metastatic Colorectal Cancer By Caroline Helwick

S

tudies presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid added insight regarding maintenance therapy in metastatic colorectal cancer, an area lacking a clear recommended strategy following first-line regimens. Two phase III trials found benefit for bevacizumab (Avastin)-based maintenance regimens but differed with regard to the value of a second maintenance drug. A third exploratory trial examined the benefit of cetuximab (Erbitux) monotherapy. Maintenance therapy with a fluoropyrimidine plus bevacizumab is a widely accepted strategy, having been shown to prolong progressionfree survival and delay second-line therapy, over a complete discontinuation of treatment. However, previous maintenance trials have failed to define a clear standard and have not prospectively compared different approaches. These studies sought to do that.

Bevacizumab/Erlotinib Combination The GERCOR DREAM trial in 452 colorectal cancer patients investigated bevacizumab at 7.5 mg/kg every 3 weeks vs bevacizumab plus erlotinib at 150 mg/d, until disease progression, following a standard induction regimen plus bevacizumab.1 The median duration of erlotinib therapy was short, at 3.6 months. In the final analysis, after a median 50-month follow-up, bevacizumab/ erlotinib was superior to bevacizumab monotherapy in terms of progressionfree survival and overall survival, according to Benoist Chibaudel, MD, of the Hôpital Saint Antoine in Paris. In the GERCOR DREAM final analysis, median progression-free survival was 4.9 months with bevacizumab alone and 5.9 months with bevacizumab/erlotinib (hazard ratio [HR] = 0.77, P = .012). Median overall survival after starting maintenance was 22.1 months and 24.9 months, respectively (HR = 0.79, P = .035), with benefit evident among all subgroups.

Dr. Chibaudel noted that postprogression therapy was similar in type and frequency between the arms. “The [epidermal growth factor receptor (EGFR)] antibody remained active in patients who received erlotinib before,” he noted. “The effect is observed whatever the KRAS status. Furthermore, a significant difference in response rate was observed during the chemotherapy-free maintenance therapy in KRAS-mutated tumors (19.7% vs 8.3%),” he added. He said that safety was acceptable, despite an increased incidence of skin rash (all grades, 89% vs 9%) and diarrhea (59% vs 14%). The results of GERCOR DREAM suggest that “bevacizumab and a short period of erlotinib therapy is a new treatment option in first-line therapy following induction chemotherapy with bevacizumab,” Dr. Chibaudel maintained.

not inferior to the standard of care (a fluoropyrimidine plus bevacizumab) as maintenance, after first-line induction with fluoropyrimidine/oxaliplatin/bevacizumab.2 Either strategy was better than no maintenance at all in prolonging remission, though neither improved overall survival, reported ­Susanna ­ Hegewisch-Becker, MD, PhD, of Hämatologisch-Onkologische Praxis Eppendorf (HOPE) in Hamburg, Germany. “Active maintenance treatment is

Bevacizumab Monotherapy

confirmed as standard for most patients, to improve [time to first progression].” she said. “However, the lack of a

In the AIO KRK 0207 trial, however, bevacizumab monotherapy was

Susanna Hegewisch-Becker, MD, PhD

EXPERT POINT OF VIEW

P

utting the maintenance trials into context was Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, who commented, “These studies inform our clinical practice and have a meaningful impact on how we treat our patients.”

DREAM Trial In the DREAM Trial, Dr. Grothey questioned the use of bevacizumab (Avastin) alone as the control arm as well as the heterogeneity of the induction regimens, but said “the results validate the trial design and make the study interesting.” Bevacizumab/erlotinib yielded a 23% reduction in progression, despite a very short duration of erlotinib treatment (median, 3.6 months), and the hazard ratio (HR) was similar for overall survival (HR = 0.79). “The study is remarkable in retaining the differences between the arms,” he said, though he cautioned that “the curves separate late and the delta is based on very few patients.” The similarity in postprogression

therapy suggests that this difference was driven by the short duration of therapy with erlotinib, a drug that has not shown efficacy as a single agent in colorectal cancer. Interestingly, no im-

AIO KRK 0207 The AIO trial contained an interesting three-arm design, but the noninferiority assumption was “too generous,” according to Dr. Grothey.

These studies inform our clinical practice and have a meaningful impact on how we treat our patients. —Axel Grothey, MD

pact from KRAS status was observed, Dr. Grothey pointed out. He noted that the bevacizumab/ erlotinib doublet is also showing interesting activity in other tumors. In non–small cell lung cancer, this regimen has reduced progression by 29% to 46% in recent studies. He concluded that the results of DREAM are “a bit puzzling” and warrant confirmatory studies.

“I am not a fan of looking for noninferiority. We are trying to get better outcomes for patients, and we should not be asking how much lower we should set the bar,” he commented. He felt the 24-week induction regimen was too long and suggested that the low rate of reinduction in the combination arm (21%) affected the primary endpoint. Nevertheless, the findings mirror

the guidelines and clinical practice, and further studies are not needed, he concluded. “We are validating that something for maintenance is better than nothing, and fluoropyrimidine/ bevacizumab is the winner here. For future maintenance studies, this regimen is the appropriate control arm.”

MACRO-2 The evaluation of the EGFR monoclonal antibody as maintenance therapy is interesting, and the findings are hypothesis-generating, said Dr. Grothey, who felt the results were “as expected” and that additional studies are warranted. “The results do not yet have implications for clinical practice, and this is clearly not a standard of care. One could question whether EGFR monoclonal antibodies are the right agents for longterm treatment,” he said. “We need to refine the population that can benefit.” n Disclosure: The Mayo Foundation has received funding from Genentech, Bayer, Pfizer, Eisai, and Eli Lilly for research conducted under Dr. Grothey’s leadership.


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 47

ESMO Congress clear overall survival benefit allows for individualized approaches.” The population included 852 metastatic patients who received 24 weeks of standard induction therapy. Among the 472 responders, the AIO KRK 0207 study investigated whether treatment discontinuation (ie, no maintenance) or continuation with bevacizumab alone was noninferior to maintenance with fluoropyrimidine/bevacizumab. Maintenance was followed by a planned reinduction of components of the induction regimen: any fluoropyrimidine with or without oxaliplatin or bevacizumab. Time to failure of strategy, the primary endpoint, was the time from randomization (ie, at the start of maintenance) to either the second progression after maintenance and reinduction, or for patients with progression but not receiving reinduction, time to the use of a new drug (ie, second-line therapy) or no further treatment. Progression-free survival (time to first progression) was a secondary endpoint, as was overall survival. Median time to failure of strategy was 6.5 months for the whole population, with no statistically significant differences among the arms. A trend favored fluoropyrimidine/bevacizumab vs no therapy (HR = 1.27, P = .054). There were no significant differences in overall survival among the arms, with a median overall survival of 23 months (P = .87). “Subgroup analyses failed to identify a group of patients with a greater or

lesser benefit with active maintenance with [fluoropyrimidine]/bevacizu­ mab,” she said. Time to first progression, from the start of maintenance, was significantly better for either active treatment vs no treatment (HR = 2.05, P < .0001 for flu-

single-agent bevacizumab was no better than no maintenance at all. The low rates of reinduction after first progression indicated “a very limited acceptance of this strategy,” she added. The study also showed that outcomes were not impacted by reducing

Bevacizumab and a short period of erlotinib therapy is a new treatment option in first-line therapy following induction chemotherapy with bevacizumab. —Benoist Chibaudel, MD

oropyrimidine/bevacizumab), but was not significantly different between the two active arms. A trend favored fluoropyrimidine/bevacizumab vs bevacizumab alone (6.2 vs 4.6 months, HR = 1.26, P = .061). “[Time to first progression] was significantly better with active treatment, whereas overall survival was not different,” Dr. Hegewisch-Becker said. “The benefit with active maintenance on [time to first progression] remained significant in all subgroups analyzed.” The study confirmed the prognostic impact of mutation status, showing that bevacizumab monotherapy was superior to no treatment (P < .001), and was as effective as combination treatment, among patients lacking mutations in RAS and BRAF. In patients with these mutations, the doublet was favored;

the dose or shortening the course of induction oxaliplatin, which can avoid cumulative neuropathy.

Cetuximab as Maintenance The phase II MACRO-2 trial found that cetuximab monotherapy was noninferior to the combination of modified fluorouracil/leucovorin/oxaliplatin (mFOLFOX) plus cetuximab after induction with mFOLFOX/cetuximab, according to Pilar Garcia Alfonso, MD, of the Gregorio Marañón Hospital in Madrid.3 In the noninferiority study, 193 patients were randomly assigned to receive mFOLFOX-6 plus cetuximab for eight

Maintenance in Colorectal Cancer ■■ Three studies presented at ESMO 2014 confirm the benefit of maintenance therapy in metastatic colorectal cancer. ■■ Two drugs were better than one in the final analysis of the GERCOR DREAM study. After a median 50-month follow-up, bevacizumab/erlotinib was superior to single-agent bevacizumab in terms of progression-free survival and overall survival. ■■ In the AIO KRK 0207 trial, single-agent bevacizumab was not inferior to the fluoropyrimidine/bevacizumab doublet as maintenance in time to failure of strategy and also progression-free survival. Either strategy was better than no maintenance at all in prolonging remission, though neither improved overall survival. ■■ In the phase II MACRO-2 trial, single-agent cetuximab was not inferior to mFOLFOX plus cetuximab after induction with mFOLFOX/cetuximab, in terms of 9-month progression-free survival.

Pilar Garcia Alfonso, MD

cycles, followed by the same regimen as maintenance, or to mFOLFOX-6 plus cetuximab for eight cycles, continuing only with single-agent cetuximab (250 mg/m2 weekly) as maintenance. The proportion of patients who were progression-free at 9 months— the primary endpoint—was 63.4% with single-agent cetuximab and 71.9% with mFOLFOX/cetuximab, which produced an odds ratio (OR) of 0.6827

that was not significantly different (P = .25), she reported. Median progression-free survival was 8.9 and 9.8 months (HR = 0.690, P = .09), median overall survival was 23.6 and 22.2 months (HR = 1.151, P = .54), and response rates were 46.5% and 39.1%, respectively (OR = 1.36, P = .33). Treatment-related adverse events were similar, except more neuropathy occurred with the combination. “The results of the present hypothesis-generating phase  II exploratory trial suggest that maintenance therapy with single-agent cetuximab following mFOLFOX plus cetuximab induction is not inferior to continuing treatment with mFOLFOX plus cetuximab,” Dr. Garcia Alfonso concluded. The study investigators do not recommend this approach at this time. “MACRO-2 is the first study to evaluate this and it suggests maintenance cetuximab is not inferior, but this must be confirmed in a phase III trial,” she said. n

Disclosure: Drs. Chibaudel, HegewischBecker, and Garcia Alfonso reported no potential conflicts of interest.

References 1. Chibaudel B, Tournigand C, Samson B, et al: Bevacizumab-erlotinib as maintenance therapy in metastatic colorectal cancer. Final results of the GERCOR DREAM study. ESMO 2014 Congress. Abstract 497O. Presented September 27, 2014. 2. Hegewisch-Becker S, Graeven U, Lerchenmueller C, et al: Maintenance strategy with fluoropyrimidines plus bevacizumab, bev alone or no treatment, following a 24-week first-line induction with FP, oxaliplatin and bev for patients with metastatic colorectal cancer: Mature data and subgroup analysis of the AIO KRK 0207 phase III study. ESMO 2014 Congress. Abstract 498O. Presented September 27, 2014. 3. Garcia Alfonso P, Benavides M, Sanchez Ruiz A, et al: Phase II study of firstline mFOLFOX plus cetuximab (C) for 8 cycles followed by mFOLFOX plus C or single agent C as maintenance therapy in patients with KRAS wild type metastatic colorectal cancer: The MACRO-2 trial (Spanish Cooperative Group for the Treatment of Digestive Tumors). ESMO 2014 Congress. Abstract 499O. Presented September 27, 2014.


For patients with bone metastases from solid tumors

Prevent bone complications longer In a prespecified integrated analysis of 3 pivotal trials (N = 5,723),

8.2

XGEVA® was proven to delay the median time to first bone complication by

months longer vs zoledronic acid1

XGEVA® is a convenient 120 mg subcutaneous injection administered once every 4 weeks.2

Bone complications, or skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2,3 Median Time to First Bone Complication1 27.7

months

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

XGEVA VA® 120 mg Q4W (n = 2,862) VA

19.5

months

zoledronic acid 4 mg Q4W (n = 2,861) 1 YEAR

HR* = 0.83 (95% CI: 0.76-0.90)

2 YEARS

P < 0.001

IMPORTANT SAFETY INFORMATION Hypocalcemia • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®. XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Hypersensitivity • XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA® therapy permanently.

*Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case a bone complication) for one group relative to that in a comparator group. P value for superiority.

Drug Products with Same Active Ingredient • Patients receiving XGEVA® should not take Prolia® (denosumab). Osteonecrosis of the Jaw • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.


XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. • RANK Ligand (RANKL) is produced by bone cells in the skeleton and is a key mediator of bone resorption4 • RANKL production is increased at sites of bone metastases, and stimulates osteoclasts to destroy bone4 • XGEVA® acts precisely to bind RANKL and inhibits osteoclast formation, function, and survival2 • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®2

Learn more at XGEVA.com

• Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA® therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity • XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

©2014 Amgen Inc. All rights reserved. 04/14 80218-R1-V1

• Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. Please see brief summary of Prescribing Information on the following page. REFERENCES: 1. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:3082-3092. 2. XGEVA® (denosumab) prescribing information, Amgen. 3. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:2215-2222. 4. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.

www.XGEVA.com


S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information

DOUS14CDNY4736_XGEVA_Tabloid_BS_V10_8pt_r13.indd 1

Body System GASTROINTESTINAL Nausea Diarrhea GENERAL Fatigue/ Asthenia IN VESTIGATIONS Hypocalcemiab Hypophosphatemiab NEUROLOGICAL Headache RESPIRATORY Dyspnea Cough

Xgeva n = 2841 %

Zoledronic Acid n = 2836 %

31 20

32 19

45

46

18 32

9 20

13

14

21 15

18 15

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes. • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva. Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. • Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy. USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. a

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation. Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated. Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth. Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake. Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a singleuse vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth • Persistent pain or slow healing of the mouth or jaw after dental surgery • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain • Pregnancy or nursing Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2014 Amgen Inc. All rights reserved. Printed in USA. 8/11/14 11:56 AM

S:13”

INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way. Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva. Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva. WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently. Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake. Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the

jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/ oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)


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PAGE 51

ESMO Congress Gastrointestinal Oncology

Phase III Study Confirms Regorafenib’s Survival Benefit in Metastatic Colorectal Cancer By Caroline Helwick

T

he phase III CONCUR trial1 of regorafenib (Stivarga) monotherapy in Asian patients with previously treated metastatic colorectal cancer confirmed the overall survival benefit seen in the previous C ­ ORRECT trial,2 and in a planned subgroup analysis, suggesting the benefit is substantial in patients not previously treated with a targeted agent. “CONCUR is the second phase III trial showing that regorafenib improves survival in patients with metastatic colorectal cancer who progress after standard therapies,” said Tae Won Kim, MD, of the University of Ulsan College of Medicine Asan Medical Center in Seoul, Korea. Dr. Kim presented the findings at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.

CONCUR Trial The multicenter study randomly assigned 136 Asian patients to regorafenib at 160 mg daily and 68 to placebo; regorafenib or placebo was administered daily at a schedule of 3 weeks on and 1 week off. In a planned subgroup analysis, the CONCUR investigators evaluated overall survival by prior targeted therapy (ie, drugs targeting the vascular endothelial growth factor [VEGF] or the epidermal growth factor receptor [EGFR]). The study met its primary endpoint, showing that regorafenib improved median overall survival from 6.3 months in the placebo arm to 8.8 months, a 45% reduction in the risk of death compared with placebo (P = .0002). In the CORRECT trial, median overall survival was 5.0 months and 6.4 months, respectively (hazard ratio [HR] = 0.77,

P = .0052). While approximately 60% of CONCUR patients received previous targeted therapy, in the CORRECT trial 100% had received previous antiVEGF agents and 51% had received anti-EGFR therapy. In the planned subgroup analysis of overall survival by prior targeted therapy, median survival was 9.7 months with regorafenib vs 4.9 months with placebo (HR = 0.31) in patients with no prior targeted therapy and was 7.4 months and 6.7 months, respectively (HR = 0.78) in the subset of those who had received any targeted agent.

Exploratory Analysis “The subgroup analysis of overall survival by prior targeted therapy generally favored regorafenib but may have been impacted by imbalances

Role of Regorafenib in Colorectal Cancer ■■ In Asian patients with previously treated colorectal cancer, single-agent regorafenib improved median overall survival from 6.3 months in the placebo arm to 8.8 months, a 45% reduction in the risk of death compared with placebo. ■■ In patients without prior treatment with a targeted agent, median overall survival was 9.7 vs 4.9 months, respectively (HR = 0.31). ■■ When censored at the time of starting subsequent postprogression therapy, patients without prior targeted therapy had a median overall survival of 10.6 months with regorafenib vs 4.8 months with placebo (HR = 0.27).

cohort to be 8.8 months in the regorafenib arm and 4.8 months in the placebo arm (HR = 0.41), and for patients who had received no prior targeted therapy (n = 82) it was 10.6 months vs 4.8 months, respectively (HR = 0.27). For patients who had received any prior targeted therapy (n = 122), median

CONCUR is the second phase III trial showing that regorafenib improves survival in patients with metastatic colorectal cancer who progress after standard therapies. —Tae Won Kim, MD

in poststudy anticancer treatments,” Dr. Kim noted. Such treatments were received by 31% of the regorafenib group compared to 43% of the placebo group. The investigators, therefore, conducted an exploratory post hoc analysis in which patients (n = 204) were censored at the start of subsequent treatment. This exploratory analysis found median overall survival for the overall

overall survival with regorafenib was 7.4 months vs 4.9 months with placebo (HR = 0.57). “The exploratory post hoc analysis of overall survival with censoring at the start of poststudy treatment favored regorafenib, irrespective of whether or not patients received prior anti-VEGF or prior anti-EGFR therapy,” he said. Dr. Kim acknowledged that the

subgroup sample sizes were small, that censoring in this exploratory analysis could be informative, and, therefore, that these results should be interpreted with caution. Adverse events in CONCUR were consistent with the known safety profile of regorafenib in metastatic colorectal cancer. Approximately 14% of patients in the regorafenib group and 6% in the placebo group discontinued treatment due to adverse events. n

Disclosure: Dr. Kim reported serving on advisory boards for Merck and AbbVie and receiving research funding from Bayer. For full disclosures of the study authors, visit www.esmo.org.

References 1. Kim T, Xu R, Yau T, et al: CONCUR: A randomized, placebo-controlled phase 3 study of regorafenib (REG) monotherapy in Asian patients with previously treated metastatic colorectal cancer (mCRC). ESMO 2014 Congress. Abstract 500O. Presented September 27, 2014. 2. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303-312, 2013.

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The ASCO Post  |   NOVEMBER 15, 2014

PAGE 52

ESMO Congress Supportive Care

Oral Rivaroxaban Has Efficacy Similar to Enoxaparin Plus Vitamin K Antagonist in Preventing Recurrent Venous Thromboembolism By Matthew Stenger

I

n a subgroup analysis of the pooled results of the EINSTEIN-DVT and EINSTEIN-PE trials reported at the 2014 European Society for Medical Oncology (ESMO) 2014 Congress and published recently in The Lancet Haematology, Martin H. Prins, MD, of Maastricht University Medical Cen-

treatment); of these, 354 received rivaroxaban, and 301 received enoxaparin/vitamin K antagonist.

Recurrence and Bleeding Among patients with active cancer, recurrent venous thromboembolism

was observed in 5% of rivaroxaban patients and 7% of enoxaparin/vitamin K antagonist patients (hazard ratio [HR]

Martin H. Prins, MD

tre, Maastricht, Netherlands, and colleagues found that the recurrence rate for venous thromboembolism in cancer patients receiving anticoagulant therapy with oral rivaroxaban (Xarelto) was similar to that in those receiving subcutaneous enoxaparin followed by vitamin K antagonist.1,2 Rivaroxaban was associated with less major bleeding but not less clinically relevant bleeding.

Study Details In the two trials, 8,281 patients with deep-vein thrombosis or pulmonary embolism were randomly assigned to receive rivaroxaban at 15 mg twice daily for 21 days followed by 20 mg once daily or standard therapy consisting of subcutaneous enoxaparin at 1.0 mg/kg twice daily and warfarin or acenocoumarol (target INR of 2.0 to 3.0). The trials included 655 patients with active cancer (at entry or diagnosed during

Rivaroxaban vs Enoxaparin/ Vitamin K in Prevention of Recurrent Venous Thromboembolism ■■ Oral rivaroxaban had efficacy similar to enoxaparin/vitamin K antagonist in preventing recurrence of venous thromboembolism and was associated with a lower rate of major bleeding. ■■ Recurrence rates were highest in patients diagnosed with cancer during the trials.

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 53

ESMO Congress = 0.67, 95% confidence interval [CI] = 0.35–1.30). Major bleeding occurred in 2% vs 5% (HR = 0.42, 95% CI = 0.18–0.99), and clinically relevant bleeding occurred in 14% vs 16% (HR = 0.80, 95% CI = 0.54–1.20).

Patients With Active Cancer Among patients in the trial without

active cancer but with a history of cancer, rates of recurrent venous thromboembolism were 2% among 233 patients in the rivaroxaban group vs 2% among 236 in the standard therapy group (HR = 0.98, 95% CI = 0.28–3.43), similar to the rates of 2% in 3,563 without cancer in the rivaroxaban group vs 2% of 3,594 without cancer in the stan-

dard therapy group (HR = 0.93, 95% CI = 0.66–1.30). Frequency of recurrence was higher both among patients with active cancer at baseline (2% of 258 vs 4% of 204, HR = 0.62, 95% CI = 0.21–1.79) and among those diagnosed with cancer during the studies (10% of 96 vs 12% of 97, HR = 0.80, 95% CI = 0.34–1.88).

Similarly, rates of major bleeding in patients with a history of cancer (< 1% vs 2%, HR = 0.23, 95% CI = 0.03–2.06) were similar to those in patients without cancer (1% vs 1%, HR = 0.58, 95% CI = 0.37–0.91), and higher in those with active cancer at baseline (2% vs 4%, HR = 0.47, 95% CI = 0.15–1.45) and those diagnosed with cancer during the studies (3% vs 7%, HR = 0.33, 95% CI = 0.08–1.31).

Summary

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

The investigators concluded: “In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number of major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular weight heparin in patients with cancer is warranted.” n

Disclosure: The study was funded by Bayer HealthCare Pharmaceuticals and Janssen Research & Development. Dr. Prins is a consultant advisor for Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Pfizer, Sanofi, Boehringer Ingelheim, GlaxoSmithKline (GSK), LEO, and ThromboGenics; For full disclosures of all of the study authors, visit www. thelancet.com.

References 1. Prins MH, Lensing AWA, Brighton TA, et al: Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism in patients with cancer. 2014 ESMO Congress. Abstract LBA48. Presented September 27, 2014. 2. Prins MH, Lensing AWA, Brighton TA, et al: Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): A pooled subgroup analysis of two randomised controlled trials. Lancet Hematol 1:e37-e346, 2014.

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The ASCO Post  |   NOVEMBER 15, 2014

PAGE 54

ESMO Congress Gastrointestinal Oncology

QUASAR2 Final Analysis: Bevacizumab Still of No Value in Adjuvant Treatment of Colorectal Cancer By Caroline Helwick

T

he final analysis of the international phase III QUASAR2 trial confirmed the lack of benefit for bevacizumab (Avastin) as part of the adjuvant treatment of colorectal cancer. “There is no role for bevacizumab in combination with capecitabine as adjuvant treatment for colorectal cancer,” said Rachel Kerr, MBChB, PhD, Associate Professor of Gastrointestinal Oncology at the University of Oxford in the United Kingdom,

mg/kg) for 16 cycles (48 weeks). At 3 years, the disease-free survival rate was 78.4% with capecitabine alone and 75.4% with capecitabine/bevacizu­ mab (P = .5), and overall survival was 89.4% vs 87.5% (P = .3), respectively, Dr. Kerr announced.

Prognostic Indicators “Studies have shown that a high tumor-stroma ratio in colorectal cancer predicts for worse prognosis, and we

There is no role for bevacizumab in combination with capecitabine as adjuvant treatment for colorectal cancer. —Rachel Kerr, MBChB, PhD

who presented the data at the European Society for Medical Oncology (ESMO) 2014 Congress.1 “This is not the happy ending we were hoping for in terms of bevacizumab as adjuvant treatment.” QUASAR randomly assigned 1,941 stage III and high-risk stage II colorectal cancer patients, postresection, to 8 cycles (24 weeks) of capecitabine or to capecitabine plus bevacizumab (7.5

postulated that this subset of patients may specifically benefit from therapy with bevacizumab. Although we were able to confirm a prognostic effect of tumor-stroma ratio, there was no evidence that this marker determined responsiveness to bevacizumab. In fact, subgroup analysis did not reveal a specific subpopulation that benefited,” she said. Microsatellite instability status

QUASAR2 Results ■■ The final analysis of QUASAR2 confirmed the lack of benefit when bevacizumab is added to capecitabine as adjuvant treatment for colorectal cancer. ■■ There were no significant differences in disease-free or overall survival. Overall survival at 3 years approached 90% in each arm. ■■ No subgroups were shown to have better outcomes with the addition of bevacizumab.

EXPERT POINT OF VIEW

I

n his discussion of the QUASAR2 presentation at the European Society for Medical Oncology (ESMO) 2014 Congress, Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, said the results “confirm what we know” and have no implications for clinical practice or for future clinical trials. The results are “as expected, with the exception of the [microsatellite instability] story,” he offered. The microsatellite Axel Grothey, MD instability interaction with treatment could warrant further evaluation but in the preclinical setting, he suggested. “QUASAR2 adds to the remarkably consistent negative results of adjuvant bevacizumab studies in multiple tumor entities,” Dr. Grothey noted. “One adjuvant lung cancer trial has not [been completed] yet, but I would not hold my breath.” While there remains some debate about whether the 12-month inhibition of the vascular endothelial growth factor (VEGF) receptor is simply too short, he said, “We will never know, because the door for bevacizumab has closed.” n

Disclosure: The Mayo Foundation has received funding from Genentech, Bayer, Pfizer, Eisai, and Eli Lilly for research conducted under Dr. Grothey’s leadership.

was not associated with differences in disease-free survival overall (P = .14); however, a greater treatment effect was seen in the microsatellite-stable group. “The results suggested that [microsatellite-stable] patients suffer a reduced disease-free survival when bevacizumab is added to single-agent capecitabine (hazard ratio = 1.43, P = .005),” Dr. Kerr indicated. The combination was associated with significantly more hypertension, proteinuria, and poor wound healing. “An excess of ‘possibly treatmentrelated’ deaths was found in patients

November Is

Pancreatic Cancer Awareness Month.

receiving bevacizumab (1.9% vs 0.9%, relative risk = 2.3), and this just reached significance (P = .05),” she added. n Disclosure: Dr. Kerr reported no potential conflicts of interest.

Reference 1. Midgley RS, Love S, Tomlinson I, et al: Final results from QUASAR2, a multicenter, international randomized phase III trial of capecitabine +/- bevacizumab in the adjuvant setting of stage II/III colorectal cancer. ESMO 2014 Congress. Abstract LBA12. Presented September 27, 2014.

See page 120 for a special report on pancreatic c­ ancer, featuring an interview with Margaret Tempero, MD.


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ESMO Congress Neuroendocrine Tumors

Clinically Relevant Survival Benefit Seen for Everolimus in Pancreatic Neuroendocrine Tumors By Alice Goodman

F

inal results from the RADIANT-3 trial showed a 6-month difference in overall survival favoring everolimus (Afinitor) plus best supportive care over placebo plus best supportive care in patients with well-differentiated advanced and progressive pancreatic neuroendocrine tumors.1 Although the difference between the two arms was not statistically significant, investigators said it was clinically relevant and noteworthy. “I think we are making some progress in pancreatic neuroendocrine tumors. The median overall survival of 44 months for everolimus is unprecedented in controlled clinical trials for advanced progressive pancreatic neuroendocrine tumors. The results affirm the importance of targeting key pathways involved in tumor growth, such as the mTOR pathway in advanced pancreatic neuroendocrine tumors,” stated lead author James C. Yao, MD, Professor in the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, in his presentation at the European Society for Medical On-

cology (ESMO) 2014 Congress. “The diagnosis of pancreatic neuroendocrine tumor is increasing,” Dr. Yao said. “Advanced pancreatic neuroendocrine tumor is incurable with a very poor prognosis. In 2011, everolimus

enrolled 410 patients from 18 countries. For the primary endpoint, median progression-free survival was 11 months with everolimus vs 4.6 months with placebo, a highly significant 65% reduction in risk of disease progres-

The results affirm the importance of targeting key pathways involved in tumor growth, such as the mTOR pathway in advanced [pancreatic neuroendocrine tumors]. —James C. Yao, MD

and sunitinib [Sutent] were approved for this indication. Before that, only one drug was available and therapeutic options were limited.”

Study Details RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors) was a pivotal phase III, randomized, placebo-controlled clinical trial that

EXPERT POINT OF VIEW

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ormal discussant of the RADIANT-3 trial at the European Society for Medical Oncology (ESMO) Congress, Alexandria Phan, MD, of Houston Methodist Cancer Center, agreed that the crossover to open-label everolimus (Afinitor) by placebo patients probably muddied the waters in the survival estimate. “The survival in the control arm reflects the beneficial effect of the study drug. This is a huge Alexandria Phan, MD selection bias. Since crossover usually occurs after disease progression, the endpoint affected the most is overall survival,” Dr. Phan told listeners. She said that the rank-preserving structural failure time analysis used in this study is the best method for adjusting for crossover bias in a randomized controlled trial. “This method assumes a common treatment effect in all patients,” she said. “The takeaway message for overall survival with everolimus is that without adjustment, it is at least 6.3 months longer than with placebo, and with adjustment, it is at most 23.4 months longer than with placebo,” she said. n Disclosure: Dr. Phan reported no potential conflicts of interest.

sion favoring everolimus (P < .001). “These data were presented previously, showing a 2.4-fold improvement in median progression-free survival,” he emphasized. At the ESMO Congress, Dr. Yao presented final overall survival and safety data for the first time. The study included patients whose tumors had well-differentiated histology. Patients were stratified according to prior chemotherapy and World Health Organization performance status and randomly assigned to placebo or everolimus. Placebo recipients were allowed to cross over to open-label everolimus at the end of the double-blind period or after disease progression. An intent-to-treat analysis found that median overall survival was 44 months for those initially assigned to everolimus and 37.7 months for those

on placebo. The high crossover rate from placebo to everolimus (85%) in the trial made it likely that a conventional intent-to-treat overall survival analysis would underestimate the survival benefit in the everolimus group, Dr. Yao explained. The investigators used a rank-preserving structural failure time estimate to adjust for survival time while on everolimus in patients who crossed over from the placebo arm. This analysis showed a survival benefit with everolimus (survival rates of 82.6% vs 74.9% at 12 months and 67.7% vs 55.6% at 24 months). No new safety concerns were reported in the final analysis. During the double-blind phase of the trial, stomatitis was reported in 54% of the everolimus group vs 13% of the placebo group. Other adverse events that occurred in at least 40% of patients receiving everolimus during the core phase of the trial were rash (53% vs 16%, respectively), diarrhea (48% vs 23.6%), and fatigue (44.6% vs 26.6%). n

Disclosure: Dr. Yao has served as a consultant to and has received research funding from Novartis. For full disclosures of the study authors, visit www.esmo.org.

Reference 1. Yao J, Pavel M, Lombard-Bohas C, et al: Everolimus (EVE) for the treatment of advanced pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results of a randomized, double-blind, placebo (PBO)-controlled, multicenter phase III trial (RADIANT-3). ESMO 2014 Congress. Abstract 1132O. Presented September 27, 2014.

RADIANT-3 Trial Results ■■ Final results of the RADIANT-3 trial show more than a 6-month survival benefit for everolimus vs placebo in advanced pancreatic neuroendocrine tumors. ■■ These results mirror progression-free survival reported earlier. ■■ Although the survival difference between treatment arms did not reach statistical significance, it was deemed clinically relevant and noteworthy. ■■ The 85% crossover rate from placebo to everolimus resulted in an underestimation of survival benefit in the everolimus arm.


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 56

ESMO Congress Genitourinary Oncology

Genomic Score Predicts Aggressiveness of Prostate Cancer in Biopsy Specimens By Alice Goodman

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prospectively designed study establishes the17-gene Oncotype DX prostate cancer test as a robust and independent predictor of the aggressiveness of prostate cancer based on a patient’s diagnostic specimen. Tumor aggressiveness, as measured by the test’s Genomic Prostate Score, was similar in African American and white men. “This study confirms the findings of a prior clinical validation study show-

Study Details The study included 402 men treated with radical prostatectomy between 1999 and 2011 at two U.S. military centers: Walter Reed National Military Center and Madigan Army Center. The Genomic Prostate Score was assessed from archival fixed paraffin-embedded needle biopsy tumor tissue, and the result was correlated with biochemical recurrence after surgery and with the finding of ad-

This study validates [the Genomic Prostate Score] as a strong and independent predictor of biochemical recurrence following radical prostatectomy within all subgroups defined by clinical and pathologic features, including race. —Jennifer Cullen, PhD, MPH

ing [the Genomic Prostate Score] as a predictor for adverse surgical pathology, a clinically actionable endpoint. The inclusion of genes representing multiple biologic pathways contributes to the robust predictive capacity of the assay. This assay should have clinical utility in informing decision-making regarding active surveillance vs immediate treatment for men with newly diagnosed prostate cancer,” said lead author Jennifer Cullen, PhD, MPH, Director of Epidemiology Research at the Center for Prostate Disease Research, Uniformed Services University, Rockville, Maryland.1 The results of this study have not been presented previously, she noted. “If this test is done on the biopsy specimen before surgery, it can help with first-line treatment decisions. It is appropriate for patients who are interested in pursuing a watch-and-wait approach to their disease, especially who appear to have clinically low-risk tumors. If the [Genomic Prostate Score] is low, it could support a decision to defer treatment. If the result is high, it indicates more aggressive disease and supports a decision in favor of immediate treatment,” she explained. “A majority of men are in this position: Can I delay treatment for my cancer? This test helps patients and physicians decide if immediate treatment is needed,” Dr. Cullen stated.

verse pathology at surgery. The primary aim of the study was to determine if the Genomic Prostate Score was associated with biochemical recurrence after surgery. The study showed that the score predicted a wide range of 5-year risk of biochemical recurrence and found

Genomic Prostate Score ■■ A 17-gene Genomic Prostate Score can predict the aggressiveness of prostate cancer from a biopsy specimen. ■■ The test score was similarly predictive in African American and white men. ■■ This score, while not yet reimbursable by most insurers, can help with treatment decisions for clinically low-risk men with prostate cancer.

that 25% of patients had a risk of less than 10% for a biochemical recurrence within 5 years of radical prostatectomy. “This study validates [the Genomic Prostate Score] as a strong and independent predictor of biochemical recurrence following radical prostatectomy within all subgroups defined by clinical and pathologic features, including race,” Dr. Cullen stated. In univariate analysis, the score was also associated with time to metastasis, she continued. In multivariate analysis adjusted for significant clinical and pathologic factors from the univariate analysis, Genomic Prostate Score was strongly associated with adverse pathology (P < .001), including both highgrade and non–organ-confined disease, in the overall cohort and within clinical and pathologic subgroups, including race and National Comprehensive Cancer Network risk groups.

Some unique aspects of this cohort of men include a high proportion of African American men, long-term subject follow-up with high retention rates, and an equal-access health-care setting. The Oncotype DX prostate cancer test is commercially available but not yet covered by most insurers, Dr. Cullen said. The data on biopsy specimens have not been presented previously, she noted. Genomic Health has a patient assistance program for patients interested in getting the test. n

Disclosure: Dr. Cullen has received research funding from Genomic Health.

Reference 1. Cullen J, Rosner I, Brand T, et al: A prospectively-designed study to determine the association of a 17-gene Genomic Prostate Score with recurrence following surgery for localized prostate cancer. ESMO 2014 Congress. Abstract LBA22. Presented September 28, 2014.

EXPERT POINT OF VIEW

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ormal discussant of the poster presented by Cullen et al at the ESMO Congress, Mark A. Rubin, MD, of Weill Cornell Medical Col-

cohort in the U.S. Army—African Americans, who tend to be understudied,” he said. “The study cohort included 20% who were African

[The study findings suggest] that we should start using these types of tests and that they should gain clinical access. —Mark A. Rubin, MD

lege, New York, said the Oncotype DX Genomic Prostate Score could be used to measure disease aggressiveness in paraffin-embedded prostatectomy and biopsy samples and should find use in the setting of active surveillance. “The poster describes a unique

American, which gets around the problem of equal access to health care for different racial groups. The important finding of this study is that using a score based on 17 genes, the assay can identify men with aggressive disease.”

Dr. Rubin continued, “This study is a nice example of biomarker development. The investigators paid careful attention as to how predictive this biomarker was in univariate and multivariate analyses.” A significant association was shown between Genomic Prostate Score and biochemical recurrence as well as aggressive pathology at surgery. “Also, no dramatic differences were observed between whites and African Americans,” he noted. “This study demonstrates in a large population with high ethnic diversity that the [Genomic Prostate Score] has a strong predictive ability to identify patients with high-risk disease. This suggests that we should start using these types of tests and that they should gain clinical access,” Dr. Rubin concluded. n

Disclosure: Dr. Rubin reported no potential conflicts of interest.


indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a doselimiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non– small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


Important Safety Information (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non–Small Cell Lung Cancer (NSCLC) Study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively • Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 04/14 US-ABR140005

Pancreatic Adenocarcinoma Study • See next page for most common adverse reactions • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

For more information, please visit www.abraxane.com.


ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

in first-line MPAC

ignite survival ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone 1.0

Median OS

0.9

ABRAXANE + gemcitabine (n=431)

Proportion of survival

0.8 0.7

Gemcitabine (n=430)

0.6 0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83)a

0.2

P<0.0001b

0.1 0.0 Patients at risk A+G: G:

0

3

6

9

12

15

18

21

24

27

30

33

36

39

431 430

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

STUDY DESIGN The multinational, randomized, phase 3 MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest period in Cycle 1, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with MPAC. The primary end point was OS.

Most common adverse reactions in the pancreatic adenocarcinoma study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)

• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)

ABRAXANE is also indicated in MBC and NSCLC ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. • The primary end point in the metastatic breast cancer (MBC) phase 3 trial was reconciled target lesion response rate (recTLRR) vs paclitaxel injection ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. • The primary end point in the NSCLC phase 3 trial was overall response rate (ORR) vs paclitaxel injection + carboplatin

Overall survival (secondary end point) was not statistically significant in the MBC and NSCLC trials vs comparator arms.

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)]. 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer. 2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

50

3

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count. Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)]. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%). In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%. Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)]. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_ALL_HCP_BSv007 10_2013


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ESMO Congress Gastrointestinal Oncology

Pazopanib Improves Progression-Free Survival in Advanced Pretreated GIST By Alice Goodman

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atients with gastrointestinal stromal tumor (GIST) can achieve remission on tyrosine kinase inhibitors, but almost all of them eventually develop resistance to these agents. The ­PAZOGIST trial results suggest that pazopanib (Votrient)—a broad-spectrum

Four-month progression-free survival was achieved in 47.7% of patients treated with pazopanib vs 19% for those in the best supportive care–alone arm. At the time of this analysis, 36 of 41 patients in the control arm had switched to pazopanib; in this group, after a me-

Pazopanib combined with best supportive care improves progressionfree survival in patients with GIST resistant to imatinib and sunitinib. —Jean-Yves Blay, MD, PhD

tyrosine kinase inhibitor—may be an effective option for patients who are resistant to or have disease progression on other tyrosine kinase inhibitors.1 “Pazopanib combined with best supportive care improves progression-free survival in patients with GIST resistant to imatinib [Gleevec] and sunitinib [Sutent],” stated lead author Jean-Yves Blay, MD, PhD, of Centre Léon Bérard, Lyon, France. “Pazopanib deserves further study in this setting.” Standard therapy is currently imatinib for first-line treatment, sunitinib for the second line, and regorafenib (Stivarga) for the third line. Previously, a small singlearm study in 25 unselected heavily pretreated patients with advanced GIST following failure of at least three treatments, including imatinib and sunitinib, showed “marginal activity [of pazopanib].” In that nonrandomized study, median progression-free survival was 1.9 months.2

PAZOGIST Trial PAZOGIST was a larger open-label phase II trial and the first randomized study of pazopanib in patients with advanced or metastatic GIST for whom imatinib and sunitinib therapy had failed. Patients were randomly assigned to receive pazopanib plus best supportive care vs best supportive care alone. In cases of disease progression, patients on the best supportive care arm could cross over to pazopanib. The primary endpoint was 4-month progression-free survival. Secondary endpoints included overall survival and overall response rates. Dr. Blay presented progression-free survival results at the European Society for Medical Oncology (ESMO) Congress in Madrid.

dian of 2.2 months following the switch, median progression-free survival was 3.6 months. From April 2011 to December 2013, 81 patients were randomly assigned to the two treatment arms. The majority of patients had primary tumors in the small

Role of Pazopanib in GIST ■■ The first randomized trial of pazopanib in heavily pretreated patients with advanced metastatic gastrointestinal stromal tumor shows a benefit in progression-free survival. ■■ These results suggest that further study of pazopanib in this setting is warranted. ■■ The design of future trials is important and should incorporate treatments aimed at the molecular environment at the time of disease progression.

intestine and stomach, more than 90% had mestastatic disease, about 45% had received two prior drugs, while about 55% had had more than two prior treatments. Both treatment arms were well balanced for disease and demographic characteristics. As would be expected, patients in the pazopanib arm had more adverse events, including gastrointestinal events and deterioration of global health ­status. n Disclosure: Dr. Blay has received research funding and honoraria from GlaxoSmithKline, Novartis, Roche, Pfizer, and Bayer.

References 1. Blay J, Domont J, Cropet C, et al: A randomized multicentre phase II study of pazopanib plus best supportive care versus best supportive care alone in metastatic gastrointestinal stromal tumors resistant to imatinib and sunitinib. ESMO Congress. Abstract LBA45. Presented September 29, 2014. 2. Ganjoo KN, Villalobos VM, Kamaya A, et al: A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumor following failure of at least imatinib and sunitinib. Ann Oncol 25:236-240, 2014.

EXPERT POINT OF VIEW

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ormal discussant of the PAZOGIST trial at the European Society for Medical Oncology (ESMO) 2014 Congress, Stefan Sleijfer, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, the Netherlands, said “The title of my talk is ‘Small Molecules: Greater Success,’ and we are not yet there.” He agreed with Dr. Blay that pazopanib (Votrient) deserves further study in patients with advanced gastrointestinal stromal tumor (GIST) but suggested that these studies be conducted using a mutational-profile treatment approach, adjusting for changes in driver mutations with disease progression. “The introduction of imatinib [Gleevec] was a miracle; median overall survival now exceeds 5 years, whereas before imatinib, it was 9 months. However, despite great success with this drug in first-line therapy, the vast majority of patients develop resistance. In the second- and third-line settings, response rates are lower and there is a need for novel therapies,” he noted. The best design of future trials should be based on the mutational drivers at the time of progression or resistance. “The drivers of GIST at diagnosis are c-KIT or [platelet-derived

growth factor receptor (PDGFR)alpha]. With a different molecular background at progression than at diagnosis, it is unlikely that one drug will produce stabilization after imatinib failure,” he said.

‘Playing Chess With Cancer’ “There are many considerations about what to do at disease progression, including combination treatments, in-

resistance. We need tools to assess mutational profile dominant clone and a randomized study comparing traditional treatment vs treatment based on mutational profile,” Dr. ­Sleijfer elaborated. “Pazopanib is a novel [tyrosine kinase inhibitor], and it deserves further study. The outcomes of this study are in contrast to the Ganjoo et al singlearm study. At first glance these results

Treatment should be adjusted based on molecular evolution of the tumor. —Stefan Sleijfer, MD, PhD

hibition of KIT signaling, and more precise targeting based on dominant clone. We are in essence playing chess with cancer,” Dr. Sleijfer commented. “In my view, treatment should be adjusted based on molecular evolution of the tumor. We have to identify which KIT mutations cause imatinib

are discordant, but the first study was conducted in a small number of heterogeneous patients. The study presented by Dr. Blay has a stronger design, and I agree that further study of pazopanib is warranted,” Dr. Sleijfer stated. n

Disclosure: Dr. Sleijfer has received research funding from GlaxoSmithKline and Novartis.


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ESMO Congress Hematology

Single-Agent Carfilzomib, Compared to Corticosteroids Plus Cyclophosphamide, Fails to Improve Survival in Myeloma By Caroline Helwick

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arfilzomib (Kyprolis), as a single agent, failed to improve survival in relapsed and refractory myeloma patients, as compared with a corticosteroid and optional cyclophosphamide, in the phase III FOCUS trial, presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.1 “Unfortunately, the FOCUS study did not meet its primary endpoint of prolonging overall survival in this heavily pretreated group of patients,” said Heinz Ludwig, MD, of Wilhelminen Cancer Research Institute in Vienna. Patients treated with carfilzomib had a median overall survival (the primary

tors allocated 315 patients with relapsed and refractory myeloma to single-agent carfilzomib (20 mg/m2 on days 1 and 2, followed by 27 mg/m2 on days 8, 9 , 15, and 16 of cycle 1, followed by 27 mg/m2 on days 1, 2, 8, 9, 15, and 16 for cycles 2–9, and on days 1, 2, 15, and 16 for cycles 10+) or low-dose corticosteroids, with or without oral cyclophosphamide (50 mg/ d)—95% received cyclophosphamide. Patients had received at least three prior regimens, and almost 30% were treated with more than six. In addition to the similar overall survival, median progression-free survival was also similar: 3.7 months in

Unfortunately, the FOCUS study did not meet its primary endpoint of prolonging overall survival in this heavily pretreated group of patients. —Heinz Ludwig, MD

endpoint) of 10.2 months, compared to 10 months in the placebo arm (hazard ratio [HR] = 0.975, P = .42). Carfilzomib was, however, superior in terms of objective responses, clinical benefit, and disease control. Dr. Ludwig and his colleagues believe the comparable outcomes are largely due to the better-than-expected survival in the placebo arm. “The trial was designed with the assumption that the control group would have a median overall survival of 6 months, based on historical reports,” he said. “The control arm performed better than expected.” He also said that contemporary regimens should include a corticosteroid, which was not done in the 2008-designed FOCUS trial. “Drugs in myeloma are not used as single agents. If dexamethasone had been introduced, the results may have been much better,” he predicted.

FOCUS Details The randomized phase III FOCUS trial aimed to show an overall survival benefit in end-stage patients. Investiga-

the carfilzomib group and 3.3 months in the control arm (HR = 1.091, P = .25). Significant benefits were observed with carfilzomib, however, in objective response rate (19.1% vs 11.4%, P = .03), clinical benefit rate (31.2% vs 20.9%, P = .02), and disease control rate (75.8% vs 67.7%, P = .05). There was a tendency for the carfilzomib group to have prolonged time to the next antimyeloma therapy (7.1 vs 5.7 months) and to be less likely to be censored because of this (7.6% vs 20.3%), he added. Time to treatment failure (progression-free survival events and nonprotocol therapy) was 3.4 and 2.2 months, respectively.

Safety of Carfilzomib The safety profile of single-agent carfilzomib was consistent with previous studies in heavily pretreated patients, except for renal impairment events. Grade ≥ 3 treatment-emergent adverse events occurred in 75.2% of the carfilzomib arm and 71.2% of the control arm, which were serious in 58.6%

Single-Agent Carfilzomib in Relapsed/Refractory Myeloma ■■ The phase III FOCUS study compared carfilzomib as a single agent to dexamethasone and cyclophosphamide. ■■ The trial did not meet its primary endpoint of improving overall survival: median overall survival was 10.2 months with carfilzomib and 10 months with placebo.

and 51.0% and led to discontinuation of a study drug in 14.6% vs 20.3%. Cardiac toxicity was not increased with carfilzomib, and peripheral neuropathy rates were low, approximately 4% per arm. More grade ≥ 3 acute renal failure events, however, were observed with carfilzomib (17.2% vs 5.2%), but in both arms, they occurred more often in patients with lower baseline creatinine clearance. Also, more patients with renal impairment or acute renal failure had light chain proteinuria or urine protein eletrophoresis positivity.

Future Directions Dr. Ludwig said the results of this study are not in line with “exciting” emerging data. “Carfilzomib-based combinations are promising,” he noted. Citing recent studies, he said that in treatment-naive patients, carfilzomib plus lenalidomide (Revlimid) and low-dose dexamethasone led to a 100% response rate, 3-year overall survival of 100%, and 3-year progression-free sur-

Faith Davies, MD

vival of 79.6%.2 In relapsed/refractory patients, increasing the dose of carfilzomib (from 20 mg/m2 to 56 mg/ m2) plus low-dose dexamethasone was associated with a 55% response rate in relapsed patients.3 In the phase  III ASPIRE study, carfilzomib/lenalido­ mide/low-dose dexamethasone yielded an 8.7-month improvement in progres-

sion-free survival, vs lenalidomide/lowdose dexamethasone.4 Faith Davies, MD, of the University of Arkansas for Medical Sciences, Little Rock, noted in her discussion that carfilzomib is “an effective treatment with a good safety profile.” The FOCUS study indicates the “difficulties in developing a drug in the relapsed/refractory myeloma space,” she suggested. She noted there is no standard control arm for studies, and in this case, the 10-month median survival in the sixth line of treatment “seems very good.” She reiterated Dr. Ludwig’s point: Single agents are not used in this population. n

Disclosure: Drs. Ludwig and Davies reported no potential conflicts of interest.

References 1. Ludwig H, Masszi T, Pertucci MT, et al: Carfilzomib vs low-dose corticosteroids and optional cyclophosphamide in patients with relapsed and refractory multiple myeloma: A phase 3 study (FOCUS). ESMO 2014 Congress. Abstract LBA28. Presented September 29, 2014. 2. Dytfeld D, Jasielec J, Griffith KA, et al: Carfilzomib, lenalidomide, and lowdose dexamethasone in elderly patients with newly diagnosed multiple myeloma. Haematologica 99:e162-e164, 2014. 3. Papadopoulos KP, Siegel DS, Vesole DH, et al: Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. September 15, 2014 (early release online). 4. Amgen: Amgen announces phase 3 ASPIRE trial of Kyprolis® in patients with relapsed multiple myeloma met primary endpoint. Press release. August 4, 2014. Available at wwwext.amgen.com. Accessed October 23, 2014.


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ESMO Congress Thoracic Oncology

Emerging Drugs Effectively Tackle Non–Small Cell Lung Cancer Mutations By Caroline Helwick and Alice Goodman

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or advanced nonsquamous non– small cell lung cancer (NSCLC), targeting of the epidermal growth factor receptor (EGFR) mutation and the ALK abnormality has become an established strategy. Later-generation drugs in these categories are now showing efficacy in trials, including for the treatment of resistant disease. In addition, promising data are emerging for compounds that target less common mutations. These advances are demonstrated by the results seen in studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.

AZD9291 in NSCLC The investigational drug AZD9291 holds promise for the treatment of EGFR mutation–positive, T790Mpositive advanced NSCLC in patients whose disease has progressed after treatment with an EGFR tyrosine kinase inhibitor. The ongoing AURA phase I and

James Chih-Hsin Yang, MD, PhD

extension study has enrolled 253 pretreated patients, and the 80-mg dose is going forward in a separate study.1 A preliminary analysis of the phase I and extension trial showed that pretreated patients with progressive disease who received AZD9291 had a median progression-free survival of 9.6 months, but these data are still immature and are based on the first 138 patients enrolled in the trial, noted lead author James Chih-Hsin Yang, MD, PhD, of National Taiwan University College of Medicine, Taipei. “We are confident that the progression-free survival will be even longer, given that most patients are still censored before the estimated median time,” he said. AZD9291 is a highly selective, irreversible inhibitor of both the activating EGFR mutation and the T790M mutation, which is thought to be responsible for resistance in about half of all patients with EGFR-positive advanced NSCLC. Thus far, no treatments are specifically approved for EGFR mutation–positive,

T790M mutation–positive patients. The drug has been given Breakthrough Therapy designation, as well as Orphan Drug and Fast Track status by the U.S. Food and Drug Administration (FDA).

These findings show the longest median [progression-free survival] we have seen in this broad [NSCLC] patient population, and it is even more striking when you consider that most of them have had up to three rounds of chemotherapy before taking ceritinib as their first ALK inhibitor.

Ceritinib in ALK-Positive NSCLC Data from the pivotal ASCEND-1 trial show that patients with ALK-positive NSCLC treated with ceritinib (Zykadia) as their first ALK inhibitor had a median progression-free survival of more than 18 months.2 Overall data from this study of 246 patients show that ceritinib is efficacious in patients whether or not they received a previous ALK inhibitor. In addition, ceritinib is active in patients with brain metastases and may be an effective therapy for this difficult-to-treat site of disease progression, shrinking brain tumors in about one-third of the 29 patients who entered the study with measurable brain lesions. “These findings show the longest median [progression-free survival] we have seen in this broad patient population, and it is even more striking when you consider that most of them have had up to three rounds of chemotherapy before taking ceritinib as their first ALK inhibitor,” said lead author Enriqueta Felip, MD, PhD, of Vall d’Hebron University, Barcelona. In the main trial (including both ALK inhibitor–pretreated and notpretreated patients), ceritinib achieved an overall response rate of 61.8% and median progression-free survival of 9 months in all patients. Among 83 patients who had not received a previous ALK inhibitor, overall response rate was 72.3% and median progressionfree survival was 18.4 months. Among a subset of 163 patients who were pre-

—Enriqueta Felip, MD, PhD

viously treated with the ALK inhibitor crizotinib (Xalkori), overall response rate was 56.4% and median progression-free survival was 6.9 months. Ceritinib is approved by the FDA for the treatment of patients with ALKpositive metastatic NSCLC who have had disease progression on or are intolerant to crizotinib.

and the BRAF V600E mutation represented 80% of the BRAF mutants. The multicenter, open-label phase II BRF113928 trial, involving 70 sites in 11 countries, enrolled 78 NSCLC

Targeting the BRAF V600E Mutation In patients with BRAF V600E mutations, the BRAF inhibitor dabrafenib (Tafinlar) has become the first drug of its class to demonstrate clinically meaningful antitumor activity and durable responses, according to a study presented by David Planchard, MD, PhD, of Gustave-Roussy in Villejuif, France.3 “NSCLCs with BRAF V600E mutations have histologic features suggestive of an aggressive tumor, and patients with these mutations demonstrate less favorable outcomes with platinum-based chemotherapy,” Dr. Planchard indicated. The Lung Cancer Mutation Consortium has indicated that BRAF V600E mutations occur in < 2% of adenocarcinomas,

New Drugs Targeting NSCLC Mutations ■■ In the phase I/II AURA trial, pretreated NSCLC patients with EGFR mutations had a median progression-free survival of 9.6 months, after treatment with AZD9291. ■■ Data from the pivotal ASCEND-1 trial show that patients with ALK-positive NSCLC treated with ceritinib as their first ALK inhibitor had a median progression-free survival exceeding 18 months. ■■ In patients with BRAF V600E mutations, the BRAF inhibitor dabrafenib has demonstrated clinically meaningful antitumor activity and durable responses. In the phase II BRF113928 trial, partial responses were observed in 32% and stable disease in 24% of patients, for a disease control rate of 56%. ■■ In the PUMA-NER-4201 study of advanced NSCLC patients with documented HER2 mutations (most with prior treatment), neratinib combined with temsirolimus achieved partial responses in 21% and stable disease in 79%.

David Planchard, MD, PhD

BRAF V600E–mutated patients who had received at least one prior line of treatment. Patients received dabrafenib at 150 mg twice daily. Investigator-assessed best confirmed responses included partial responses in 32% and stable disease in 24% of patients (14% were not evaluable), for a disease control rate of 56%. Response rates appeared to be higher in nonsmokers. All but a few patients actually had a reduction in tumor burden but did not meet the criteria of ≥ 30% reduction in diameter (to be labeled responders), he added. “We saw that 52% of the partial responses are still ongoing,” he said. The median duration of response was 11.8 months, and median progression-free survival was 5.5 months, with 62% of patients having had disease progression or died. “The safety profile was manageable and generally consistent with previous studies in melanoma,” Dr. Planchard reported. The most common adverse events were pyrexia, asthenia, hyperkeratosis, decreased appetite, nausea, cough, fatigue, and skin papilloma. Cutaneous squamous cell carcinomas and keratoacanthomas were reported in 18% of patients. A second cohort is to be treated with dabrafenib plus the MEK inhibi-


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ESMO Congress tor trametinib (Mekinist), and this arm is actively recruiting. Dr. Planchard indicated that a larger phase III trial may not be feasible, considering the rare occurrence of this abnormality.

Targeting the HER2 Mutation Similar to the frequency of BRAF mutations, somatic HER2 mutations occur in about 2% of NSCLC patients, mostly in tumors with adenocarcinoma histology. Comprehensive molecular profiling suggests that HER2 mutations are mutually exclusive of other driver aberrations in NSCLC, including KRAS, EGFR, and ALK. The most common type of HER2 mutations are in-frame insertions within the kinase domain, according to Benjamin Besse, MD, also of the Institut Gustave-Roussy. The investigational agent neratinib is a potent, irreversible, pan-HER tyrosine kinase inhibitor that has been shown to inhibit the growth of tumor xenografts that harbor aberrant HER2 pathway activation. Preclinical and phase I data suggest there may be synergistic efficacy with combined HER2 and mTOR

inhibition, in HER2 mutation–positive NSCLC, Dr. Besse indicated. The PUMA-NER-4201 study included 27 advanced NSCLC patients with documented HER2 mutations; all but two patients had received prior treatment.4 In the first stage of the study, patients were randomly assigned to neratinib at 240 mg/d or neratinib plus the mTOR inhibitor temsirolimus (Torisel) at 8 mg/wk. In the absence of toxicity, the dose was increased to 15 mg/wk for cycle 2. Crossover from single-agent neratinib was allowed after disease progression. Antidiarrheal prophylaxis was given to all patients. The study design calls for expansion to a second stage with 39 patients if there are two or more responders at 12 weeks. At the ESMO meeting, Dr. Besse presented the stage 1 analysis. In the neratinib/temsirolimus combination arm, partial responses were observed in 21% and stable disease in 79%; no patients demonstrated progressive disease. With neratinib alone, there were no responders, and 54% of patients had stable disease. Median progression-free survival was 4.0 months vs 2.9 months,

respectively, Dr. Besse reported. The median duration of treatment was 17.5 weeks with the combination and 9.1 weeks with neratinib alone. Dose reductions or holds were necessary for neratinib in 13 of 14 patients in the combination arm compared with 6 of 13 patients in the single-agent arm. For temsirolimus, 9 of 14 patients had doses withheld. “We observed no apparent correlation between HER2 mutation type and response,” he said. Five patients in the neratinib arm have crossed over to receive the combination, and of them, one is still on treatment while four have had disease progression. n Disclosure: Dr. Yang serves on advisory boards for Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, and Clovis Oncology and has received research support from Boehringer Ingelheim. Dr. Felip has served on advisory boards for Boehringer Ingelheim, Novartis, Roche, Bristol-Myers Squibb, and Lilly. Dr. Planchard has received personal fees for participating in advisory boards from AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, and Bristol-Myers

Squibb. Dr. Besse has received research grants from Puma.

References 1. Yang JC, Kim D, Planchard D, et al: Updated safety and efficacy from a phase I study of AZD9291 in patients with EGFRTKI-resistant non-small cell lung cancer. ESMO Congress. Abstract 449PD. Presented September 27, 2014. 2. Felip E, Kim D, Mehra R, et al: Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)rearranged non-small cell lung cancer: An update of ASCEND-1. ESMO Congress. Abstract 1295P. Presented September 27, 2014. 3. Planchard D, Kim TM, Mazieres J, et al: Dabrafenib in patients with BRAF V600Emutant advanced non-small cell lung cancer: A multicenter, open-label phase II trial (BRF113928). ESMO Congress. Abstract LBA38_PR. Presented September 29, 2014. 4. Besse B, Soria J-C, Yao B, et al: Neratinib with or without temsirolimus in patients with non-small cell lung cancer carrying HER2 somatic mutations: An international randomized phase II study. ESMO Congress. Abstract LBA39_PR. Presented September 29, 2014.

Multidisciplinary Symposium in Thoracic Oncology Lung Cancer

Postoperative Radiation Therapy Improves Overall Survival for Patients With Resected Pathologic N2 Non–Small Cell Lung Cancer

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atients who received postoperative radiation therapy lived an average of 4 months longer when compared to the patients who had the same disease site, tumor histology, and treatment criteria and who did not receive postoperative radiotherapy, according to research presented at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.1 This study reviewed the records of patients with non–small cell lung cancer (NSCLC) treated from 2004 to 2006 from the National Cancer Data Base. The study authors acquired the data for patients who had surgically

resected NSCLC with pathologically involved N2 lymph nodes and who received chemotherapy.

Key Data The database was further queried to exclude patients with positive margins, incomplete survival data, those who did not receive adjuvant chemotherapy, histology other than NSCLC, and patients treated with cobalt-60, nonbeam radiotherapy or neoadjuvant radiotherapy. A total of 2,115 patients met all study criteria. About 43% (n = 918) received postoperative radiotherapy, and 56.6%

Postoperative Radiation Therapy for Patients With Resected Pathologic N2 NSCLC ■■ Patients with resected pathologic N2 NSCLC treated with postoperative radiotherapy had an improved median overall survival of 42 months, vs 38 months for those who did not receive postoperative radiotherapy (P = .048). ■■ Multivariable analysis revealed that female gender, adenocarcinoma histology, higher income, urban/rural vs metropolitan setting, lower T stage, one to two involved lymph nodes vs at least three, and younger age correlated with better overall survival (P < .05).

(n = 1,197) were not treated with postoperative radiotherapy. Factors associated with overall survival were assessed through a multivariable Cox proportional hazards model. Inverse probability of treatment weighting using the propensity score was also implemented to reduce biased treatment selection. Using an adjusted Kaplan-Meier estimator and the weighted log-rank test, patients treated with postoperative radiotherapy had an improved median overall survival of 42 months compared to 38 months for the patients not treated with postoperative radiotherapy (P = .048). Multivariable analysis revealed that female gender, adenocarcinoma histology, higher income, urban/rural setting vs metropolitan setting, lower T stage, one to two involved lymph nodes vs at least three examined and involved lymph nodes, and younger age correlated with better overall survival (P < .05). No direct relation was found between the effects of postoperative radiotherapy and the number of involved lymph nodes.

Implications for Practice “These results reinforce the value of [postoperative radiotherapy] for non– small cell lung cancer patients with involved mediastinal lymph nodes. Our data indicate that with modern radiotherapy equipment and treatment techniques, [postoperative radiotherapy] can improve survival for these patients,” said John L. Mikell, MD, lead study author and Chief Resident in the Department of Radiation Oncology at Emory University Winship Cancer Institute in Atlanta. “The data in this study, the largest, most recent cohort of patients with involved mediastinal nodes treated with chemotherapy, reinforce that [postoperative radiotherapy] should be considered in addition to chemotherapy following resection of non– small cell lung cancer,” he said. n Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Mikell JL, et al: Abstract 128. 2014 Multidisciplinary Symposium in Thoracic Oncology. Presented October 30, 2014.


For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed on or after prior fluoropyrimidineor platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe

events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.


CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly delayed disease progression1 MAJOR OUTCOME MEASURE

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

Placebo

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.8

OS PROBABILITY

CYRAMZA

0.6

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

4

238 117

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

5

154 66

92 34

49 20

17 7

• The percentage of deaths at the time of analysis was 75% (179 patients) and 85% (99 patients) in the CYRAMZA and placebo arms, respectively1

7 4

3 2

37%

• Median progression-free survival (PFS) with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1 — The percentage of events at the time of analysis was 84% (199 patients) and 92% (108 patients), respectively The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measure was PFS. All patients were Eastern Cooperative Oncology Group Performance Status 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg every 2 weeks + best supportive care (BSC) (n=238) or placebo + BSC (n=117).1 CI=confidence interval.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZAtreated patients vs 8.7% of patients who received placebo. • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZAtreated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. • As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZAtreated patients with post-baseline serum samples tested positive for anti-ramucirumab antibodies using an enzymelinked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant. • Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility. Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page. RB HCP ISI 21JUL2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

Visit CYRAMZAhcp.com RB92521 08/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.


CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CYRAMZA as a single agent was evaluated in 570 patients, including patients in Study 1 who received CYRAMZA. Study 1 randomized patients (2:1) to receive CYRAMZA 8 mg/kg intravenously every two weeks (n=236) versus placebo every two weeks (n=115) in a double-blind, placebo-controlled trial in previously treated gastric cancer. In Study 1, patients with an ECOG performance status of 2 or greater, bilirubin greater than or equal to 1.5 mg/dL, uncontrolled hypertension, major surgery within 28 days, or receiving chronic anti-platelet therapy other than once daily aspirin were excluded. Patients received a median of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months. In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo. Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 (MedDRA)a All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0. Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo). Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In  Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients.  Two patients discontinued CYRAMZA due to proteinuria.  The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay TM

CYRAMZA (ramucirumab) injection

PA000IPAM00-BS 9.25x13.25

methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal drug interaction studies have been conducted. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent. Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over. Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab. Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus. Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment. Additional information can be found at www.CYRAMZAhcp.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2014, Eli Lilly and Company. All rights reserved. RB HCP BS 21JUL2014 CYRAMZATM (ramucirumab) injection

PA000IPAM00-BS 9.25x13.25


ASCOPost.com  |   NOVEMBER 15, 2014

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ESMO Congress Thoracic Oncology

IMPRESS Trial continued from page 1

combine it with platinum-based doublet chemotherapy, Dr. Mok explained.

Key Data The IMPRESS trial included patients who achieved response greater than 4 months on standard gefitinib and then had disease progression less than 4 weeks prior to randomization. The study enrolled 265 patients from 71 centers in Europe and Asia Pacific. Patients were randomly assigned to cisplatin/pemetrexed (Alimta) plus gefitinib vs cisplatin/pemetrexed plus placebo. At baseline, 65% were female and mean age was about 60. There was an imbalance in brain metastases, with 33% in the gefitinib arm and 23% in the chemotherapy arm. Also, the rate

Implications of the IMPRESS Study ■■ In EGFR-positive non–small lung cancer progressing on first-line EGFR tyrosine kinase inhibitor treatment, do not continue the agent. ■■ A platinum-based chemotherapy doublet remains standard of care, according to results of the IMPRESS trial.

of complete responses to first-line treatment was higher in the chemotherapy arm: 76% for those receiving cisplatin/pemetrexed vs 68% for those receiving cisplatin/pemetrexed plus gefitinib. Overall response rate was 31.6% for gefitinib vs 34.1% for chemotherapy alone, and the disease control rate was 84.2% vs 78.2%, respectively. Median progression-free survival (the primary endpoint) was identical in both

groups: 5.4 months. No significant difference between treatment arms was found in any subgroup.

Overall Survival Findings Overall survival data are immature, with only 33% of required events. Nevertheless, “because of a potential detrimental effect [of gefitinib], we feel obligated to share survival data with the audience,” Dr. Mok said. “Survival from the time of randomization is 14.8 months with gefitinib vs 17.2 months with chemotherapy. The hazard ratio is 1.62, and the difference is potentially significant,” he noted. One possible explanation for this finding could be fewer brain metastases in the control arm, but a post hoc analysis found that there was still no benefit for gefitinib. No significant difference between treatment arms was observed in rates of adverse events, serious adverse events, and events leading to death. “IMPRESS is the only randomized phase III trial to compare continuation of gefitinib in combination with chemotherapy vs chemotherapy alone in patients with advanced ­EGFR-mutation positive NSCLC with resistance to first-line gefitinib. This study does not support continuation of gefitinib after disease progression by RECIST criteria on firstline gefitinib,” Dr. Mok stated. n Disclosure: Dr. Mok reported no potential conflicts of interest.

EXPERT POINT OF VIEW

“T

he IMPRESS trial asks a simple question: Should you continue an [epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor] while you switch to chemotherapy,” said Solange Peters, MD, PhD, Head of the Thoracic Malignancies Program at the University of Lausanne, Switzerland, at the European Society for Medical Oncology (ESMO) 2014 Congress. Dr. Peters was formal discussant of the study at the ESMO meeting.

This study showed us that we should not combine EGFR tyrosine kinase inhibitors in this setting. A platinum-based chemotherapy doublet remains a standard of care. —Solange Peters, MD, PhD

“This was a well conducted trial restricted to EGFR-mutated non–small cell lung cancer with known sensitivity to gefitinib. There were imbalances, with higher response rates in placebo arm patients and older patients as well as more brain metastasis in the gefitinib arm. The [progression-free survival] is absolutely similar and in line with what we expect in unselected patients, even when data were adjusted for these covariates, in an exploratory post hoc anaylsis regarding brain metastasis,” she said. The overall survival difference is around 3 months in favor of the placebo arm. “Knowing that survival data are immature, the placebo arm appears to be performing significantly better than the experimental arm,” Dr. Peters commented. “Importantly, more patients in the placebo arm received subsequent postprogression platinum-based chemotherapy or EGFR [tyrosine kinase inhibitor] rechallenge, partially explaining for such difference. We don’t know why these imbalances were present,” she added.

Possible Strategy Reference 1. Mok TSK, Nakagawa W, Kim S, et al: Gefitinib/chemotherapy versus chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer after progression on first-line gefitinb: The phase III, randomized IMPRESS study. ESMO 2014 Congress. Abstract LBA2_PR. Presented September 28, 2014.

A possible strategy in the patient population of IMPRESS might be a sequential EGFR tyrosine kinase inhibitor rechallenge (ie, reintroduction after intervening treatment) rather than continuation. “Several retrospective analyses show consistent activity,” she said. “There are several other potential treatment strategies, but this study showed us that we should not combine EGFR tyrosine kinase inhibitors with chemotherapy in this setting. A platinum-based chemotherapy doublet remains a standard of care,” she stated. n Disclosure: Dr. Peters reported no potential conflicts of interest.

Centers for Medicare & Medicaid Services Proposes Decision on Lung Cancer Screening

See next month’s issue of The ASCO Post for comprehensive coverage of the recent proposed decision by the Centers for Medicare & Medicaid Services (CMS) to cover low-dose computed tomography screening for high-risk c­ urrent and former smokers. CMS announced its decision on November 11, 2014.


The ASCO Post  |   NOVEMBER 15, 2014

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ESMO Congress Thoracic Oncology

Moving Forward With Biomarkers in Non–Small Cell Lung Cancer By Alice Goodman

T

he effort to identify new biomarkers for response and outcomes in lung cancer is advancing, according to studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid. Immunohistochemical expression of folate receptor for vintafolide

Markus Joerger, MD, PhD

and thymidylate synthase for pemetrexed (Alimta) holds promise for individualizing second-line treatment of metastatic non–small cell lung cancer (NSCLC), in keeping with the theme of “precision medicine” at this year’s Congress. Second-line therapy with vintafolide added to docetaxel vs docetaxel alone made no difference in overall survival

in patients with NSCLC in the phase II TARGET trial population, but vintafolide improved overall survival in a subgroup of patients with adenocarcinoma.1

We saw a clinically meaningful improvement with the addition of vintafolide across all endpoints, but the most robust improvement was in the predefined adenocarcinoma patients.

TARGET Trial Details Vintafolide is an investigational small-molecule drug conjugate targeted to the folate receptor. The 199 patients included in this trial were selected for folate receptor expression, and results provide a clue that folate receptor overexpression may be useful for therapy selection in patients with adenocarcinoma, suggested Markus Joerger, MD, PhD, Associate Professor of Medical Oncology and Clinical Pharmacology at Cantonal Hospital, St. Gallen, Switzerland, who wrote about these results in the Congress Daily. Rohit Lal, MD, Consultant Medical Oncologist at Guy’s and St. Thomas’ Hospital, London, presented the TARGET results, standing in for lead author Nasser Hanna, MD. “We saw a clinically meaningful improvement with the addition of vintafolide across

—Rohit Lal, MD

all endpoints, but the most robust improvement was in the predefined adenocarcinoma patients. The safety was manageable and as expected with both single agents. Going forward, we need to figure out the best trial design for this drug and patient selection,” Dr. Lal said. The rationale for the study was partly based on preclinical data showing complete suppression of tumor growth with the combination of docetaxel plus vintafolide. Rodryg Ramlau, MD, PhD, a study coauthor from the Lung Disease Centre in Poznan, Poland, said that an early trial showed that single-agent

EXPERT POINT OF VIEW

F

ormal discussant Giorgio V. Scagliotti, MD, PhD, Professor and Chair of Medical Oncology at the University of Turin and San Luigi Hospital, Orbassano, Italy, tackled each of the studies presented at the European

cer trials of vintafolide, but questions remain about use of this biomarker in NSCLC, including the number of patients who were folate receptor–positive, the threshold values for folate receptor positivity, no assessment of genomic al-

Biomarker-driven chemotherapy is still a matter of clinical research, and, remember, the jury is not yet in. There is still huge room for improvement in terms of selecting candidate patients and treatments. —Giorgio V. Scagliotti, MD, PhD

Society for Medical Oncology (ESMO) session on metastatic non–small cell lung cancer (NSCLC).

Three Studies Beginning with the TARGET trial, he said that the use of functional imaging to select patients who are folate receptor–positive was an interesting aspect of the study. “Patients selected for [folate receptor] expression did best in ovarian can-

teration in adenocarcinoma, and lack of poststudy information,” he commented. Turning to the study by Kim et al, Dr. Scagliotti could draw no meaningful conclusion because the study was stopped after only 156 patients enrolled, despite a planned enrollment of 562 patients. “Noninferiority cancer clinical trials need to be realistic and correct.” This study failed to meet that bar, in his opinion. He noted that the design of the study

did not reflect current practice, which includes maintenance therapy and more than four cycles of chemotherapy. In the study reported by Ahn et al, Dr. Scagliotti commented that thymidylate synthase is potentially the most reliable biomarker identified for pemetrexed (Alimta), but the predictive/prognostic role of this biomarker is unresolved. “Thus far, there are no data to support the use of this biomarker in clinical practice. Standardization of measurement techniques is still an issue,” he said.

Overview Remarks Looking at all three studies, Dr. Scagliotti said that pemetrexed-based chemotherapy remains the preferred doublet for first-line treatment of non–oncogene-addicted nonsquamous NSCLC. “Biomarker-driven chemotherapy is still a matter of clinical research, and, remember, the jury is not yet in. There is still huge room for improvement in terms of selecting candidate patients and treatments,” he stated. Disclosure: Dr. Scagliotti has received honoraria from Eli Lilly, AstraZeneca, Roche, Pfizer, and Clovis Oncology.

vintafolide exerted disease control in 57.1% of 14 heavily pretreated patients. Patients selected for the trial had target lesions that were folate recep-

Nasser Hanna, MD

tor–positive on imaging, and they were randomly assigned 1:1:1 (n = 199) to vintafolide, the combination of both drugs at the same dose and schedule as the monotherapy arms, and docetaxel monotherapy. Treatment was continued until disease progression or unacceptable toxicity. Treatment arms were well balanced for all patient characteristics. Median progression-free survival was 1.6 months with vintafolide, 4.2 months for the combination, and 3.3 months with docetaxel monotherapy. Median overall survival was 8.4 months for vintafolide, 11.5 months for the combination, and 8.8 months for docetaxel. The disease control rate was 40% for vintafolide, 70% for the combination, and 60% for docetaxel. In the subgroup of patients with adenocarcinoma, combination therapy reduced the risk of disease progression by 32% and reduced the risk of death by 49% compared with monotherapy with either drug (P = .0147). No unexpected adverse events occurred. Neutropenia and peripheral neuropathy were increased with the combination.

Doublets Comparable A small phase III noninferiority trial showed that pemetrexed/cisplatin and docetaxel/cisplatin had comparable outcomes as first-line treatment of continued on page 73


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ESMO Congress Breast Cancer

Studies Evaluate Maintenance Bevacizumab in Metastatic Breast Cancer By Caroline Helwick

A

lthough bevacizumab (Avastin) may no longer be an active player in metastatic breast cancer, phase III studies presented at this year’s European Society for Medical Oncology (ESMO) Congress reignited interest in the drug as part of maintenance therapy. The TANIA trial met its primary endpoint, improving progression-free survival when bevacizumab was continued after progression on first-line bevacizumab-containing regimens.1 In the IMELDA trial, the addition of capecitabine to maintenance bevacizumab provided a statistically significant improvement in progression-free survival and overall survival.2

TANIA Trial Gunter von Minckwitz, MD, PhD, Chairman of the German Breast Group, Neu-Isenburg, and Professor of Gynecology at the University Women’s Hospital

Biomarkers in NSCLC continued from page 72

stage IV nonsquamous NSCLC, but pemetrexed/cisplatin had an improved safety profile, with less severe febrile neutropenia compared with docetaxel/ cisplatin.2 Grade 3/4 neutropenia were reported in 1.3% of the pemetrexed/ cisplain arm vs 13.9% of the docetaxel/ cisplatin arm. Febrile neutropenia occurred in 1.3% vs 11.1%. Among 149 evaluable patients enrolled in the trial, median progressionfree survival was 4.7 months with pemetrexed/cisplatin and 4.6 months with docetaxel/cisplatin. Patients with

Continuous VEGF suppression appears to be important, consistent with findings in metastatic colorectal cancer. —Gunter von Minckwitz, MD, PhD

in Frankfurt, Germany, presented the mature prespecified second-line progression-free survival analysis of the TANIA trial, which evaluated the importance of continued suppression of the vascular endothelial growth factor (VEGF) with maintenance therapy.1 TANIA, which was conducted in 12 countries, randomly assigned 494 HER2negative patients to second-line treatment

with a single chemotherapy agent, alone or with bevacizumab, as maintenance. Capecitabine was the investigator’s choice in 60% of patients, and vinorelbine was used by 11%. “The primary objective was met, showing statistically significant improved progression-free survival with bevacizumab after progressive disease on firstline bevacizumab-containing therapy,”

one doublet over another. Moreover, expected median progression-free survival was 6.4 months,” he said. “Response rates were not that different, and progression-free survival was almost identical,” he added. He suggested that the disappointing results were related to giving only four cycles of chemotherapy in this trial.

thase] biomarker study in NSCLC. The data suggest that [thymidylate synthase] is a predictive and prognostic biomarker,” she added. In 315 patients with stage IIIB/IV nonsquamous NSCLC, thymidylate synthase–negative status on immunohistochemistry was significantly associated with improved response rates and improved progression-free survival in patients receiving pemetrexed/cisplatin vs those treated with gemcitabine/ cisplatin. Response rates were 38% vs 21%, respectively (P = .007), and median progression-free survival was 6.4 vs 5.5 months, respectively (P = .013).

Biomarker for Outcome? A phase II study at the same ESMO session suggested that thymidylate synthase expression may be a potential biomarker for predicting outcome with pemetrexed treatment of metastatic NSCLC in the second-line setting.3

Biomarkers in Lung Cancer Treatment ■■ Studies are paving the way forward for identification of predictive and prognostic biomarkers for second-line treatment of non–small cell lung cancer.

Young-Chul Kim, MD, PhD

EGFR-activating mutations were excluded from the trial. Lead author Young-Chul Kim, MD, PhD, of Chonnam National University Hwasun Hospital, Hwasun Gun, Korea, explained that the study was designed when maintenance was not standard of care and four cycles of chemotherapy was preferred over six cycles. “We failed to show superiority of

■■ Folate receptor expression may be useful in selecting patients for treatment with vintafolide, and thymidylate synthase negativity appears to predict for response to pemetrexed. ■■ These are still early trials, and these markers are not ready for routine use in the clinical setting.

The patients were stratified for thymidylate synthase expression, which is a predictive factor for response in pemetrexed-treated patients, explained lead author Myung-Ju Ahn, MD, PhD, Sungkyunkwan University School of Medicine, Seoul, Korea. “This is the first [thymidylate syn-

Irrespective of treatment group, overall survival was related to thymidylate synthase status, she said. Thymidylate synthase–negative patients had survived a mean of 30.3 months, whereas thymidylate synthase–positive patients survived a mean of 15.2 months. Thymidylate synthase negativity was an

Dr. von Minckwitz reported. “TANIA showed that in bevacizumab-pretreated locally recurrent or metastatic breast cancer, further bevacizumab improves second-line progression-free survival.” After a median follow-up of approximately 16 months, the median second-line progression-free survival was 6.3 months with chemotherapy plus bevacizumab vs 4.2 months with chemotherapy alone (hazard ratio [HR] = 0.75; P = .0068). All subgroups appeared to benefit from the combination. He noted that the progression-free survival in the control arm was shorter than expected but consistent with subgroup data from contemporary trials evaluating second-line capecitabine. Stable disease rates increased with the combination (48.9% vs 33.5%), though overall response rates were not substantially better (20.9% vs 16.8%; P = .3457). continued on page 74

independent prognostic factor for favorable overall survival, she said. For the study, thymidylate synthase positivity was defined as expression of the enzyme in more than 10% of tumor cells, and thymidylate synthase negativity as expression in 10% or fewer tumor cells. Thymidylate synthase–negative patients tended to be female, younger, and never-smokers. n

Disclosure: Dr. Joerger reported no potential conflicts of interest. Dr. Kim received funding for the trial and honoraria from Sanofi-Aventis Korea.

References 1. Hanna N, Juhász E, Cainap C, et al: TARGET: A randomized phase II trial comparing vintafolide versus vintafolide plus docetexel versus docetaxel alone in secondline treatment of folate receptor-positive non-small cell lung cancer patients. ESMO 2014 Congress. Abstract LBA40_PR. Presented September 27, 2014. 2. Kim Y, Oh I, Kim K, et al: A randomized phase II study of docetaxel plus cisplatin versus pemetrexed plus cisplatin in first-line non-squamous non-small cell lung cancer. ESMO 2014 Congress. Abstract LBA41_PR. Presented September 27, 2014. 3. Ahn M, Sun J, Ahn JS, et al: Cisplatin plus pemetrexed versus cisplatin plus gemcitabine according to thymidylate synthase expression in non-squamous NSCLC: A biomarker-stratified randomized phase II trial. ESMO 2014 Congress. Abstract LBA42_PR. Presented September 27, 2014.


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ESMO Congress Bevacizumab in Breast Cancer continued from page 73

Second-line safety results were as expected from previous bevacizumab trials. “Continuous VEGF suppression appears to be important, consistent with findings in metastatic colorectal cancer,” Dr. von Minckwitz suggested. Biomarker and additional subgroup analyses will be reported at the San Antonio Breast Cancer Symposium in December. Final analysis of overall survival and third-line endpoints is anticipated in 2015.

IMELDA Trial The open-label randomized phase III IMELDA trial tested whether, after three to six cycles of bevacizumab/docetaxel, maintenance therapy with bevacizumab alone or bevacizumab plus capecitabine would prolong the time until disease progression. Joseph Gligorov, MD, PhD, a medical oncologist at Tenon University Hospital in Paris, presented the findings.2 The study enrolled 287 patients with HER2-negative metastatic disease who had received no prior chemotherapy.

After bevacizumab/docetaxel, patients without progressive disease were randomly assigned to continue bevacizumab alone or in combination with capecitabine until disease progression. A total of 185 patients were ultimately assigned to maintenance. The primary endpoint was progression-free survival. Adding capecitabine to maintenance bevacizumab significantly improved progression-free survival, from 4.3 months with bevacizumab alone to 11.9 months with bevacizumab/capecitabine (HR = 0.38, P < .001). Median overall survival from the time of randomization was also significantly improved, from 23.7 months to 39 months (HR = 0.43, P = .0003), despite the smaller-than-planned sample size (accrual was terminated early). The investigators cautioned that overall survival remains immature, as only 47% of patients have died. Adverse events were increased in the combination arm, particularly hand-foot syndrome, which occurred in one-third of the patients on the combination and resulted in treatment discontinuation in

Maintenance Bevacizumab in Breast Cancer ■■ Two studies presented at ESMO evaluated bevacizumab alone and in combination with single-agent chemotherapy as maintenance after a response to first-line treatment of metastatic breast cancer. ■■ TANIA found that median second-line progression-free survival was 6.3 months with chemotherapy plus bevacizumab vs 4.2 months with chemotherapy alone (HR = 0.75, P = .0068). ■■ IMELDA found that bevacizumab plus capecitabine significantly improved progression-free survival, to 11.9 months vs 4.3 months with bevacizumab alone (HR = 0.38, P < .001).

10%. Thromboembolism, myocardial infarction, and hypertension were also more common with the doublet. Dr. Gligorov concluded that in patients benefiting from first-line bevacizumab-containing therapy, continuing bevacizumab with capecitabine improves outcomes. The investigators are now evaluating postprogression regimens and patient-reported outcomes. n Disclosure: Drs. von Minckwitz and Gligorov are paid members on Roche’s advisory boards and have received speaker honoraria and conducted Roche-sponsored research.

References 1. von Minckwitz G, Puglisi F, Cortes J, et al: Efficacy and safety in TANIA, a randomized phase III trial of continued or reintroduced bevacizumab after 1st-line bevacizumab for HER2-negative locally recurrent/metastatic breast cancer. ESMO 2014 Congress. Abstract 353O. Presented September 28, 2014. 2. Gligorov J, Doval D, Bines J, et al: Efficacy and safety of maintenance bevacizumab with or without capecitabine after initial first-line bevacizumab plus docetaxel for HER2-negative metastatic breast cancer: IMELDA randomized phase III trial. ESMO 2014 Congress. Abstract 352O. Presented September 28, 2014.

EXPERT POINT OF VIEW

H

ope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education for the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the two studies on maintenance bevacizumab (Avastin) for metastatic breast cancer presented at the European Society for Medical Oncology (ESMO) Congress in Madrid. Dr. Rugo summed up TANIA and IMELDA as showing that for patients who respond to first-line treatment, continued maintenance improves outcomes, though the contribution of bevacizumab remains unclear and this drug should not be used as a single agent. “Extending bevacizumab after progression into the second line prolongs progression-free survival,” she said. The studies suggested the benefit is greatest for patients with estrogen receptor–positive disease and triple-negative tumors. Toxicity was as expected, although these patients had already been shown to tolerate bevacizumab in the first-line setting, she pointed out.

Key Findings The results of these studies are comparable to those from RIBBON-2, which found median progression-free survival to be 7.2 months for bevacizumab/che-

motherapy in the second line (HR = 0.78, P = .0072),1 Dr. Rugo indicated. The findings are in accordance with the preclinical rationale for continuing bevacizumab, which counteracts the rapid mobilization of circulating endothelial progenitor cells triggered by chemotherapy. The discontinuation of

11.9 months, is “rarely seen in HER2negative advanced breast cancer.” Median progression-free survival from the start of first-line treatment, an exploratory endpoint, also doubled to more than 16 months, which is longer than the median progression-free survival of about 11 months observed in three previous ran-

It is unclear what additional benefit we get from bevacizumab, and we need to balance this against cost and toxicity … and bevacizumab alone should not be used for maintenance. —Hope S. Rugo, MD

bevacizumab in previous trials could be one reason they failed to show an overall survival improvement, she suggested. The TANIA trial asked whether bevacizumab should continue after progression on first-line bevacizumab, and it found a significant improvement in progression-free survival with this approach. The IMELDA study questioned whether instead of maintenance chemotherapy, bevacizumab could be given alone but found that bevacizumab plus chemotherapy was significantly more beneficial. Dr. Rugo commented that the median progression-free survival for capecitabine/bevacizumab in IMELDA,

domized phase III trials of bevacizumab plus paclitaxel, she pointed out. She further commented on the impressive median overall survival of 39 months in IMELDA, with the caveat that fewer than half the patients had died—“a rather pleasant complication to the data analysis in this study of advanced breast cancer.”

Practical Implications Based on the data from these two studies, Dr. Rugo asked, “Should we continue this expensive drug with known toxicities into the second-line setting in countries where bevacizumab is still approved?” The data on TANIA,

on overall survival and biomarker analyses, to be presented at the San Antonio Breast Cancer Symposium, will help answer this question, she said. “We need to understand how to apply bevacizumab in the clinic in a way that will maintain quality of life, not increase costs, and give an overall survival advantage, where possible,” Dr. Rugo suggested. She concluded that while maintenance chemotherapy does improve outcomes, “it is unclear what additional benefit we get from bevacizumab, and we need to balance this against cost and toxicity … and bevacizumab alone should not be used for maintenance.” She concluded, “Bevacizumab clearly has an impact in breast cancer. We just don’t know in whom, and how to use it.” n

Disclosure: Dr. Rugo has received research funding from Genentech/Roche.

Reference 1. Brufsky AM, Hurvitz S, Perez E, et al: RIBBON-2: A randomized, doubleblind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2–negative metastatic breast cancer. J Clin Oncol 29:4286-4293, 2011.


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ESMO Congress Breast Cancer

Adding Sorafenib to Capecitabine Fails to Improve Progression-Free Survival in Advanced Breast Cancer By Caroline Helwick

I

n patients with locally advanced or metastatic breast cancer, the addition of sorafenib (Nexavar), a broad-spectrum tyrosine kinase inhibitor, to capecitabine did not improve progression-free or overall survival in the phase III RESILIENCE

has to be higher, or we have to have a very strong scientific hypothesis.”

RESILIENCE Details The randomized phase III RESILIENCE trial enrolled 537 women with

This ought to make us think more about when to go forward with phase III trials. The bar has to be higher, or we have to have a very strong scientific hypothesis. —José Baselga, MD, PhD

trial. The findings were presented at the European Society for Medical Oncology (ESMO) 2014 Congress by José Baselga, MD, PhD, who is Physician-in-Chief at Memorial Sloan Kettering Cancer Center, New York.1 The combination of sorafenib and capecitabine led to a median progression-free survival of 5.5 months vs 5.4 months for capecitabine plus placebo (hazard ratio [HR] = 0.973, P = .406). Median overall survival was 18.9 months with capecitabine/sorafenib and 20.3 months with capecitabine/ placebo (HR = 1.195, P = .93). “The trial did not meet its primary endpoint [progression-free survival],” Dr. Baselga announced. No subgroup was identified that derived benefit from the addition of this targeted agent. The results were in contrast to those from previous preclinical and selected clinical studies. In a phase IIb trial,2 the combination of sorafenib and capecitabine improved progressionfree survival in patients with advanced HER2-negative breast cancer (HR = 0.58, P = .001), and the drug has conferred a survival benefit in several other tumors, including advanced renal cell and hepatocellular carcinoma, Dr. Baselga indicated. Although the sorafenib/capecitabine phase II trial was clearly positive, other phase II trials were either negative or demonstrated borderline superiority, including a combination study with paclitaxel or gemcitabine/capecitabine. Dr. Baselga noted that the results of the R ­ ESILIENCE trial, in light of the combined phase II trials, should make us think more about when to go forward with phase III trials. The bar

locally advanced or metastatic HER2negative breast cancer who had received no more than one prior regimen. The trial excluded women previously treated with a vascular endothelial growth factor (VEGF) receptor inhibitor. Patients received capecitabine at 1,000 mg/m2 twice daily plus sorafenib or placebo 600 mg/d.

Sorafenib in Advanced Breast Cancer ■■ A phase III trial of sorafenib plus capecitabine in advanced breast cancer patients who had received zero or one prior regimen did not meet its primary endpoint of improved progression-free survival. ■■ Median progression-free survival was 5.5 months with the combination and 5.4 months with capecitabine alone.

Of note, the dose of sorafenib was reduced for the phase III trial to manage toxicity observed in the phase II trial. The impact of dose reduction on efficacy is unknown. In addition to the lack of benefit with sorafenib for the primary endpoint, the overall response rate was numerically higher in the capecitabine/placebo arm (15.5% vs 13.5%). The disease-control rate was numerically higher in the sorafenib arm (60.5% vs 58.3%). Adverse events were consistent with known safety profiles of sorafenib and capecitabine. Sorafenib was associated with more treatment-emergent adverse events of grade 3 (58.5% vs 39.3%), grade 4 (5.8% vs 4.5%), and grade 5 (6.2% vs

4.5%). This arm also had more serious adverse events, adverse events leading to dose reductions, and adverse events leading to treatment discontinuation. However, Dr. Baselga indicated, “The trend for lower median overall survival in patients treated with sorafenib plus capecitabine was not readily explainable by study treatment-related toxicity.” n

Disclosure: Dr. Baselga reported no potential conflicts of interest. For full disclosures of the study authors visit www.esmo.org.

References 1. Baselga J, et al: ESMO Congress. Abstract LBA8. Presented September 28, 2014. 2. Baselga J, et al: J Clin Oncol 30:14841491, 2012.

EXPERT POINT OF VIEW

H

ope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the results of the RESILIENCE trial presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid. “With sorafenib [Nexavar] we

in the development of sorafenib, we started with an interesting approach: large randomized phase II trials designed to power a better phase III trial with a higher chance of success.”

Toxicity Concerns The phase II studies of sorafenib in combination with various chemotherapy agents returned mixed results, and toxicity was still concerning for the com-

We clearly haven’t figured out how to use oral tyrosine kinase inhibitors in breast cancer. —Hope S. Rugo, MD

had a glimmer of hope from phase II studies,” she said. With other smallmolecule kinase inhibitors (sunitinib [Sutent], axitinib [Inlyta], motesanib), multiple trials had been negative and toxicity was a concern, she said. “But

bination of sorafenib plus capecitabine (despite improved progression-free survival). The decision was made to reduce the dose of sorafenib from 800 mg to 600 mg for the phase III trial. Even with this dose reduction, the

combination arm received a lower dose intensity of capecitabine, had a shorter duration of treatment, and had a markedly higher number of dose interruptions or reductions of both agents, compared with the placebo arm. The combination arm also suffered a 20% increase in grade ≥ 3 adverse events, including hand-foot syndrome, hypertension, mucositis, and diarrhea, she noted. Dr. Rugo suggested that the toxicity and the dose reductions “potentially limited the combined efficacy” of this regimen. Nevertheless, she added, “It’s hard to believe that a difference of 200 mg is the cause [of the negative results], but it may have contributed.” She continued, “What we thought initially to be an advantage in the treatment of cancer [multiple targeting], may, for breast cancer, turn out to be a significant disadvantage: off-target toxicities that limit the dose of the targeted agent and also its accompanying chemotherapy. We clearly haven’t figured out how to use oral tyrosine kinase inhibitors in breast cancer.” n Disclosure: Dr. Rugo has received research funding from Genentech/Roche.


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ASTRO Annual Meeting Breast Cancer

Patient-Reported Data Indicate that Radiation Therapy Does Not Increase Risk of Lymphedema in Patients With Node-Negative Breast Cancer

A

secondary analysis of the National Surgical Adjuvant Breast and Bowel Project B-32 trial1 indicates that radiation therapy does not increase the incidence of lymphedema in patients with node-negative breast cancer, according to research presented at the American Society for Radiation Oncology’s (ASTRO’s) 56th Annual Meeting.

Original NSABP B-32 Study The original NSABP B-32 study was a randomized trial of sentinel node biopsy vs sentinel node biopsy plus axillary lymph node dissection in 5,611 women with clinically node-negative breast cancer. The study was initiated to determine if sentinel node biopsy was as effective as axillary lymph node dissection with fewer side effects.            Although designed to assess the impact of type of axillary surgery specifically on lymphedema risk, the NSABP B-32 trial also provided the opportunity to evaluate the impact of radiation therapy on lymphedema risk.  Lymphedema is commonly caused by the removal of or damage to lymph nodes and it is a significant concern for women undergoing breast cancer treatment. Measures of lymphedema were collected at baseline prior to radiation therapy and every 6 months during the 3-year follow-up period. Lymphedema was assessed both by standardized arm measurements by clinicians (objective lymphedema) and via questionnaires completed by patients (subjective lymphedema). Objective lymphedema (clinician measured) was defined as relative arm volume difference >1%, and was determined by a water displacement method. Subjective lymphedema was defined as patient-reported ipsilateral swelling that was “somewhat,” “quite” or “very” bothersome. Repeated mea-

sures analyses, chi-square and Fisher’s exact tests were used to evaluate the association between measures of lymphedema and radiation therapy. Kappa coefficient was used to assess agreement between objective and subjective lymphedema measures at individual time points.

Secondary Analysis Among 3,916 women in the trial with lymphedema assessments, including 1,936 randomly assigned to sentinel node biopsy plus axillary lymph node dissection and 1,980 randomly assigned to sentinel node biopsy, 82.2%

not contribute to lymphedema risk beyond surgery over time. Interestingly, although receipt of radiation did not impact either, there was a lack of agreement between patient reports of bothersome swelling (subjective lymphedema) and clinician measurements of arm swelling (objective lymphedema) throughout the 3 years of follow-up. At 36 months follow-up of the sentinel node biopsy plus axillary lymph node dissection group that had received radiation therapy, 12.4% (147/1,183) had relative arm volume difference >10% (objective lymphedema), and 7.4% (16/216) reported bothersome

This analysis suggests that lymphedema concerns should not be an impediment to women choosing breast conservation and radiation therapy. —Susan McClosky, MD

(3,220) received radiation therapy and 17.2% (674) did not undergo radiation therapy. The status was unknown for 0.6% (22) of the patients. The original study results showed that sentinel node biopsy plus axillary lymph node dissection were associated with significantly greater risk of lymphedema vs sentinel node biopsy alone. Upon secondary analysis, researchers found no greater risk of lymphedema among women receiving radiation therapy vs among women who did not receive radiation therapy. There was no significant difference in standardized arm measurements and no significant difference in patient reports of bothersome arm swelling during 3 years of follow up, suggesting that radiation does

swelling (subjective lymphedema). Within the sentinel node biopsy plus axillary lymph node dissection group that did not receive radiation therapy, 16.7% (36/216) had relative arm volume difference >1%, and 8.8% (5/57) of the group reported bothersome swelling. Within the sentinel node biopsyonly group, 7.4% (90/1,218) of radiation therapy recipients had relative arm volume difference >10% (objective lymphedema) at 36 months of followup, with only 3.2% (8/250) of radiation therapy patients reporting bothersome arm swelling. For the sentinel node biopsy-only patients who did not undergo radiation therapy, 4.5% (10/220) had relative arm volume dif-

ference >1%, whereas 4.8% (3/63) reported bothersome swelling.

Impact of Radiation Therapy on Lymphedema Risk “These results provide much needed reassurance to breast cancer patients regarding the impact of radiation therapy on lymphedema risk,” said Lead Study Author Susan McCloskey, MD, MSHS, Assistant Professor of Radiation Oncology at The David Geffen School of Medicine at University of California, Los Angeles. “The study findings argue convincingly that radiation therapy to the Level 1 axilla, considered unavoidable “collateral damage” when radiating the whole breast, does not contribute to lymphedema risk beyond surgery. Several recent analyses have suggested that mastectomy rates are on the rise in the United States, and some have suggested that a desire to avoid radiation and its associated toxicities is a contributing factor. This analysis suggests that lymphedema concerns should not be an impediment to women choosing breast conservation and radiation therapy.” n References 1. Krag DN, Anderson SJ, Julian TB, et al: Sentinel-lymph-node resection compared with conventional axillary-lymphnode dissection in clinically node-negative patients with breast cancer: Overall survival findings from the NSABP B-32 Randomized Phase 3 trial. Lancet Oncol 11(10): 927-933, 2010. 2. McClosky SA, Bandos H, Julian TB, et al: The impact of radiation therapy on lymphedema risk and the agreement between subjective and objective lymphedema measures: NSABP B32 Secondary Data Analysis. 56th ASTRO Annual Meeting. Abstract CT-06. Presented September 14, 2014.

Visit The ASCO Post at These Upcoming Oncology Meetings American Society of Hematology Annual Meeting, Harborside Press booth 741 San Antonio Breast Cancer Symposium, Harborside Press booth T1 Or visit The ASCO Post online at ASCOPost.com


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The ASCO Post  |   NOVEMBER 15, 2014

PAGE 78

Direct From ASCO

Spotlight on ASCO’s 2015 Presidential Election

Interviews With Candidates for 2015-2016 ASCO President-Elect

T

he ASCO Nominating Committee has selected Daniel F. Hayes, MD, FASCO, and Patrick J. Loehrer, Sr, MD, FASCO, as candidates for the position of 2015-2016 President-Elect (2016-2017 President). In the abridged interviews below, the candidates discuss their vision for the Society and their leadership experience. Visit www.asco.org/election to read the candidates’ full responses, watch video interviews, and learn more about their qualifications.

Daniel F. Hayes, MD, FASCO

Patrick J. Loehrer, Sr, MD, FASCO

Daniel F. Hayes, MD, FASCO Stuart B. Padnos Professor of Breast Cancer Research and Clinical Director of the Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

W

hy do you want to serve as ASCO President? I fundamentally believe in the mission of ASCO: “ASCO is a professional oncology society committed to conquering cancer through research, education, prevention, and delivery of high-quality patient care.” During my 3-year term on the Board of Directors, a placemat with this mission statement was in front of us at every meeting. Every decision we made during the last 3 years, whether it was to argue for payment reform, “sundown” a sponsored meeting that had run its course, or initiate a multimillion dollar “game-changer” like CancerLinQTM, was based on this mission statement.

What key issues are ASCO and the oncology field facing? I believe the following are three key issues (among many) facing ASCO and oncology in general:

• Federal health-care reform and the evolution of patient management in an era of increasing needs and limited resources. There are many subissues embedded in this concern, including: ■■ Novel reimbursement strategies for patient management ■■ Workforce needs as our population, and our membership, ages and becomes more diverse ■■ The increasing “push” at the medical school level to encourage students to consider primary care careers • The new diagnostic technologies that offer unprecedented amounts of genomic-based information to oncologists and patients with varied understanding of their meaning or clinical utility • The rising specter of cancer as a major cause of morbidity and mortality in low- and middle-income countries

What specific skills and talents do you bring to this position that make you different from the past Presidents? I am not sure I have skills and talents that make me different from past Presidents, but this perception stems from my incredible respect for the historical leadership of this organization. Like many past Presidents, I come from an academic background, in which I have been a clinician; a laboratory, clinical, and translational researcher; and educator. I have also served as a clinical administrator of breast cancer programs in three different institutions (Harvard’s Dana-Farber Cancer Institute, Georgetown’s Lombardi Cancer Center, and since 2001, the Breast Oncology Program at the University of Michigan’s Comprehensive Cancer Center), and I have established and served as Chair of translational research committees in the Cooperative Groups. Also like many past Presidents, I have

served in many roles in ASCO: the Scientific Program Committee (I served on the Breast Cancer track twice, most recently as Chair, and I chaired the entire Scientific Program Committee for the 2009 Annual Meeting); the Tumor Marker Guidelines Committee (I was a charter member, and I chaired the Committee from the mid-2000s up to the last year or so); and I have been on the Board of Directors the last 3 years. However, perhaps my most unique accomplishment in ASCO has been my ability to generate new initiatives that have pushed the envelope for the organization, especially in regard to ASCO’s reaching out beyond its own membership. I believe my strengths are to combine vision and realistic expectations, enthusiasm, hard work, and listening skills to lead important initiatives that will improve patient care on a global basis. n

Patrick J. Loehrer, Sr, MD, FASCO

Director, Indiana University Simon Cancer Center, and H.H. Gregg Professor of Oncology and Associate Dean for Cancer Research, Indiana University School of Medicine

W

hy do you want to serve as ASCO President? Having served in many capacities within this Society and enjoying the privilege of working alongside its outstanding staff, I consider ASCO

among the greatest professional joys of my life. Being President would allow me to serve our profession and our Society at the highest level and pay back that which has given me so much. Serving as President would also

provide the opportunity to lead several initiatives (including those outlined below) that I believe will maintain the preeminence of our profession and deepen our impact upon oncology worldwide.

What key issues are ASCO and the oncology field facing? For ASCO to maintain its credibility to the public, it must offer candid discourse and self-examination on the continued on page 79


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 79

Direct From ASCO ASCO President-Elect Candidates continued from page 78

rising costs of cancer care. I suspect, perhaps naively, that if we make strong efforts to impact federal health-care savings, we will be in a stronger position to argue for increased research dollars needed to advance progress in our field. Disparities in cancer care delivery have many faces—nationally and internationally. They include improved access to care and broader participation in translational research trials. Proudly, ASCO has been at the forefront of public advocacy on behalf of our patients, but we should help lead the conversation of alternative health-care models for cancer care delivery. What specific skills and talents do you bring to this position that make you different from the past presidents? During my professional career, I have had a wide array of leadership roles locally, nationally, and internationally involving health-care professionals from the community and academic settings. I have had institutional leadership roles at Indiana University (IU), including being the Director of the Division of Hematology-Oncology and in my current role as the Director of the IU Simon Cancer Center and Associate Dean of Cancer Research for the School of Medicine. Nationally, I have also served as Chair of the Eastern Cooperative Oncology Group Genitourinary Committee, Chair of the Medical Oncology Committee and Board of Directors of the American Board of Internal Medicine, and as a member of the Food and Drug Administration Oncologic Drugs Advisory Committee. I thoroughly enjoy working with smart and passionate people and firmly believe that the collective wisdom can yield productive and sustainable outcomes, far superior to individual efforts. In that capacity, I have led the development of several novel clinical research cooperatives, including the founding of the Hoosier Cancer Research Network (formerly known as “the

Save the Date Gastrointestinal Cancers Symposium January 15-17, 2015 Moscone West Building San Francisco, California

HOG”); helping to establish the newly formed Big Ten Cancer Research Consortium; and building the multi-institutional, multinational AMPATH (Academic Model Providing Access to Healthcare)-Oncology Program in western Kenya. Having been Chair of numerous committees within ASCO (eg, Scientific Program, Professional Develop-

ment, Bylaws, and the Leadership Development Program), I have a broad perspective on the organization and the staff. Witnessing the strengths and struggles of all of our members, academic, community, and international, I believe that I am uniquely positioned to serve our Society and all its members as ASCO President. n

Originally printed in ASCO Connection. All rights reserved. © American Society of Clinical Oncology. "Interviews with Candidates for 2015-2016 ASCO President-Elect." ASCO Connection November 2014:30-31. All rights reserved.

Visit www.asco.org/election to learn more about the candidates.

For HR+, early-stage invasive breast cancer

Confidence begins with a highly accurate risk assessment

Introducing Prosigna™: Guide your decisions with the power of PAM50-based molecular profiles1 • Prosigna translates a patient’s underlying tumor biology into an individualized risk assessment

• Prosigna is the only genomic assay for breast cancer that is FDA 510(k) cleared for use in local qualified laboratories

• Prosigna’s PAM50-based genomic assay quickly and accurately provides prognostic information you need

• Obtain precise, reproducible results from formalin-fixed paraffin-embedded (FFPE) tissue in as few as 3 days

To find a Prosigna provider and for a copy of the Package Insert, visit Prosigna.com today. Reference: 1. Prosigna [Package Insert]. Seattle, WA: NanoString Technologies, Inc; 2013.

Prosigna is indicated for use in postmenopausal women with hormone receptor–positive, node-negative or node-positive early-stage (stages I and II) breast cancer to be treated with adjuvant endocrine therapy. Special conditions for use: Prosigna is not intended for diagnosis, to predict or detect response to therapy, or to help select the optimal therapy for patients. © 2014 NanoString Technologies, Inc. All rights reserved. NanoString, the NanoString Technologies logo, Prosigna and the Prosigna logo are trademarks and/or registered trademarks of NanoString Technologies, Inc. in various jurisdictions. USPS_PM0006 04/14

Proceed with confidence


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 80

Direct From ASCO

Clinical Trials Participation Awards Recognize Community-Based Practice Dedicated to Research

S

ince 2003, the Conquer Cancer Foundation of ASCO has recognized more than 100 high-quality, community-based clinical research sites through the Clinical Trial Participation Award (CTPA). The program has been generously supported by the Coalition of Cancer Cooperative Groups for the past decade.

Annual Meeting. Principal Investigator, Gary Unzeitig, MD, was present to receive the award. CTPA recipients have demonstrated outstanding work in the area of patient clinical trials and Doctors Hospital of Laredo is no exception. It is the only hospital within a 150-mile radius in the South Texas border town. In spite of

Involvement in clinical trials gives our patients access to treatments that they previously had to travel great distances to receive. —Gary Unzeitig, MD

Doctors Hospital of Laredo, 2009 and 2014 CTPA recipient, was one of eight practices recognized during the CTPA ceremony at the 2014 ASCO

the challenges that come with serving a largely underserved population, Dr. Unzeitig and his team are committed to providing the people of Laredo with

access to clinical trials and new cancer therapies.

Increasing Access to Clinical Trials in Underserved Areas Dr. Unzeitig is a breast surgeon and Principal Investigator of Clinical Trials at Doctors Hospital of Laredo. Before his arrival, clinical trials were rarely seen in Laredo and most that were available occurred at larger academic centers. In 2001, he brought cancer clinical trials to Laredo and began enrolling patients in cooperative group trials. Thirteen years later, more than one-third of his patients are on clinical trials, giving them access to cutting-edge medicine. And his commitment to contribute to the further growth of clinical research and breast cancer medicine in Laredo is as strong as it was in 2001. “Involvement in clinical trials gives our patients access to treatments that they previously had to travel great distances to receive,” said Dr. Unzeitig. “It’s

also enhanced the hospital’s reputation as the provider of choice for cancer care.” Receiving the CTPA has enhanced Dr. Unzeitig’s efforts to provide clinical trials as an option for his patients. Dr. Unzeitig pointed out that “each time there is news about our Clinical Trials Participation Award, we receive lots of calls from patients asking if they can be on a trial. The publicity has essentially motivated the community to expect this advanced level of cancer care.” Learn more about the Clinical Trials Participation Award at­ www.conquercancerfoundation.org/ CTPA. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCO Submits Comments to NIH on Data Standards in Biomedical Science

A

SCO has submitted comments to the National Institutes of Health regarding the role of data standards in biomedical science. The comments were in response to a Request for Information from the National Cancer Institute, Input on Information Resources for Data-Related Standards Widely Used in Biomedical Science (notice number NOT-CA-14-053). ASCO’s Health Information Technology Work Group and Data Standards and Interoperability Taskforce has worked on developing interoperable standards. Standards development work is costly and time-consuming, and dissemination remains a challenge. ASCO offered the following specific

suggestions for additional types of standards most critical to include in the NIH Standards Information Resource (NSIR): • There is a critical need for standards for genomic data, with raw data entry, interpretation including storage algorithms and statistical algorithms, and storage to keep raw primary data for future analysis (eg, in the case of an initial solution which is adopted and then found to be incorrect, insufficient, or immature for subsequent analysis). • A source of most standards in biomedicine is the National Centers for Biomedical Computing’s BioPortal site with approximately 384 ontologies; this is helpful because all of the

different ontologies are contained within one site for easy access and ranked in terms of specific review criteria. Submission to a similar site could be required for all ontologies going forward, and an analogous site evaluating commercial solutions/ standards in terms of these ontologies could be established. • We suggest that all standards for use by oncologists be submitted to the National Library of Medicine’s Unified Medical Language System. This will require that standardization of raw data, interpretation, and algorithmic tools all are available at one site for better accessibility. Thus, we very strongly support the formation

of the NSIR. We believe that such a resource would be invaluable to organizations engaged in standards development, as well as primary and secondary users of data generated through the use of standards. A central, vetted repository containing the metadata proposed by NIH would be highly useful for specialty areas such as oncology, as well as medicine more generally. Read ASCO’s full comments at www. asco.org/sites/www.asco.org/files/ nih_biomedical_data_­standards_rfi. pdf. n © 2014. American Society of Clinical Oncology. All rights reserved.

Help Your Patients Learn How to Navigate Common Challenges

A

SCO’s latest video series, Navigating Challenges: Perspectives from Survivors and Doctors, available at

www.cancer.net/navigatingchallenges, offers information for people newly diagnosed with cancer who are facing real-world barriers to high-quality cancer care. In the four featured videos, health professionals and cancer survivors discuss specific challenges that

many patients encounter, such as finding emotional support, managing costs, making treatment decisions, and talking with the health care team. This ASCO patient education video series was made possible by a grant from the LIVESTRONG Founda-

tion to the Conquer Cancer Foundation. Learn more at www.cancer.net/ about-us/about-conquer-cancerfoundation. n © 2014. American Society of Clinical Oncology. All rights reserved.


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 81

Direct From ASCO

ASCO Members Reflect on ‘Lessons From Chernobyl’ As part of ASCO’s 50th anniversary, the Society has published a weekly series on special moments in its history. In this edition of The ASCO Post, we revisit a unique time when ASCO’s history intersected with major world events. To read the entire series, visit the “News and Views” page on CancerProgress.Net.

O

n April 26, 1986, the world witnessed the worst nuclear disaster in history. After a surge of power during a reactor systems test destroyed Unit 4 at Chernobyl Nuclear Power Plant in the former Soviet Union, a fire erupted, releasing dangerous amounts of radioactive material. Many of Chernobyl’s employees were able to evacuate immediately following the accident. Local firefighters, however, were called upon to extinguish the flames, exposing them to deadly levels of radiation. Although the explosion increased radiation levels across Europe, residents living in areas closest to Chernobyl experienced the worst side effects of exposure.

Radiation Exposure Side Effects ASCO member Robert Peter Gale, MD, PhD, FACP, an Associate Professor of Medicine at UCLA who had followed Soviet nuclear activity for many years, decided to contact Soviet leader Mikhail Gorbachev through Armand

Hammer, an American businessman with ties to the Soviet Union, to offer to help. Dr. Gale had gained the trust of Soviet leaders through several previous meetings in years past and his offer was accepted. He traveled to Moscow to work in a hospital specializing in care for patients exposed to radiation. Eventually, Dr. Gale was allowed to bring ASCO member and UCLA colleague Richard E. Champlin, MD, UCLA

“Because of the extent of their injuries, many of the patients died weeks after the accident. However, at least two people had the transplant work, allowing them to recover blood counts fast enough to survive,” recalled Dr. Champlin. Radiation accidents are especially difficult given the unpredictable nature of the long-term health effects, including several forms of cancer, which places oncologists and hematologists

Today we face not only the risks of nuclear accidents, but also nuclear terrorism, and it’s not inconceivable that any hematologist or oncologist could encounter these kinds of events. It’s quite important that oncologists are up to speed on radiation biology. —Robert Peter Gale, MD, PhD, FACP

physician and researcher Paul I. Terasaki, MD, and immunologist Yair Reisner, PhD. The small team of doctors worked with Russian colleagues to perform several bone marrow transplants in attempts save the lives of those exposed to the highest levels of radiation. As Dr. Champlin explains, many of the patients not only faced the effects of radiation exposure, but also had severe external burns caused by the fire.

in a critical role. Because many radiation side effects are not immediately detectable and instead require ongoing surveillance, Dr. Gale often travels back to monitor ongoing developments.

Learning From the Past In 1987, Dr. Gale led, “Lessons from Chernobyl,” a standing-room-only session at ASCO’s Annual Meeting. “These kinds of activities were un-

precedented, medically and politically, so many people were interested in the medical and technological part of our activities, while others were equally interested in the politics that allowed us to enter into the Soviet Union,” said Dr. Gale. The experiences with Chernobyl influenced the later work of both Drs. Gale and Champlin. Dr. Champlin, now Chair of the Department of Stem Cell Transplantation & Cellular Therapy at The University of Texas MD Anderson Cancer Center, said his work in Chernobyl provided him with rare insight on radiation therapy and the use of transplantation. Since 1986, Dr. Gale, now Visiting Professor of Hematology at Imperial College London and an international authority on the health effects of nuclear disasters, has traveled to Brazil and Japan following similar nuclear accidents. In much of his work, Dr. Gale urges oncologists to learn more about treatments for radiation exposure. “Today we face not only the risks of nuclear accidents, but also nuclear terrorism, and it’s not inconceivable that any hematologist or oncologist could encounter these kinds of events,” said Dr. Gale. “It’s quite important that oncologists are up to speed on radiation biology.” n © 2014. American Society of Clinical Oncology. All rights reserved.

A Gift for Your List: A Donation to Help Conquer Cancer

All Donations in November and December Will Be Matched 2-to-1 for Triple the Impact

W

hether it’s the approaching end of the tax year or simply the altruism of the season, many donors prefer to make charitable gifts in November and December.

Raj Mantena, RPh

This year, those donors who have a passion for conquering cancer have an added incentive to consider a tax deductible year-end gift to the Conquer

Cancer Foundation of the American Society of Clinical Oncology. Thanks to the success of his matching gift challenge in September, Raj Mantena, RPh, is renewing his 2-to-1 matching gift offer in November and December up to $1 million, meaning that all yearend gifts to the Conquer Cancer Foundation will have triple the impact. Donations to the Conquer Cancer Foundation fuel breakthrough research and education, patient information resources, and programs dedicated to improving the quality of cancer care. Guided by the expertise of ASCO and its membership, Conquer Cancer Foundation programs like the flagship Conquer Cancer Foundation of ASCO Young Investigator Award and Career Development Award are accel-

erating new discoveries and launching research careers, while ­A SCO’s Foundation-supported patient education website Cancer.Net shares trusted, oncologist-approved cancer information with millions of patients and their families around the clock. Whether your passion is improving cancer care internationally, training the next generation of researchers, strengthening prevention efforts, or simply improving the lives of patients with cancer, your gift to the Conquer Cancer Foundation strengthens the field of oncology in the face of new challenges and opportunities and gives our patients hope for a world free from the fear of cancer. To take advantage of the 2-for1 year-end matching gift, make your donation online today at

www.­conquercancerfoundation.org/ donate or by mail via secure lockbox at Conquer Cancer Foundation, PO Box 896076, Charlotte, NC 28289-6076. n © 2014. American Society of Clinical Oncology. All rights reserved. Shopping online at Amazon this holiday season? Visit smile.amazon.com and 0.05% of the purchase price of your qualifying items will be donated by Amazon to the charity of your choice. To support the Conquer Cancer Foundation simply search for “Conquer Cancer Foundation” on the Amazon Smile site.


NEW INDICATION

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

sion s e r g o r p e diseas your patients t a I D N A Start XT static CRPC fo1 r to meta therapy* on GnRH

*Or af

1 omy. chiect r o l a r e r bilat

te

Important Safety Information Contraindications XTANDI (enzalutamide) capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In Study 1, conducted in patients

with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of patients who were treated with XTANDI and 0% treated with placebo. In Study 2, conducted in patients with chemotherapy-naïve metastatic CRPC, seizure occurred in 0.1% of patients who were treated with XTANDI and 0.1% treated with placebo. Patients experiencing a seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited clinical trial experience in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Adverse Reactions The most common adverse reactions (≥ 10%) reported from the two combined clinical trials that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Other Adverse Reactions include: • Laboratory Abnormalities: In the two studies, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). • Infections: In Study 1, 1% of XTANDI versus 0.3% of placebo patients and in Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.


Significantly extended radiographic progression-free survival†1

Significantly improved overall survival†1 • 29% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.71 [95% CI, 0.60-0.84]; P < 0.0001)

• 83% reduction in risk of radiographic disease progression or death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (co-primary endpoint: HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001)

• Estimated median overall survival was 32.4 months (95% CI, 30.1-not reached) for XTANDI + GnRH therapy* and 30.2 months (95% CI, 28.0-not reached) for placebo + GnRH therapy*1

• Estimated median radiographic progression-free survival was not reached (95% CI, 13.8-not reached) for XTANDI + GnRH therapy* and was 3.7 months (95% CI, 3.6-4.6) for placebo + GnRH therapy*1

Oral, once-daily dosing with no required steroid coadministration1

Significantly delayed time to chemotherapy initiation†1 • Delayed time to chemotherapy initiation by a median of 28.0 months with XTANDI + GnRH therapy* vs 10.8 months with placebo + GnRH therapy* (HR = 0.35 [95% CI, 0.30-0.40]; P < 0.0001)

• Dosage: XTANDI 160 mg (four 40 mg capsules) is administered orally, once daily • Steroids were allowed but not required‡

Visit XtandiHCP.com or snap the QR code for more information

• Falls: In the two studies, falls including fall-related injuries occurred in 9% of XTANDI patients vs 4% treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. • Hypertension: In the two studies, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of XTANDI or placebo treated patients.

Drug Interactions • Effect of Other Drugs on XTANDI - Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers may alter the plasma exposure of XTANDI and should be avoided if possible.

© 2014 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-0292-PM 8/14 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.

• Effect of XTANDI on Other Drugs - XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. †As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC that progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,2 ‡In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial (Study 1), 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. AFFIRM was a phase 3, multicenter, placebocontrolled, randomized trial that enrolled 1199 patients with metastatic CRPC who had previously received docetaxel.1 References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.


Table 2. Adverse Reactions in Study 2

Table 1. Adverse Reactions in Study 1 XTANDI N = 800 XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)]. WARNINGS AND PRECAUTIONS Seizure In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDItreated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

XTANDI N = 871

Placebo N = 399

Grade Grade Grade Grade 3-4 1-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 Conditionsb Peripheral 15.4 1.0 13.3 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 Arthralgia 20.5 Musculoskeletal 15.0 Pain Muscular 9.8 Weakness Musculoskeletal 2.6 Stiffness Gastrointestinal Disorders Diarrhea

21.8

9.3 0.8

4.0

2.5

17.3

1.8

1.3

11.5

0.3

1.5

6.8

1.8

0.3

0.3

0.0

Grade 1-4a (%)

Grade Grade Grade 3-4 1-4 3-4 (%) (%) (%)

General Disorders Asthenic 46.9 3.4 33.0 Conditionsb Peripheral 11.5 0.2 8.2 Edema Musculoskeletal And Connective Tissue Disorders

2.8 0.4

Back Pain

28.6

2.5

22.4

3.0

Arthralgia

21.4

1.6

16.1

1.1

Gastrointestinal Disorders Constipation

23.2

0.7

17.3

0.4

Diarrhea

16.8

0.3

14.3

0.4

Vascular Disorders 1.1

17.5

0.3

Vascular Disorders Hot Flush

20.3

0.0

10.3

0.0

Hypertension

6.4

2.1

2.8

1.3

Hot Flush

18.0

0.1

7.8

0.0

Hypertension

14.2

7.2

4.1

2.3

Nervous System Disorders

Nervous System Disorders

Dizzinessc

11.3

0.3

7.1

0.0

Headache

11.0

0.2

7.0

0.4

7.6

0.1

3.7

0.0

5.7

0.0

1.3

0.1

2.1

0.1

0.4

0.0

0.6

8.5

0.6

10.5

0.0

4.7

1.1

0.1

5.7

0.0

1.3

5.8

1.3

Headache

12.1

0.9

5.5

0.0

Dysgeusia

Dizzinessc Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disordersd Hypoesthesia

9.5

0.5

7.5

0.5

7.4

6.6

4.5

3.8

Mental Impairment Disordersd Restless Legs Syndrome

6.6

0.0

4.5

0.0

Respiratory Disorders

4.3

0.3

1.8

0.0

4.0

0.3

1.8

0.0

0.0

6.5

0.3

2.4

4.8

1.3

Infections And Infestations Upper Respiratory 10.9 Tract Infectione Lower Respiratory 8.5 Tract And Lung f Infection Psychiatric Disorders 8.8

0.0

6.0

0.5

Anxiety

6.5

0.3

4.0

0.0

11.0

Infections And Infestations Upper Respiratory 16.4 0.0 Tract Infectionf Lower Respiratory Tract And 7.9 1.5 Lung Infectiong Psychiatric Disorders 8.2

Renal And Urinary Disorders Hematuria

8.8

Injury, Poisoning And Procedural Complications

Renal And Urinary Disorders Hematuria

6.9

1.8

4.5

1.0

Pollakiuria

4.8

0.0

2.5

0.0

Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 Non-pathologic 4.0 1.4 0.8 Fractures Skin And Subcutaneous Tissue Disorders

0.0 0.3

Pruritus

3.8

0.0

1.3

0.0

Dry Skin

3.5

0.0

1.3

0.0

0.1

1.3

0.3

Respiratory Disorders 3.3

Dyspneae

Insomnia

Insomnia

Epistaxis

Placebo N = 844

a CTCAE v4 b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebotreated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Fall

12.7

1.6

5.3

NonPathological 8.8 2.1 3.0 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 Appetite

0.7 1.1

0.7

Investigations Weight Decreased

12.4

0.8

8.5

0.2

Reproductive System and Breast Disorders Gynecomastia

3.4

0.0

1.4

0.0

a b c d

CTCAE v4 Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with

XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included nonpathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology (12.3)]. Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold in healthy volunteers [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology (12.3)]. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology (12.3)]. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category X [see Contraindications (4)]. Risk Summary XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no human data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. Enzalutamide caused embryo-fetal toxicity in mice at exposures that were lower than in patients receiving the recommended dose. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during


ASCOPost.com  |   NOVEMBER 15, 2014

MEDXT14535_PREVAIL Brief Summary PI-TAB Colors: Black Trim/live: DO NOT PRINT Bleed: None Trim: 10.5"w × 13.5"h Live: 9.5"w × 12.5"h Output @ 100% Giant Creative Strategy

treatment with XTANDI. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day,and cleft palate and absent palatine bone at 30 mg/kg/ day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology (12.3)]. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day

(0.3 times the human exposure based on AUC). Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Revised: September 2014 14B006-XTA-BRFS Rx Only © 2014 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-0516-PM

PAGE 85

Awards

David G. Nathan, MD, Wins Lifetime Impact Award at Boston Children’s Hospital Innovation Summit

D

avid G. Nathan, MD, President Emeritus of Dana-Farber Cancer Institute and Physician-in-Chief Emeritus of Boston Children’s Hospital, was recently honored as the inaugural recipient of

cine and research who call him a mentor.” In nominating Dr. Nathan for the award, David Williams, MD, Chief of Hematology/Oncology at Boston Children’s and Associate Chairman of Pediatric Oncology at Dana-Farber, called his mentor a “proverbial ‘triple threat’” who “combined outstanding clinical care, research, and teaching leadership,... while he also steered two major academic institutions to greater heights.”

Education and Experience David G. Nathan, MD

the Boston Children’s Hospital Lifetime Impact Award at the Hospital’s second Annual Global Pediatric Innovation Summit in Boston. In addition to his leadership at both Harvard teaching hospitals, Dr. Nathan was a pioneer in pediatric hematology/oncology and continues to be a mentor to generations of leading clinicians and physician-scientist researchers.

Lifetime Impact Award The Boston Children’s Lifetime Impact Award recognizes a clinician and/ or researcher who has devoted his entire career to accelerating innovation in pediatric medicine. It also provides national and international recognition to an individual who has made extraordinary and sustained leadership contributions throughout his career to improve health care in the field of pediatrics. The presentation of the Lifetime Impact Award and companion Rising Star Award in a ceremony at the Seaport World Trade Center on October 31 marked the culmination of a 2-day summit that brought together innovators and thought leaders from across the globe to examine opportunities in pediatric innovation.

Patient-Centered Researcher “With the selection of David Nathan as the inaugural recipient of Boston Children’s Lifetime Impact Award, we have set the bar high for this new honor,” said Boston Children’s President Sandra L. Fenwick, MPH. “David is the consummate patient-centered researcher who is not only a giant in the development of the field of pediatric hematology/oncology but also a superb leader and teacher. His legacy lives in the greater excellence he has brought to Boston Children’s and Dana-Farber, his scientific discoveries, and the many leaders in clinical medi-

After graduating from Harvard Medical School in 1955, Dr. Nathan trained in internal medicine at Boston’s Peter Bent Brigham Hospital and completed a fellowship in hematology/oncology at the National Cancer Institute. At NCI, he was exposed to children with leukemia at a time when multiagent chemotherapy was improving the survival of young patients. This, combined with his interest in the production of red blood cells, led him to pediatrics. Under Dr. Nathan’s leadership, the Division of Pediatric Hematology/Oncology at Boston Children’s and Dana-Farber developed as the country’s premier program.

A Life’s Work for Patients “It is difficult to imagine another individual whose impact on the field of pediatrics has been so broad and deep,” Stuart H. Orkin, MD, Chairman of Pediatric Oncology at Dana-Farber and Associate Chief of Hematology/Oncology at Boston Children’s, wrote in seconding Dr. Nathan’s nomination. “His influence has been felt by those in research laboratories, by those at the bedside, and, most importantly, by the patients to whom he has dedicated a life’s work.” n Disclosure: “Taking on Tomorrow” features IBM as its premier sponsor. Additional corporate partners include Philips Healthcare, Genzyme, Claritas Genomics, Deloitte, Verizon, RCN, Alere Analytics, Siemens Healthcare, American Well, Cerner Corporation, Shire, Vertex Pharmaceuticals, Janssen Research & Development, LLC, Alexion, Cisco, Astra Zeneca and Pfizer’s Centers for Therapeutic Innovation. Summit Association Partners include the Massachusetts Biotechnology Council, Healthcare Information and Management Systems Society, National Organization for Rare Disorders, Network for Excellence in Health Innovation, The Institute for Pediatric Innovation, The Institute for Healthcare Improvement, The Massachusetts Medical Device Industry Council and Mass Technology Leadership Council. Media partners feature Modern Healthcare, Boston Business Journal, WBUR-90.9 FM (Boston’s NPR News Station), MIT Technology Review, Clinical Informatics News, and Bio-IT World.


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 86

Perspective Hematology

Managing APL continued from page 1

three phenomena unique to APL among the subtypes of acute myeloid leukemias (AML): the availability of molecularly targeted therapy, the unusual sensitivity to anthracyclines of the leukemic promyelocytes, and the lack of primary resistance to ATRA and arsenic trioxide. Furthermore, among every other subtype of AML, new genetic mutations are constantly being identified, which influence outcome and, in some cases, treatment strategy. However, the most important prognostic factor in APL and the one that, other than age, influences treatment strategy is the white blood cell count. The disease is characteristically associated with a life-threatening, potentially catastrophic, and complex coagulopathy, which involves disseminated intravascular coagulation, primary and secondary fibrinolysis, and proteolysis. The bleeding diathesis accounts for the majority of early deaths, which occur often within the first 24 hours after presentation to medical care.1 Since there is no inherent primary resistance to treatment, early death has emerged as the major cause of treatment failure in APL. It is now the nextto-last frontier to conquer in the effort to cure every patient with the disease. The very last frontier will be revealed shortly to those who read on.

Scope of the Problem Cooperative group studies indicate that approximately 10% of patients with APL die early. However, such studies include patients who survive long enough to be seen in an emergency room, stabilized, evaluated, and registered for study enrollment. Population-based studies in which an attempt is made to account for every patient with the disease report that the rate of early death is much higher. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program suggest that close to 20% of younger patients die early.2 The early death rate in older adults is even higher. Other studies suggest that the early death rate may be as high as 30%. The majority of early deaths are at-

tributable to bleeding. Such bleeding occurs most often in the brain and less often in the gastrointestinal tract and lungs. Somewhat surprisingly, infection accounts for approximately 30% of early deaths. A small percentage of early deaths are due to the unique complication of either ATRA or arsenic trioxide treatment called the “differentiation syndrome.” This is a cardiorespiratory distress syndrome manifested by shortness of breath, pleural and pericardial effusions, episodic

150 mg/dL for fibrinogen, respectively, should be considered. These levels should be maintained during the first few days of therapy until the coagulopathy resolves. Maintaining these levels may be as important in preventing early death from bleeding as commencing ATRA early. Third, since the differentiation syndrome still accounts for some cases of early death, prophylactic dexamethasone—at least for high-risk patients— at the very earliest suspicion of the

Since early death due to bleeding is now the major cause of treatment failure rather than resistant disease, strategies to decrease the early death rate are critical to increase the cure rate. —Martin S. Tallman, MD

hypotension, and acute renal failure. The early recognition of the syndrome and perhaps prophylactic steroids for high-risk patients may have decreased its incidence.

Decreasing the Early Death Rate Since early death due to bleeding is now the major cause of treatment failure rather than resistant disease, strategies to decrease the early death rate are critical to increase the cure rate. First, there is some evidence, in addition to intuitive reasoning, that ATRA should be administered very early at the first suspicion of the diagnosis of APL.3 ATRA should be administered even in an emergency room based on the history, physical examination, and review of the peripheral blood smear, but only after urgent consultation with a hematologist. One should not wait for a bone marrow biopsy to be performed or for cytogenetic or molecular studies to confirm the diagnosis. Such early introduction of ATRA serves both as antileukemia therapy as well as treatment for the coagulopathy. Second, very aggressive blood products should be given, and thresholds of 50,000/μL for platelets and

Save the Date

syndrome may be helpful. Steroids should be started before studies investigating the etiology of cardiorespiratory symptoms such as imaging studies or ­bronchoscopy. While there are no studies proving that early steroids will decrease the incidence of the syndrome, intuitive reasoning suggests such an approach may be useful. Some institutional and cooperative group protocols prescribe prophylactic steroids for all patients. If the syndrome develops and is severe (requiring transfer to the intensive care unit, for example), ATRA or arsenic trioxide likely should be temporarily discontinued. Once resolved, ATRA and/or arsenic trioxide can be resumed, but with steroid coverage, since the syndrome can recur. Fourth, both ATRA and arsenic trioxide improve the coagulopathy. In addition, the combination of both agents has emerged as an excellent treatment for low-risk newly diagnosed patients with APL. In fact, a large prospective randomized trial comparing the combination of ATRA plus arsenic trioxide to ATRA plus anthracyclinebased chemotherapy demonstrated an improvement in disease-free and overall survival in low-risk patients, es-

tablishing ATRA plus arsenic trioxide without any chemotherapy as a new standard of care. The routine adoption of ATRA plus arsenic trioxide for low-risk patients, representing approximately 75% of newly diagnosed patients, may decrease the incidence of the syndrome.

Last Frontier in APL Now that the great majority of patients with APL are cured of their disease and even more patients in the future will likely be cured with the strategies above, the last frontier in APL encompasses survivorship issues. Several facts make APL conducive to survivorship studies. The median age at the time of diagnosis in APL is approximately 40 years, and therefore cured patients can anticipate many years of productive life. Patients who receive ATRA plus anthracycline-based regimens are exposed to relatively large doses of anthracyclines, and long-term follow-up cardiac studies will be important. Finally, several reports have suggested that there may be a risk of therapy-related malignancies such as myelodysplastic syndromes. The remarkable progress made in APL during the past 25 years, since the first reports of the effectiveness of ATRA, has afforded us the luxury of studying survivorship in at least one subtype of AML. n

Disclosure: Dr. Tallman reported no potential conflicts of interest.

References 1. Lehmann S, Ravn A, Carlsson L, et al: Continuing high early death rate in acute promyelocytic leukemia: A population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 11281134, 2011. 2. Park JH, Quao B, Panageas KS, et al: Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 118:1248-1254, 2011. 3. Altman JK, Rademaker A, Cull E, et al: Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res 37:10041009, 2013.

The 13th International Conference on Malignant Lymphoma Lugano, Switzerland, June 17-20, 2013 For more information, visit http://www.lymphcon.ch/imcl/index.php


ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 87

ASTRO Annual Meeting Radiation Oncology

ASTRO Initiatives Aimed at Practice Improvement By Alice Goodman

A

t the opening press conference of the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO), 2014 President Bruce G. Haffty, MD, FASTRO, Professor and Chairman of the Department of Radiation Oncology at Rutgers–Rob-

Stereotactic Radiosurgery The stereotactic radiosurgery registry represents a joint partnership between ASTRO and the American Association of Neurological Surgeons (AANS). This

comprehensive databank will define national patterns of care in radiosurgery, provide data to inform treatment benchmarks, improve patient care, and hopefully lower the cost of care for patients.

Dr. Haffty told listeners that the data will be gathered over the next 3 years from 30 diverse, high-volume sites with stereotactic radiosurgery–specific data. continued on page ASCO Post88

IN THE INDICATED POPULATION OF EGFR M+ mNSCLC PATIENTS WITH COMMON MUTATIONS*

GILOTRIF: Nearly double the PFS vs pemetrexed/cisplatin1 Common mutations population1,2,a,b

Median PFS in LUX-Lung 3 1.0

—Bruce G. Haffty, MD, FASTRO

75C, 63M, 63Y

5

75K

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reduction in risk of death or progression

6.9

months

0.2

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Time of PFS (months) a

In a prespecified subgroup analysis of patients with exon 19 deletions or exon 21 L858R substitution mutations. Measured by an independent central radiology review.

b

Overall survival (OS) • 30.3 months OS with GILOTRIF vs 26.2 months with pemetrexed/cisplatin in patients with common EGFR mutations (HR: 0.82; 95% CI, 0.59-1.14)3,4 — More than 70% of patients in LUX-Lung 3 received subsequent treatment at progression4

25 75 M+Y

25

50 75

• Del 19 (exon 19 deletions; 49%) and L858R (exon 21 substitution mutations; 40%) are the most common EGFR mutations3,5

C+Y

25

25K

95

25 75

25 25

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M+Y

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25 50 75 C+Y

50 50 50 50

50C, 39M, 39Y

25 25

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25 50 75 C+M

75 75 75 75

Indication: GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations.

SELECTED IMPORTANT SAFETY INFORMATION

5

4

3

300%

50 50

50K

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50 50

75 75 75 75

GATF/SWOP Digital Proofing Bar 2

99.5

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99.5 0.5

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■■ ASTRO and AAPM are jointly launching the Radiation Oncology Incident Learning System, a patient safety initiative that will encourage radiologists and others to anonymously share errors or near misses in the delivery of radiation, creating a database that will have important implications for practice.

CI=confidence interval; EGFR=epidermal growth factor receptor; HR=hazard ratio; mNSCLC=metastatic non-small cell lung cancer. *Common mutations=Del 19 and L858R.

INDICATION AND LIMITATION OF USE

WARNINGS AND PRECAUTIONS 25C, 16M, 16Y

C+M

50

25

53%

0.4

• Primary endpoint was progression-free survival (PFS); key secondary endpoint was OS; randomization stratified according to mutation type (Del 19 vs L858R vs other)1

1

0.5

HR: 0.47 (95% CI, 0.34-0.65)

LUX-Lung 3: Largest global trial in EGFR M+ mNSCLC to date1,2

■■ ASTRO and AANS are jointly launching a stereotactic radiosurgery registry. The data collected will be used to define national patterns of care related to the procedure at high-volume centers, to inform and improve patient care.

99.5

months

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Joint Initiatives in Radiation Oncology

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ert Wood Johnson Medical School and Associate Director at the Cancer Institute of New Jersey, New Brunswick, outlined important initiatives that the Society hopes will go a long way toward improving patient care, patient safety, and ensuring appropriate use of radiation therapy and newer techniques. They include a national registry for stereotactic radiosurgery patients and the Radiation Oncology Incident Learning System™ (RO-ILS).

13.6 13.6 months

0.8

Estimated PFS probability

Radiation is an extremely safe modality. Nonetheless, ASTRO wants to strive for zero errors. We want to look at our mistakes.

G GILOTRIF (40 mg orally once daily; n=204) Pemetrexed/cisplatin P (500 mg/m2 / 75 mg/m2 every 3 weeks, up to 6 cycles; n=104)

Diarrhea • Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3. • For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours. Please see additional Important Safety Information and brief summary of full Prescribing Information on following pages.

THINK DEL 19. THINK GILOTRIF.


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 88

ASTRO Annual Meeting Practice Improvement

and functional disorders. We are also getting support from the Neurosurgery Research & Education Foundation,” he said. Stereotactic radiosurgery is a minimally invasive approach that utilizes imaging guidance and stereotactic principles to deliver radiation to targeted cells in the body. It has gained a prominent role in the treatment of brain metastasis, benign brain

continued from page 87

“Multiple groups are putting their data together. We are excited about this initiative,” Dr. Haffty said. “The registry provides new opportunities for achieving major advances in the management of patients with complex problems such as brain tumors, vascular malformations,

tumors, and arteriovenous malformations. New data suggest that stereotactic radiosurgery will have an expanded role in treating other malignancies, including non–small cell lung cancer and pancreatic cancer. As its applications expand, registry data will help inform practice. A Scientific Advisory Committee will oversee the registry, approving sites that

contribute data, plan and manage data collection, develop plans for data analysis, and develop procedures for responding to requests for access to registry data. The committee will also review and approve public presentations of the data. The data will be made available to the scientific community and the public, but no patient names will be included.

IN THE 1ST-LINE IN THE TREATMENT IN 1ST-LINE THE 1ST-LINE TREATMENT OF EGFR TREATMENT M+OF mNSCLC EGFR OF EGFR M+ vs CHEMOTHERAPY mNSCLC M+ mNSCLC vs CHEMOTHERAPY vs CHEMOTHERAPY

GILOTRIF: GILOTRIF: GILOTRIF: Only agent Only Only to agent demonstrate agent to to demonstrate demonstrate improved improved improved OS OSOS in patients in patients inwith patients Del with 19 with Del EGFR Del 19mutations 19 EGFR EGFR mutations mutations

GILOTR mutatio

1.0

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1.0

Estimated OS probability

Estimated OS probability

3 3 3 6,a,b Del 19 mutations Del 19 Del population mutations 19 mutations population population Median OS Median in LUX-Lung Median OS inOS 3LUX-Lung in LUX-Lung 36,a,b 36,a,b

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a a In a prespecified subgroup In a prespecified analysis In a prespecified of subgroup patientssubgroup with analysis exonanalysis of 19patients deletions of patients with forexon thewith secondary 19 exon deletions 19endpoint deletions for the of secondary for OS. the secondary endpoint endpoint of OS. of OS. b b Measured by an independent Measured Measured central by an independent radiology by an independent review. central radiology central radiology review. review.

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References: 1. Se in patients with m 2. Data on file. Bo • In 3865 patients •who In 3865 received • Inpatients 3865 GILOTRIF patients who received across who received clinical GILOTRIF trials, GILOTRIF across 10.1%clinical across had liver clinical trials, test 10.1% trials, abnormalities, 10.1% had liver had test ofliver which abnormalities, test7abnormalities, (0.18%) of were which fatal. of7which (0.18%) In the 7 pivotal (0.18%) were fatal. study, wereInfatal. the pivotal In the pivotal study, study, Boehringer Ingelh liver test abnormalities liver test of liver any abnormalities test grade abnormalities occurred of anyingrade of17.5% any occurred grade of theoccurred patients in 17.5% treated in of 17.5% thewith patients of the GILOTRIF. patients treatedtreated with GILOTRIF. with GILOTRIF. PFS table. 5. Seq • Obtain periodic •liver Obtain testing • Obtain periodic in patients periodic liver testing during liver testing in treatment patients in patients with during GILOTRIF. during treatment treatment Withhold with GILOTRIF. with GILOTRIF GILOTRIF. Withhold in patients Withhold GILOTRIF whoGILOTRIF develop in patients worsening in patients who develop of who liver develop worsening function. worsening of liver of function. liver function. factor receptor a Boehringer Ingel In patients who develop In patients In severe patients whohepatic develop who impairment develop severe severe hepatic while hepatic impairment takingimpairment GILOTRIF, while taking treatment while taking GILOTRIF, should GILOTRIF, treatment be discontinued. treatment shouldshould be discontinued. be discontinued.

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ASCOPost.com  |   NOVEMBER 15, 2014

PAGE 89

ASTRO Annual Meeting BrainLAB is providing financial sponsorship, and other sponsors are actively being pursued.

RO-ILS Safety Inititative The Radiation Oncology Incident Learning System, a joint effort of A ­ STRO and the American Association of Physicists in Medicine (AAPM), is a patient

safety initiative. Dr. Haffty called it the tion oncology community to be alerted to “centerpiece” of ASTRO’s Target Safely potential problems, Dr. Haffty explained. plan. Annual Meeting attendees were The data collection enables detection urged to participate by accessing the guide of patterns related to safety. “The anonymavailable via www.astro.org/ROILS. ity provides confidentiality and creates a Participation is open to all members of secure environment for sharing internal the radiation oncology team. Data on radi- incidents with a national database,” he ation errors or near misses will be submit- said. Reports will be generated for dissemASCO Post ASCO ASCO Post Postaggregate data on events ted anonymously and will allow the radiaination, including

RIF: GILOTRIF: Median GILOTRIF: PFS Median Median and PFS OS PFS results andand OSfor OS results patients results for for patients with patients L858R withwith L858R L858R ons mutations (n=138) mutations (n=138) (n=138)

1-3 1-3 nths• PFS 10.8•with months 10.8GILOTRIF months PFS with PFS vs 8.1 GILOTRIF with months GILOTRIF vswith 8.1vs pemetrexed/cisplatin months 8.1 months with pemetrexed/cisplatin with pemetrexed/cisplatin (HR: 0.73; 95% (HR: CI, 0.73; (HR: 0.46-1.17) 0.73; 95% 1-3 CI, 95%0.46-1.17) CI, 0.46-1.17)

6 6 nths• OS 27.2with • months 27.2GILOTRIF months OS with OS vs not GILOTRIF withestimable GILOTRIF vs not with vsestimable not pemetrexed/cisplatin estimable with pemetrexed/cisplatin with pemetrexed/cisplatin (HR: 1.30; 95% (HR: CI, 1.30; (HR: 0.76-2.23) 1.30; 95% 6CI, 95%0.76-2.23) CI, 0.76-2.23)

n ofLimitation use Limitation of use of use

3 3 3 ficacy • Safety of GILOTRIF • and Safety efficacy and haveefficacy not of GILOTRIF been of GILOTRIF established have not have inbeen patients notestablished been whose established tumors in patients in have patients whose otherwhose tumors EGFR mutations tumors have other have EGFR othermutations EGFR mutations

mutations • Uncommon (n=37) • Uncommon mutations mutations (n=37) (n=37)

re 26 GILOTRIF-treated — There — were There26were GILOTRIF-treated patients 26 GILOTRIF-treated in the “other” patients (uncommon) patients in the “other” in the “other” (uncommon) (uncommon) 3 3 ations subgroup, EGFR mutations EGFR which mutations consisted subgroup, subgroup, of which 9 unique consisted which mutation consisted of 9patterns unique of 93unique mutation mutation patterns patterns

FS: 2.8—months Median — with Median PFS: GILOTRIF 2.8 PFS: months 2.8 vsmonths 9.9 withmonths GILOTRIF with with GILOTRIF vs pemetrexed/ 9.9 months vs 9.9 months with pemetrexed/ with pemetrexed/ 3,4 3,4 3,4 HR: 1.89;cisplatin 95% CI, cisplatin (HR: 0.84-4.28) 1.89; (HR:95% 1.89; CI,95% 0.84-4.28) CI, 0.84-4.28)

OS: 15.9 — months Median — Median with OS: GILOTRIF; 15.9 OS: months 15.9pemetrexed/cisplatin months with GILOTRIF; with GILOTRIF; pemetrexed/cisplatin pemetrexed/cisplatin 3,6 3,6 3,6 able (HR:not 3.08; estimable 95% not estimable CI,(HR: 1.04-9.15) 3.08; (HR:95% 3.08; CI,95% 1.04-9.15) CI, 1.04-9.15)

ommon Identify Identify EGFR common mutations. common EGFREGFR Treat mutations. with mutations. TreatTreat with with and GILOTRIF support GILOTRIF and patients support and support through patients patients the through through the the TM TM program. program. program. Plus Solutions Solutions PlusTM Plus

D IMPORTANT SELECTED SELECTED IMPORTANT SAFETY IMPORTANT INFORMATION SAFETY SAFETY INFORMATION INFORMATION

NDWARNINGS PRECAUTIONS WARNINGS AND PRECAUTIONS AND PRECAUTIONS Keratitis Keratitis

aracterized • Keratitis, •as Keratitis, acute characterized orcharacterized worsening as acute eye asinflammation, or acute worsening or worsening eye lacrimation, inflammation, eye inflammation, light sensitivity, lacrimation, lacrimation, blurred light sensitivity, vision, light sensitivity, eyeblurred pain, and/or blurred vision,red vision, eyeeye pain, eye occurred and/or pain, and/or red eyered occurred eye occurred atientsintreated with GILOTRIF among across clinical Keratitis was reported in Keratitis 5 was (2.2%) patients 0.8%inof0.8% patients of patients treated treated with 3865 GILOTRIF withpatients GILOTRIF among among 3865 patients 3865trials. patients across across clinical clinical trials. Keratitis trials. reported was reported inin 5 the (2.2%) inpivotal 5 patients (2.2%) patients in the pivotal in the pivotal Grade study, 3 in 1 (0.4%). Withhold during evaluation of patients with suspected and ifsuspected diagnosis ofand ulcerative with study, Grade with Grade 3 in 1GILOTRIF (0.4%). 3 in 1 (0.4%). Withhold Withhold GILOTRIF GILOTRIF during during evaluation evaluation of patients of keratitis, patients with suspected with keratitis, keratitis, if diagnosis and ifkeratitis diagnosis of ulcerative of ulcerative keratitis keratitis treatment with GILOTRIF should interrupted orshould discontinued. Ifor keratitis diagnosed, the benefits risks of continuing is confirmed, is confirmed, treatment treatment with be GILOTRIF with GILOTRIF should be interrupted be interrupted discontinued. or is discontinued. If keratitis If keratitis is diagnosed, is and diagnosed, the benefits the benefits and risks and ofrisks continuing of continuing ould be carefully considered. GILOTRIF should be usedGILOTRIF with caution in patients with history ofpatients keratitis, ulcerative keratitis, or ulcerative treatment treatment should should be carefully be carefully considered. considered. GILOTRIF should should be used bewith used caution withacaution in patients in with a history with a history of keratitis, of keratitis, ulcerative keratitis, keratitis, or or ye. Contact usedry isContact also risk keratitis and ulceration. severelens severe dry eye. eye.aContact lensfactor use lens isfor also use ais risk alsofactor a risk for factor keratitis for keratitis and ulceration. and ulceration.

ditional Important Safety Information and Safety brief summary ofbrief full Prescribing Please Please see additional see additional Important Important Safety Information Information and and summary brief summary of full Prescribing of full Prescribing n following pages. Information Information on following on following pages.pages.

t www.GILOTRIF.com. Learn more Learn at more www.GILOTRIF.com. at www.GILOTRIF.com.

equist References: LV, Yang References: JC, 1. Sequist Yamamoto 1. Sequist LV, Yang N, etLV, JC, al.Yang Phase Yamamoto JC, III Yamamoto study N, et of afatinib al.N, Phase et al. orIIIPhase cisplatin studyIII ofstudy plus afatinib pemetrexed of afatinib or cisplatin or cisplatin plus pemetrexed plus pemetrexed metastatic in patients lung in patients with adenocarcinoma metastatic with metastatic lung with adenocarcinoma EGFR lung adenocarcinoma mutations. with J Clin EGFR with Oncol. mutations. EGFR 2013;31(27):3327-3334. mutations. J Clin Oncol. J Clin 2013;31(27):3327-3334. Oncol. 2013;31(27):3327-3334. ® ® (afatinib) Prescribing (afatinib) (afatinib) Information. tablets Prescribing tablets Ridgefield, Prescribing Information. CT: Information. Ridgefield, Ridgefield, CT: CT: oehringer 2. DataIngelheim. 2. onData file. Boehringer onCTR. file. 3. Boehringer Gilotrif Ingelheim. Ingelheim. CTR. tablets 3. CTR. Gilotrif 3.®Gilotrif heim Boehringer Pharmaceuticals, Boehringer Ingelheim Inc.; Ingelheim Pharmaceuticals, April 2014. Pharmaceuticals, 4. Data Inc.;on April file. Inc.; 2014. Boehringer April 4.2014. DataIngelheim. 4. onData file. Boehringer onOther file. Boehringer mutations Ingelheim. Ingelheim. Other mutations Other mutations quistPFS LV, Bell table. PFS DW, 5.table. Sequist Lynch5.TJ, Sequist LV,Haber Bell DW, LV, DA. Bell Lynch Molecular DW,TJ, Lynch Haber predictors TJ,DA. Haber Molecular of DA. response Molecular predictors to epidermal predictors of response growth of response to epidermal to epidermal growth growth antagonists factor receptor factor in non–small-cell receptor antagonists antagonists lung in cancer. non–small-cell in non–small-cell J Clin Oncol. lung cancer. 2007;25(5):587-595. lung cancer. J Clin Oncol. J Clin 2007;25(5):587-595. 6. Oncol. Data 2007;25(5):587-595. on file. 6. Data 6. onData file. on file. THINK DEL 19.THINK THINK THINK DEL GILOTRIF. 19. DEL THINK 19. THINK GILOTRIF. GILOTRIF. lheim. Boehringer OS tables. Boehringer Ingelheim. Ingelheim. OS tables. OS tables.

that occur throughout the country. “Radiation is an extremely safe modality. Nonetheless, ASTRO wants to strive for zero errors. We want to evaluate our errors or near misses, learn from these events, and modify our processes to improve patient safety and quality, ” Dr. Haffty said. n Disclosure: Dr. Haffty reported no potential conflicts of interest.


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 90

Journal Spotlight Gastrointestinal Oncology

Incidence of Colorectal Cancer in Young Adults Expected to Rise

W

hile the incidence of colorectal cancer in people 50 years or older has declined, the incidence among people 20 to 49 years has increased, according to a report published online recently by JAMA Surgery.1 From 1998 through 2006, the incidence of colorectal cancer declined

3% per year in men and 2.4% in women, a decrease largely attributed to an increase in screening, which is recommended for all adults over 50 years old. However, incidence of colorectal cancer in adults younger than 50, for whom screening is not recommended, appears to be increas-

ing and those patients are more likely to present with advanced disease, according to background information in the study.

SEER Colorectal Cancer Registry Researcher Christina E. Bailey, MD, MSCI, a surgical oncology fellow

at The University of Texas MD Anderson Cancer Center, Houston, and her coauthors analyzed age disparities in trends in colorectal cancer incidence in the United States. The authors used data from the Surveillance, Epidemiology and End Results (SEER) ASCOcolorecPost

Indication and Important Safety Information INDICATION AND LIMITATION OF USE Indication: GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations. WARNINGS AND PRECAUTIONS Diarrhea • Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3. • For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.

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0.5

Bullous and Exfoliative Skin Disorders • Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmarplantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. Interstitial Lung Disease (ILD) • ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In the pivotal study, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. • Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD. Hepatic Toxicity • In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF. • Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued. Keratitis • Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Embryofetal Toxicity • GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. • Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF. Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer • An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving GILOTRIF in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of GILOTRIF and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. GILOTRIF combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer. ADVERSE REACTIONS • In GILOTRIF-treated patients (n=229) the most common adverse reactions in the pivotal study (≥20% all grades and vs pemetrexed/ cisplatin-treated patients (n=111)) were diarrhea (96% vs 23%), rash/ dermatitis acneiform (90% vs 11%), stomatitis (71% vs 15%), paronychia (58% vs 0%), dry skin (31% vs 2%), decreased appetite (29% vs 55%), pruritus (21% vs 1%). • Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). • More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). DRUG INTERACTIONS Effect of P-glycoprotein (P-gp) Inhibitors and Inducers • Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib. • Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib. USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether afatinib is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Renal Impairment • GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated. Hepatic Impairment • GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated. GF PROF ISI APR 2014

Please see brief summary of full Prescribing Information on following pages. Copyright © 2014. Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (10/14) GF623200PROF

THINK DEL 19. THINK GILOTRIF.


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Journal Spotlight

tal cancer registry. Data were obtained from the National Cancer Institute’s SEER registry for all patients diagnosed with colon or rectal cancer from 1975 through 2010 (N = 393,241). The study results indicate that overall, the colorectal cancer incidence rate declined 0.92% between 1975 and 2010. The colorectal cancer

incidence rates declined overall by 1.03% in men and 0.91% in women. The most pronounced decline was 1.15% in patients 75 years or older, while the rate for patients 50 to 74 years dropped 0.97%. However the colorectal cancer incidence rates increased for patients 20 to 49 years old, with the biggest increase of 1.99% in

GILOTRIF® (afatinib) tablets, for oral use

rhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue antidiarrheal therapy until loose bowel movements cease for 12 hours. Bullous and Exfoliative Skin Disorders: Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials [see Adverse Reactions]. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions [see Dosage and Administration]. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration]. Interstitial Lung Disease (ILD): ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients. Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD [see Dosage and Administration]. Hepatic Toxicity: In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF. Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function [see Dosage and Administration]. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued. Keratitis: Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued [see Dosage and Administration]. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye [see Adverse Reactions]. Contact lens use is also a risk factor for keratitis and ulceration. Embryofetal Toxicity: Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2

Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE: GILOTRIF is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumors have other EGFR mutations. DOSAGE AND ADMINISTRATION: Patient Selection: Select patients for the first-line treatment of metastatic NSCLC with GILOTRIF based on the presence of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations in tumor specimens [see Indications and Usage]. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics. Recommended Dose: The recommended dose of GILOTRIF is 40 mg orally once daily until disease progression or no longer tolerated by the patient. Take GILOTRIF at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose. Dose Modification: Withhold GILOTRIF for any drug-related adverse reactions of: NCI CTCAE* Grade 3 or higher; Diarrhea of Grade 2 or higher persisting for 2 or more consecutive days while taking anti-diarrheal medication [see Warnings and Precautions]; Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable [see Warnings and Precautions]; Renal dysfunction of Grade 2 or higher. Resume treatment when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute GILOTRIF at a reduced dose, i.e., 10 mg per day less than the dose at which the adverse reaction occurred. Permanently discontinue GILOTRIF for: Life-threatening bullous, blistering, or exfoliative skin lesions [see Warnings and Precautions]; Confirmed interstitial lung disease (ILD) [see Warnings and Precautions]; Severe drug-induced hepatic impairment [see Warnings and Precautions]; Persistent ulcerative keratitis [see Warnings and Precautions]; Symptomatic left ventricular dysfunction; Severe or intolerable adverse reaction occurring at a dose of 20 mg per day. P-gp Inhibitors: For patients who require therapy with a P-glycoprotein (P-gp) inhibitor, reduce GILOTRIF daily dose by 10 mg if not tolerated. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated [see Drug Interactions]. P-gp Inducers: For patients who require chronic therapy with a P-gp inducer, increase GILOTRIF daily dose by 10 mg as tolerated. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer [see Drug Interactions]. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS: Diarrhea: Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks [see Adverse Reactions]. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3. For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diar*National Cancer Institute Common Terminology Criteria for Adverse Events, v 3.0

patients 20 to 34 years old. The rate increased 0.41% in patients 35 to 49 years old.

Trend Toward Increasing Incidence in Younger People The authors estimate that by 2020 and 2030, the incidence rate of colon cancer will increase by 37.8% and 90%, weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations]. Combination with Vinorelbine in HER2 Positive Metastatic Breast Cancer: An early interim overall survival analysis of a randomized Phase 3 trial in HER2 positive metastatic breast cancer showed an increased mortality in patients receiving GILOTRIF in combination with vinorelbine compared to trastuzumab and vinorelbine. The combination of GILOTRIF and vinorelbine was also associated with a higher rate of adverse events (such as diarrhea, rash) and fatal events related to infections and cancer progression. GILOTRIF combined with vinorelbine should not be used in patients with HER2 positive metastatic breast cancer. ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: Diarrhea [see Warnings and Precautions]; Bullous and Exfoliative Skin Disorders [see Warnings and Precautions]; Interstitial Lung Disease [see Warnings and Precautions]; Hepatic Toxicity [see Warnings and Precautions]; Keratitis [see Warnings and Precautions]; Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety evaluation of GILOTRIF is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving GILOTRIF monotherapy at or above the recommended dose. Controlled Study: The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naïve GILOTRIF-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m² followed after 30 minutes by cisplatin 75 mg/m² every three weeks for a maximum of six treatment courses. The median exposure was 11.0 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%). Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%). Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%). Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%). Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced

respectively, for patients 20 to 34 years old, while decreasing by 23.2% and 41.1%, respectively, for patients older than 50 years. By 2020 and 2030, the incidence rates for rectosigmoid and rectal cancers are expected to increase by 49.7% and 124.2%, respectively, for patients continued on page 92 ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). Table 1 Adverse Reactions Reported in ≥10% of Gilotrif™ (afatinib) tablets-Treated Patients in Study 1 Pemetrexed/ Cisplatin n=111 All Grade All Grade Adverse Grades 3* Grades 3* Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 96 15 23 2 71 9 15 1 Stomatitis1 Cheilitis 12 0 1 0 Skin and subcutaneous tissue disorders Rash/Dermatitis 90 16 11 0 acneiform2 Pruritus 21 0 1 0 Dry skin 31 0 2 0 Infections and infestations Paronychia3 58 11 0 0 Cystitis 13 1 5 0 Metabolism and nutrition disorders Decreased 29 4 55 4 appetite Respiratory, thoracic and mediastinal disorders Epistaxis 17 0 2 1 Rhinorrhea 11 0 6 0 Investigations Weight 17 1 14 1 decreased General disorders and administration site conditions Pyrexia 12 0 6 0 Eye disorders Conjunctivitis 11 0 3 0 GILOTRIF n=229

*None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity. 1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration 2 Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform 3 Includes paronychia, nail infection, nail bed infection

Table 2 Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in ≥5% of GILOTRIF-Treated Patients in Study 1 GILOTRIF n=229 Adverse Reaction

Pemetrexed/ Cisplatin n=111 All Grades All Grades Grades 3-4 Grades 3-4 (%) (%) (%) (%) 11 2 4 0

Alanine aminotransferase increased Hypokalemia1 11 Aspartate 8 aminotransferase increased

4 2

5 2

4 1

1 Includes hypokalemia, blood potassium decreased SOC=system organ class

DRUG INTERACTIONS: Effect of P-glycoprotein (P-gp) Inhibitors and Inducers: Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of GILOTRIF increased systemic exposure to afatinib by 48%. There was


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Journal Spotlight Colorectal Cancer Incidence continued from page 91

20 to 34 years old, while decreasing 23.2% and 41%, respectively, for patients older than 50 years, according to the results. “The increasing incidence of colorectal cancer among young adults is concerning and highlights the need ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1). Table 1 Adverse Reactions Reported in ≥10% of Gilotrif™ (afatinib) tablets-Treated Patients in Study 1 Pemetrexed/ Cisplatin n=111 All Grade All Grade Adverse Grades 3* Grades 3* Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 96 15 23 2 71 9 15 1 Stomatitis1 Cheilitis 12 0 1 0 Skin and subcutaneous tissue disorders Rash/Dermatitis 90 16 11 0 acneiform2 Pruritus 21 0 1 0 Dry skin 31 0 2 0 Infections and infestations Paronychia3 58 11 0 0 Cystitis 13 1 5 0 Metabolism and nutrition disorders Decreased 29 4 55 4 appetite Respiratory, thoracic and mediastinal disorders Epistaxis 17 0 2 1 Rhinorrhea 11 0 6 0 Investigations Weight 17 1 14 1 decreased General disorders and administration site conditions Pyrexia 12 0 6 0 Eye disorders Conjunctivitis 11 0 3 0 GILOTRIF n=229

*None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity. 1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration 2 Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform 3 Includes paronychia, nail infection, nail bed infection

Table 2 Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in ≥5% of GILOTRIF-Treated Patients in Study 1 GILOTRIF n=229

Adverse Reaction

Pemetrexed/ Cisplatin n=111 All Grades All Grades Grades 3-4 Grades 3-4 (%) (%) (%) (%) 11 2 4 0

Alanine aminotransferase increased Hypokalemia1 11 Aspartate 8 aminotransferase increased

4 2

5 2

4 1

1 Includes hypokalemia, blood potassium decreased SOC=system organ class

DRUG INTERACTIONS: Effect of P-glycoprotein (P-gp) Inhibitors and Inducers: Oral administration of a P-gp inhibitor (ritonavir at 200 mg twice daily) 1 hour before administration of GILOTRIF increased systemic exposure to afatinib by 48%. There was

to investigate potential causes and external influences such as lack of screening and behavioral factors,” the authors concluded. Colorectal cancer is the third most common malignancy among both men and women, with an estimated 142,820 new cases and an estimated 50,830 deaths in the United States in 2013. no change in afatinib exposure when ritonavir was administered simultaneously with or 6 hours after GILOTRIF. Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib [see Dosage and Administration]. Co-administration with oral dose of a P-gp inducer (rifampicin at 600 mg once daily for 7 days) decreased exposure to afatinib by 34%. Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib [see Dosage and Administration]. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category D. Risk Summary: Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions]. Animal Data: Administration of afatinib to pregnant rabbits at doses of 5 mg/kg (approximately 0.2 times the exposure by AUC at the recommended human dose of 40 mg daily) or greater during the period of organogenesis caused increased post implantation loss and, in animals showing maternal toxicity, abortion at late gestational stages. In the same study, at the high dose level of 10 mg/kg (approximately 0.7 times the exposure by AUC at the recommended human dose of 40 mg daily) there were reduced fetal weights, and increases in the incidence of runts, as well as visceral and dermal variations. In an embryofetal development study in rats, there were skeletal alterations consisting of incomplete or delayed ossifications and reduced fetal weight at a dose of 16 mg/kg (approximately twice the exposure at the recommended human dose of 40 mg daily). Nursing Mothers: It is not known whether afatinib is present in human milk. Afatinib was present in the milk of lactating rats at concentrations 80150 times higher than those found in plasma from 1 to 6 hours after administration. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of GILOTRIF in pediatric patients have not been established. Geriatric Use: Of the 3865 patients in the clinical studies of GILOTRIF, 32% of patients were 65 years and older, while 7% were 75 years and older. No overall differences in safety were observed between patients 65 years and over and younger patients. In Study 1, 39% of the 345 patients were 65 years of age or older and 4% were 75 years or older. No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Females and Males of Reproductive Potential: Contraception: Females: Counsel patients on pregnancy planning and prevention. Advise female patients of reproductive potential to use highly effective contraception during treatment with GILOTRIF, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations]. Renal Impairment: GILOTRIF has not been studied in patients with severely impaired renal function (creatinine clearance [CLcr] <30 mL/min). Adjustments to the starting dose of

“While our study observations are limited to colorectal cancer, similar concerns are being raised about breast cancer, as we see incidence increasing among younger women,” said principal investigator George J. Chang, MD, MS, Associate Professor, Departments of ASCO Post and Health Services Surgical Oncology Research, at MD Anderson Cancer Cen-

ter. “Identifying these patterns is a crucial first step toward initiating important shifts in cancer ­prevention.” n Reference 1. Bailey CE, Hu CY, You N, et al: Increase in incidence of colorectal cancer in young adults, rates expected to rise. JAMA Surg. November 5, 2014 (early release online).

GILOTRIF are not considered necessary in patients with mild (CLcr 60-89 mL/min) renal impairment. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated. Hepatic Impairment: GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Adjustments to the starting dose of GILOTRIF are not considered necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

Commentary: Screening Young Adults for Nonhereditary Colorectal Cancer

OVERDOSAGE Overdose was reported in 2 healthy adolescents each of whom ingested 360 mg of GILOTRIF (as part of a mixed-drug ingestion) resulting in nausea, vomiting, asthenia, dizziness, headache, abdominal pain, and elevated amylase (<1.5 times upper limit of normal [ULN]). Both subjects recovered.

n a related commentary, ­Kiran K. Turaga, MD, MPH, of the Medical College of Wisconsin, Milwaukee, writes: “In the setting of these congratulatory reports of a successful public health screening program, this report from Bailey et al is rather unsettling.” “Nevertheless, assuming that this increasing incidence of colorectal cancer in young adults is a real phenomenon, it begs the question of why this is occurring and what one should do about it,” Dr. Turaga continues. “Hence, widespread application of colonoscopic screening might add significant cost and risk without societal benefit. However, this report should stimulate opportunities for development of better risk-prediction tools that might help us identify these individuals early and initiate better screening/prevention strategies. The use of stool DNA, genomic profiling and mathematical modeling might all be tools in the armamentarium of the oncologist in the near future,” the author concludes. n

PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling (Patient Information). Diarrhea: Advise patients that diarrhea occurs in nearly all patients who receive GILOTRIF. Inform patients that diarrhea may result in dehydration and renal impairment if not treated. Advise patients to notify their physician if diarrhea develops and to seek medical attention promptly for severe or persistent diarrhea [see Warnings and Precautions (5.1) and Adverse Reactions]. Bullous and Exfoliative Skin Disorders: Advise patients to minimize sun exposure with protective clothing and use of sunscreen while taking GILOTRIF [see Warnings and Precautions]. Interstitial Lung Disease: Advise patients to immediately report any new or worsening lung symptoms, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, fever [see Warnings and Precautions]. Hepatic Toxicity: Advise patients that they will need to undergo liver function monitoring periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy) [see Warnings and Precautions]. Keratitis: Advise patients to immediately report eye problems (e.g., eye pain, swelling, redness, blurred vision, or other vision changes) [see Warnings and Precautions]. Left Ventricular Dysfunction: Advise patients to contact a healthcare professional immediately for any of the following: new onset or worsening shortness of breath or exercise intolerance, cough, fatigue, swelling of the ankles/legs, palpitations, or sudden weight gain [see Dosage and Administration and Adverse Reactions]. Instructions for Taking GILOTRIF: Advise patients to take GILOTRIF on an empty stomach at least 1 hour before or 2 hours after eating [see Dosage and Administration]. Advise patients not to take a missed dose within 12 hours of the next dose. Embryofetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after taking the last dose of GILOTRIF [see Warnings and Precautions and Use in Specific Populations]. Nursing Mothers: Advise patients to discontinue nursing while taking GILOTRIF [see Use in Specific Populations)].

I

Reference 1. Turaga KK: Commentary: Screening young adults for nonhereditary colorectal cancer. JAMA Surg. November 5, 2014 (early release online).

Copyright © 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED Revised: April 2014 GF-BS (4-14) GF612024PROF

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Journal Spotlight Hematology

Continuous Lenalidomide/Dexamethasone Improves Progression-Free Survival in Transplant-Ineligible Patients With Myeloma By Matthew Stenger

I

n the phase III FIRST trial reported in The New England Journal of Medicine, Lotfi Benboubker, MD, Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU), Tours, France, and colleagues found that continuous lenalidomide (Revlimid) plus dexamethasone significantly improved progression-free survival vs MPT (melphalan, prednisone, thalidomide [Thalomid]) in transplant-ineligible myeloma patients.1 An interim analysis suggested an overall survival benefit with continuous lenalidomide/dexamethasone.

Study Details In this open-label trial, 1,623 patients from 246 treatment centers in 18 countries in Europe, North America, and the Asia-Pacific region were randomly assigned between August 2008 and March 2011 to receive continuous lenalidomide plus dexamethasone in 28-day cycles until disease progression (n = 535), lenalidomide/dexamethasone for 72 weeks (18 cycles; n = 541), or MPT for 72 weeks (n = 547). Patients were either aged ≥ 65 years or both < 65 years and ineligible for stem-cell transplantation. Lenalidomide was given at 25 mg on days 1 to 21, and dexamethasone was given at 40 mg on days 1, 8, 15, and 22 of each 28-day cycle. The primary endpoint was progression-free survival with continuous lenalidomide/dexamethasone vs MPT. The three patient groups were generally balanced for age (median, 73 years in all, 94%–95% ≥ 65 years), sex (50%–55% male), race/ethnicity (89%–90% white, 7%–8% Asian), Eastern Cooperative Oncology Group performance status (0 in 29%–30%, 1 in 48%–50%), International Staging System stage (I or II in 59%–60%), myeloma subtype (IgG in 61%-64%, IgA in 22%–26%), lactate dehydrogenase level (lower in 79%–84%), creatinine clearance (<  30 mL/min in 8%–10%, ≥  60 mL/min in 50%–53%), history of bone lesions (71%–72%), and high-risk cytogenetic profile (17%–20% in 248–261 assessed patients).

Improved Progression-Free Survival Median duration of follow-up among surviving patients was 37.0 months. Median progression-free survival was 25.5 months with continuous lenalidomide/ dexamethasone, 20.7 months with 18 cycles of lenalidomide/dexamethasone, and 21.2 months with MPT, with hazard ratios (HRs) of 0.72 (P < .001) for continuous lenalidomide/dexamethasone vs MPT and 0.70 (P < .001) for continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone.

mide/dexamethasone was not associated with significantly different 4-year overall survival vs 18 cycles of lenalidomide/ dexamethasone (HR = 0.90, P = .31). Benefits of continuous lenalidomide/ dexamethasone vs MPT for both progression-free and overall survival were observed in most subgroups, including younger patients and those aged > 75 years. Benefit was questionable in subgroups with poor prognostic features, including patients with high-risk cytogenetic profiles and those with elevated lactate dehydrogenase.

[T]reatment with continuous lenalidomidedexamethasone, an alkylator-free doublet oral regimen, significantly improved progression-free survival, as compared with the alkylator-based triplet regimen MPT among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. —Lotfi Benboubker, MD, and colleagues

There was no difference in progression-free survival between the 18-cycle lenalidomide/dexamethasone group and the MPT group (HR = 1.03, P = .70). The progression-free survival benefit of continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone was greatest among patients with very good partial response or complete response.

Overall Survival Interim Analysis On interim analysis, 3-year overall survival was 70% with continuous lenalidomide/dexamethasone, 66% with 18 cycles of lenalidomide/dexamethasone, and 62% with MPT, and 4-year overall survival was 59%, 56%, and 51%, respectively. The difference in overall survival did not cross the prespecified superiority boundary (P < .0096), but the hazard ratio for death favored continuous lenalidomide/dexamethasone vs MPT (0.78, P = .02). Continuous lenalido-

Doublet vs Triplet Regimen in Myeloma ■■ Continuous lenalidomide/dexamethasone improved progression-free survival vs melphalan/prednisone/thalidomide. ■■ Interim analysis of overall survival suggests a benefit of continuous lenalidomide/dexamethasone.

Responses Response rates were 75% with continuous lenalidomide/dexamethasone, 73% with 18 cycles of lenalidomide/ dexamethasone, and 62% with MPT (P < .001 for comparisons with both lenalidomide regimens); rates of very good partial response were 44%, 43%, and 28%, and rates of complete response were 15%, 14%, and 9%. Median time to response was significantly shorter in the two lenalidomide groups vs the MPT group (1.8 months in both vs 2.8 months, P < .001). Responses were more durable with continuous lenalidomide/dexamethasone vs 18 cycles of lenalidomide/dexamethasone or MPT (P < .001 for both comparisons). Second-line therapy was used in 43% of patients in the continuous lenalidomide/dexamethasone group, 55% of the group receiving 18 cycles of lenalidomide/dexamethasone, and 56% of the MPT group. Time to second-line therapy was 39.1, 28.5 months (P < .001 vs continuous lenalidomide), and 26.7 months (P < .001 vs continuous lenalidomide). The progression-free survival benefit of continuous lenalidomide/dexamethasone continued through the second-line of therapy, with median progression-free

survival including second-line treatment being 42.9 months in the initial continuous lenalidomide group vs 36.3 months in the initial MPT group (HR = 0.78, P = .005).

Toxicity Grade 3 or 4 adverse events occurred in 85% of the continuous lenalidomide/ dexamethasone group, 89% of the 18-cycle lenalidomide/dexamethasone group, and 89% of the MPT group. The most common hematologic grade 3 or 4 adverse events were neutropenia (28%, 26%, and 45%) and anemia (18%, 16%, and 19%). The most common nonhematologic grade 3 or 4 adverse events were infection (29%, 22%, and 17%) and cardiac disorders (12%, 7%, and 9%). Febrile neutropenia occurred in 1%, 3%, and 3% of patients. Deep-vein thrombosis or pulmonary embolism occurred in 8%, 6%, and 5%. Peripheral sensory neuropathy occurred in ≤ 1% of lenalidomide recipients vs 9% of MPT recipients. Cataracts occurred in 6%, 3%, and 1% of patients. Invasive second primary cancers were found in 3%, 6%, and 5% of patients, with hematologic cancers found in < 1%, < 1%, and 2% and solid tumors found in 3%, 5%, and 3%. Most adverse events in the continuous lenalidomide/dexamethasone group occurred during the first 18 months of treatment. The investigators concluded: [T]reatment with continuous lenalidomide-dexamethasone, an alkylatorfree doublet oral regimen, significantly improved progression-free survival, as compared with the alkylator-based triplet regimen MPT among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. A survival benefit was also seen with continuous lenalidomide-dexamethasone in an interim analysis…. [The findings thus far suggest that patients] who are elderly or are ineligible for stem-cell transplantation may benefit from continuous therapy. n Disclosure: The study was funded by Intergroupe Francophone du Myélome and Celgene. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: N Engl J Med 371:906-917, 2014.

See commentary by S. Vincent Rajkumar, MD, on page 94.


The ASCO Post  |   NOVEMBER 15, 2014

PAGE 94

Perspective

Treatment of Newly Diagnosed Multiple Myeloma With Lenalidomide Plus Low-Dose Dexamethasone By S. Vincent Rajkumar, MD

T

he FIRST trial—reported by Benboubker and colleagues in The New England Journal of Medicine and summarized in this issue of The ASCO Post (page 93)—is a landmark study.1 It is one of the largest randomized trials in multiple myeloma ever conducted. More importantly, it is a well-designed trial that answers important questions in myeloma. The issues addressed include the role of melphalan in an era of new drugs and the value of continuous suppressive therapy vs treatment delivered for a fixed period of time. Remarkably, the trial also provides reassuring information on the association of second primary malignancies with lenalidomide (Revlimid) maintenance, an issue that was not recognized as a consideration when the trial was initially designed.2

Widely Used Regimen The Rd (lenalidomide plus lowdose dexamethasone) regimen was developed first in the Eastern Cooperative Oncology Group (ECOG) E4A03 clinical trial.3 In that trial, Rd had the best 1-year survival rate of any published regimen at the time (96%), virtually eliminating early deaths from toxicity that plagued many other regimens. I am, therefore, not surprised that this well-tolerated, highly effective doublet administered until disease progression was found to improve overall survival compared with the previous standard of MPT (melphalan, prednisone, thalidomide [Thalomid]). It took over 40 years for a regimen (ie, MPT) to beat MP (melphalan/ prednisone) in overall survival.4 It took only 7 years for us to get a regimen (ie, Rd) to beat MPT in overall survival!1 Rd is widely used in the United States (and elsewhere) as initial therapy for both transplant-eligible and transplant-ineligible patients. It is also the backbone on which nuDr. Rajkumar is Professor of Medicine, Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota.

merous other regimens are built (eg, bortezomib [Velcade]/Rd, carfilzomib [Kyprolis]/Rd, ixazomib/Rd, elotuzumab/Rd, etc).

Unresolved Question A major unresolved question in the minds of many is that although progression-free survival is markedly better with Rd administered until progression compared with Rd given for 18 months, overall survival did not significanlty differ between these two arms. I think that superiority of continuous Rd will be seen, but will take more follow-up to demonstrate. Nevertheless, in this case, given

leg cramps. Diarrhea occurs in only a small subset of these patients but can be particularly difficult to treat. One of the unexpected benefits of this study is that it addressed whether lenalidomide maintenance given without melphalan exposure would increase the risk of second primary malignancies. In other trials so far, the risk of second primary malignancies has been found only when lenalidomide maintenance has been given following standard-dose or high-dose melphalan therapy. Thankfully, this study found no difference in the incidence of second primary malignancies with long-term

VCD and other bortezomib-based regimens are commonly used in the United States as an alternative to Rd. Unfortunately, no randomized trials have compared Rd to either VCD or VMP, so this is a judgment call we need to make based on economics, patient preferences, and certain disease characteristics. —S. Vincent Rajkumar, MD

that progression occurred within a median of 2 to 4 months after stopping Rd in the fixed-duration arm, I recommend that if clinicians use Rd as initial therapy, they continue therapy until progression. This recommendation is made easier by the fact that Rd is convenient and well tolerated. In my practice, I usually reduce the dose of dexamethasone as much as possible, and even try and stop it after the first 1 to 2 years.5 In some patients, we may need to re-increase the dose of dexamethasone, but in many patients, one can continue suppressive therapy with lenalidomide alone. I also try to reduce the dose of lenalidomide if needed to reduce side effects. One should be aware of some long-term problems—ie, diarrhea, fatigue, and

Rd compared with either MPT or, more importantly, fixed-duration Rd. These are very reassuring data.

Economic Considerations I will conclude by pointing out some economic considerations that must be kept in mind. Rd is not an inexpensive regimen. And, in many countries, there is considerable outof-pocket cost for the therapy. Thus, Rd given for many years may not be a financially viable option for some, even though it is such a well-tolerated oral regimen and ideal for elderly patients. Therefore, in some settings, it may be better to use a bortezomib-based regimen such as VCD (bortezomib/ cyclophosphamide/dexamethasone),

which can be given for a limited duration. VCD is a better-tolerated version of VMP (bortezomib/melphalan/ prednisone), another regimen that has been shown to improve survival compared with MP.6 VCD and other bortezomib-based regimens are commonly used in the United States as an alternative to Rd. Unfortunately, no randomized trials have compared Rd to either VCD or VMP, so this is a judgment call we need to make based on economics, patient preferences, and certain disease characteristics. n

Disclosure: Dr. Rajkumar reported no potential conflicts of interest.

References 1. Benboubker L, Dimopoulos MA, Dispenzieri A, et al: Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 371:906-917, 2014. 2. Dimopoulos MA, Richardson PG, Brandenburg N, et al: A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 119:2764-2767, 2012. 3. Rajkumar SV, Jacobus S, Callander NS, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomised controlled trial. Lancet Oncol 11:29-37, 2010. 4. Facon T, Mary JY, Hulin C, et al: Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomised trial. Lancet 370:1209-1218, 2007. 5. Rajkumar SV: Multiple myeloma: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 89:998-1009, 2014. 6. San Miguel JF, Schlag R, Khuageva NK, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906-917, 2008.


The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.


TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

+

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often


TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets


Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%). The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%). Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions. To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets


BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)]. 5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. 5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. 5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.


Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. 5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. 5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent. In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination. Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0


National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness. Gastrointestinal Disorders: Stomatitis, pancreatitis. General Disorders and Administration Site Conditions: Asthenia. Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular. Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma. Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension. Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. 7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)]. Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight. MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)]. Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals. 8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives


ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients. Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)]. Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)]. MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal. TAFINLAR is a registered trademark of GlaxoSmithKline. MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved. Revised: 01/2014 TFR:4BRS © 2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014


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Journal Spotlight Breast Cancer

Study Finds Significant Increase in Bilateral Mastectomy for Unilateral Breast Cancer Despite Lack of Survival Benefit By Matthew Stenger

I

n an observational cohort study reported in JAMA, Allison W. Kurian, MD, MSc, Assistant Professor of Medicine and of Health Research and Policy at Stanford University School of Medicine, and colleagues assessed use of and mortality after bilateral mastectomy, breast-conserving surgery plus radiation, and unilateral mastectomy between 1998 and 2011 in California women with unilateral stage 0 to III breast cancer.1 Use of bilateral mastectomy has increased markedly, particularly among younger women. All-cause and breast cancer–specific mortality were similar with bilateral mastectomy and breast-

Chinese, 0.61 for Filipina, 0.63 for Hispanic, and 0.53 for black women), those with private insurance (eg, OR = 0.66 for public insurance or Medicaid), and those who received care at a National Cancer Institute (NCI)-designated cancer center (OR = 1.13). Other characteristics significantly associated with increased use of bilateral mastectomy were younger age (eg, ORs = 2.00 for 40–49 years and 3.81 for < 40 years vs 50–64 years), larger tumors (OR = 1.36 per cm), involved lymph nodes (OR = 1.66), lobular vs ductal histology (OR = 2.19), higher tumor grade (ORs = 1.17 for II vs I and 1.30 for III vs I), hormone receptor–

Among all women diagnosed with early-stage breast cancer in California, the percentage undergoing bilateral mastectomy increased substantially between 1998 and 2011, despite a lack of evidence supporting this approach. —Allison W. Kurian, MD, MSc, and colleagues

conserving surgery plus radiation and lower with these two treatments vs unilateral mastectomy. The study involved data from 189,734 patients in the populationbased California Cancer Registry. Median follow-up was 89.1 months.

Use of Bilateral Mastectomy Use of bilateral mastectomy increased from 2.0% in 1998 to 12.3% in 2011, an annual increase of 14.3%. Among women aged < 40 years, use increased from 3.6% to 33%. Use of breast-conserving surgery plus radiation remained fairly stable, increasing from 51.7% in 1998 to 54.2% in 2011. Use of unilateral mastectomy decreased from 46.3% in 1998 to 33.4% in 2011. Compared with breast-conserving surgery plus radiation, bilateral mastectomy was more often used by nonHispanic white women (eg, multiple regression odds ratios [ORs] = 0.41 for

negative status (OR = 1.12 vs positive), no receipt of adjuvant therapy (OR = 0.91 for receipt), higher neighborhood socioeconomic quintile (eg, ORs = 1.41 for quintile 5 and 1.22 for 4 vs 1), unmarried status (OR = 0.95 for married), treatment at a hospital with > 50% of patients in lower socioeconomic status quintiles (eg, OR = 1.12 for 1 and 2 vs 4 and 5), and diagnosis in 2005 to 2011 vs 1998 to 2004 (OR = 2.73).

Use of Unilateral Mastectomy Compared with breast-conserving surgery plus radiation, unilateral mastectomy was more often used by racial/ ethnic minorities (eg, ORs = 2.00 for Filipina and 1.16 for Hispanic vs nonHispanic white women) and patients with public/Medicaid insurance (eg, OR = 1.08 vs private insurance). Other factors significantly associated with increased use of unilateral mastectomy were age (ORs = 1.15 for 40–49 years, 1.31 for < 40 years, and

Boom in Bilateral Mastectomies ■■ Use of bilateral mastectomy increased from 2.0% to 12.3%. ■■ No reduction in overall or breast cancer–specific mortality was observed for bilateral mastectomy vs breast-conserving surgery plus radiation.

1.34 for ≥ 65 years vs 50–64 years), larger tumor size (OR = 1.61 per cm), lymph node involvement (OR = 2.16), lobular vs ductal histology (OR = 1.36), higher tumor grade (ORs = 1.18 for II vs I and 1.24 for III vs I), hormone receptor–negative status (OR = 1.17 vs positive), lower neighborhood socioeconomic quintile (eg, ORs = 0.91 for 2, 0.85 for 3, and 0.73 for 5 vs 1), married status (OR = 1.07), treatment at a hospital with >50% of patients in lower socioeconomic status quintiles (eg, OR = 1.49 for 1 and 2 vs 4 and 5), receipt of care at a non–NCI-designated cancer center (OR = 0.81 for care at NCI-designated center), and diagnosis in 1998 to 2004 vs 2005 to 2011 (OR = 0.84 for 2005–2011).

Overall and Breast Cancer– Specific Mortality On multiple regression analysis, unilateral mastectomy was associated with significantly greater risk of 10-year all-cause mortality (20.1% vs 16.8%, hazard ratio [HR] = 1.35, 95% confidence interval [CI] = 1.32–1.38) and breast cancer–specific mortality (HR = 1.29, 95% CI = 1.23–1.35) vs breast-conserving surgery plus radiation. There was no significant difference between bilateral mastectomy (18.8%) and breast-conserving surgery in 10year overall mortality (HR = 1.02, 95% CI = 0.94–1.11) or cancer-specific mortality (HR = 1.09, 95% CI = 0.98–1.21). Compared with unilateral mastectomy, bilateral mastectomy was associated with significantly lower risk of 10-year overall mortality (HR = 0.75, 95% CI = 0.70–0.82) and breast cancer–specific mortality (HR = 0.85, 95% CI = 0.76–0.94). Other factors associated with increased risk of overall mortality on

multiple regression analysis included non-Hispanic white race vs all other race/ethnicity groups except black race, age < 40 or ≥  65 at diagnosis, increased tumor size, lymph node involvement, ductal histology, higher tumor grade, hormone receptor–negative status, no receipt of adjuvant therapy, residence in lower socioeconomic status quintiles, and unmarried status. The investigators concluded: Among all women diagnosed with early-stage breast cancer in California, the percentage undergoing bilateral mastectomy increased substantially between 1998 and 2011, despite a lack of evidence supporting this approach. Bilateral mastectomy was not associated with lower mortality than breastconserving surgery plus radiation, but unilateral mastectomy was associated with higher mortality than the other options. These results may inform decision-making about the surgical treatment of breast cancer.

Scarlett L. Gomez, PhD, of Stanford University School of Medicine, is the corresponding author for the JAMA article. n

Disclosure: The study was supported by the JanWeimer Junior Faculty Chair in Breast Oncology, Suzanne Pride Bryan Fund for Breast Cancer Research at Stanford Cancer Institute, and the NCI. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Kurian AW, Lichtensztajn DY, Keegan THM, et al: Use of and mortality after bilateral mastectomy compared with other surgical treatments for breast cancer in California, 1998-2011. JAMA 312:902914, 2014.

See commentary by Lisa A. Newman, MD, MPH, FACS, FASCO, on page 104.


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Perspective

Complexity of the Contralateral Prophylactic Mastectomy Decision By Lisa A. Newman, MD, MPH, FACS, FASCO

T

he powerful and important study by Kurian et al,1 reviewed in this issue of The ASCO Post (page 103), adds vital information to the discussion regarding use of contralateral prophylactic mastectomy among patients with unilateral breast cancer in the United States.2,3 Based upon data from the California Cancer Registry, this study looked at surgical treatment patterns as well as outcomes for nearly 200,000 breast cancer patients diagnosed between 1998 and 2011. As has been shown by others,4-6 bilateral mastectomy rates have increased over time, and contralateral prophylactic mastectomy tends to be more common among white American and socioeconomically advantaged patients. A relatively novel and extremely compelling aspect of the Kurian et al study is the inclusion of outcomes data for breast-conserving surgery patients, as most prior studies have compared outcomes for unilateral vs bilateral mastectomy among patients with unilateral disease. Kurian et al demonstrated no survival advantage for patients choosing bilateral mastectomy.

Important Questions These treatment and outcome patterns prompt several questions: What is motivating patients to pursue more extensive surgery than is actually necessary to address the known cancer? Are the motivating factors oncologically sound? And what are the public health implications of contralateral prophylactic mastectomy in terms of balancing health-care costs with addressing the burden of breast cancer? Data from Hawley et al6 generated appropriate attention because these investigators found that contralateral prophylactic mastectomy patients were often motivated by the perception that they were achieving a survival or local recurrence advantage. Studies of outcome for unilateral vs metachronous bilateral breast cancer patients have historically demonstrated that survival tends to be driven by the stage and effectiveness of treatment for the initially detected cancer.7 This Dr. Newman is Professor of Surgery and Director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center, Ann Arbor.

outcome equivalence is a biologically plausible observation, since unilateral breast cancer patients are typically receiving close surveillance and most second breast cancers will be detected at an early stage when they are likely to be successfully treated; the initially diagnosed breast cancer therefore has the lead-time advantage in establishing distant organ micrometastases. Studies revealing surveillance equivalence for contralateral prophylactic mastectomy compared to no–contralateral prophylactic mastectomy patients8-10 are consistent with pathology studies revealing very

nificant life-threatening risk from a second/metachronous breast cancer. It is therefore conceivable that contralateral prophylactic mastectomy might improve survival by reducing the incidence of new primary/metachronous disease. However, many of our systemic therapy agents are also effective in decreasing the incidence of contralateral breast cancer, thereby mitigating the potential for contralateral prophylactic mastectomy to confer an outcome advantage. Studies revealing a contralateral prophylactic mastectomy survival advantage are also confounded by selection bias,15 since

[T]he patient may feel that the goals of avoiding future chemotherapy and/or future axillary staging surgery may be worth the operative risks of undergoing more extensive surgery. —Lisa A. Newman, MD, MPH, FACS, FASCO

low rates of incidentally detected cancers in the contralateral prophylactic mastectomy specimens.11 The data demonstrate that the procedure is extremely unlikely to be beneficial to our breast cancer patients from the perspective of eradicating an occult, preexisting contralateral malignancy.

Conflicting Evidence On the other hand, some recent studies have demonstrated a survival advantage associated with the contralateral prophylactic mastectomy choice among unilateral breast cancer patients.12-14 This observation is also biologically plausible, in light of several related issues that affect outcomes to varying degrees as our treatment strategies evolve: first, a personal history of breast cancer is a risk factor for developing a new primary breast cancer; second, survival for most unilateral breast cancer patients is driven by the micrometastatic potential of their disease; and third, as effectiveness of systemic therapy for breast cancer has improved, we are likely seeing a larger pool of patients who have been “cured” of their initial breast cancer, and who might then be facing a sig-

unilateral breast cancer patients facing a diminished life expectancy because of advanced age, high-risk disease, or extensive comorbidity are less likely to undergo preventive surgery.

Other Motivations Some patients may be motivated to pursue contralateral prophylactic mastectomy purely for body habitus and symmetry advantages. The patient with large pendulous breasts requiring mastectomy for unilateral disease may prefer to have a symmetrically flat chest wall (to avoid the sensation of torso imbalance or the need to be fitted for a large/heavy unilateral prosthesis) if she has medical contraindications precluding immediate reconstruction or contralateral reduction mammoplasty surgery. Patients with unilateral breast cancer undergoing reconstruction using an abdominal flap may opt for bilateral mastectomy/bilateral reconstruction because of the knowledge that the abdominal flap can only be harvested once, regardless of whether it is being utilized for unilateral or bilateral reconstruction. Many unilateral breast cancer pa-

tients, even if fully cognizant of the data supporting survival equivalence for unilateral vs bilateral surgery, will continue to be motivated to pursue contralateral prophylactic mastectomy because of emotional reasons related to the risk-reducing benefits of this strategy. Often our breast cancer patients profess a clear desire to do anything possible in order to minimize the risk of repeating the breast cancer diagnosis and treatment experience, knowing that a second primary breast cancer would indeed warrant delivery of appropriate multidisciplinary care. In this scenario, the patient may feel that the goals of avoiding future chemotherapy and/or future axillary staging surgery may be worth the operative risks of undergoing more extensive surgery.

Surgeon’s Perspective Surgeons can be subject to a comparable emotional component in the discussion of contralateral prophylactic mastectomy. Any surgeon with a substantial breast cancer patient population has had the heartbreaking experience of dealing with women who successfully battled their first breast cancer, only to be diagnosed with an aggressive/locally advanced or inflammatory contralateral breast cancer during long-term follow-up. These cases may defy the odds, but they nonetheless leave the patient and surgeon alike wondering whether contralateral prophylactic mastectomy might have been a lifesaving procedure when the first cancer was detected. Along those same lines of speculation—but with the advantage of statistical support—there are also published decision-analysis studies regarding the cost-efficiency of contralateral prophylactic mastectomy. At least two of these studies suggest that contralateral prophylactic mastectomy may actually be comparable or preferable to long-term surveillance in unilateral breast cancer/unilateral breast surgery patients who have a particularly elevated risk of developing a new primary breast cancer, such as those with hereditary susceptibility.16,17 Furthermore, despite the preponderance of data supporting survival equivalence for unilateral vs bilat-


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Perspective

eral mastectomy, individual surgeons know that the contralateral prophylactic mastectomy option is widely available in the health-care “marketplace.” They therefore feel obligated to include it in the spectrum of treatment strategies offered to the patient. Clinical judgment for the safety of our patients is of course of paramount importance; surgeons are therefore also obligated to inform patients of the increased perioperative risks associated with bilateral surgery and that only medically fit patients should entertain this surgical option. Surgeons must take the time to clearly explain that the potentially life-threatening distant metastatic risk from the known cancer is unaffected by the choice of mastectomy vs breast-conserving surgery, and that recommendations for systemic therapy/chemotherapy are similarly unaffected by breast surgery choice. Nor does mastectomy surgery completely eliminate the risk of a local recurrence or of a new primary tumor, since the former is related to individual tumor biology and the latter can still occur as a function of microscopic foci of residual breast tissue left behind in the skin flaps or in the axilla.

Decision-Making Factors As clearly shown by Kurian et al, breast-conserving surgery is comparable to mastectomy surgery with regard to survival and patients should bear in mind that breast-conserving surgery does not eliminate the option of pursuing more extensive mastectomy surgery for risk-reducing purposes in the future. Among patients for whom lumpectomy appears technically feasible, breast-conserving surgery may even be preferable to mastectomy in light of clinical trial data that document the safety of avoiding axillary lymph node dissection in lumpectomy/breast irradiation patients with limited-volume disease in the sentinel nodes.18 In contrast, mastectomy patients with sentinel node metastases will usually require completion axillary lymph node dissection in order to define the benefits of postmastectomy radiation. Furthermore, the nodepositive mastectomy patient is often discouraged from undergoing immediate reconstruction, because of the

potential risk for irreversible radiation damage to the reconstructed breast. Encouraging our newly diagnosed breast cancer patients who are breast conservation candidates to pursue a methodical surgical plan initiated with sentinel lymph node biopsy (with or without a concomitant lumpectomy)

a subsequent new primary tumor, we cannot summarily or paternalistically dismiss the contralateral prophylactic mastectomy option among our patients who express prevention as a personal priority. As members of the cancer-treating team, we can empower our patients by

As members of the cancer-treating team, we can empower our patients by underscoring the fact that although expeditious cancer treatment is important, they should not feel that they are racing the clock. —Lisa A. Newman, MD, MPH, FACS, FASCO

can be a useful approach—this strategy provides valuable staging information without burning any bridges. If nodal metastases are identified, the patient may feel more comfortable with the lumpectomy/radiation option so that the morbidity of axillary lymph node dissection can be avoided. Breast conservation for the known disease then obviates the consideration of contralateral prophylactic mastectomy, although elective bilateral prevention surgery (with immediate reconstruction) remains an option after comprehensive cancer treatment is completed.

Empowering Patients Facing a new breast cancer diagnosis is understandably a terrifying experience for our patients. The shock and mortality fears can have polar extreme effects—paralyzing some patients with indecisiveness and catapulting others into a tailspin of reflex preference for bilateral mastectomy because of the instinctive impression that the most aggressive surgery possible might be lifesaving. Thus far, however, a myriad of complex and conflicting theories and data inform the discussion of contralateral prophylactic mastectomy. It is irrefutable that such surgery is increasing in the United States, but at this point in time the procedure does not appear to confer any definitive survival advantage. Prophylactic mastectomy is, however, a legitimate (albeit aggressive) strategy to reduce risk of a second primary breast cancer. Since a history of breast cancer is indeed a significant risk factor for developing

underscoring the fact that although expeditious cancer treatment is important, they should not feel that they are racing the clock. As we educate our patients regarding the nature of their diagnosis and their treatment options, we must also encourage them to carefully process this information before hastily committing to irreversible surgical plans. n

Disclosure: Dr. Newman reported no potential conflicts of interest.

References 1. Kurian AW, Lichtensztajn DY, Keegan TH, et al: Use of and mortality after bilateral mastectomy compared with other surgical treatments for breast cancer in California, 1998-2011. JAMA 312:902914, 2014. 2. Newman LA: Understanding the reasonable, but limited benefits of the CPM strategy. Ann Surg 254:8-9, 2011. 3. Newman LA: Contralateral prophylactic mastectomy: Is it a reasonable option? JAMA 312:895-897, 2014. 4. Tuttle TM, Abbott A, Arrington A, et al: The increasing use of prophylactic mastectomy in the prevention of breast cancer. Curr Oncol Rep 12:16-21, 2010. 5. Tuttle TM, Habermann EB, Grund EH, et al: Increasing use of contralateral prophylactic mastectomy for breast cancer patients. J Clin Oncol 25:5203-5209, 2007. 6. Hawley ST, Jagsi R, Morrow M, et al: Social and clinical determinants of contralateral prophylactic mastectomy. JAMA Surg. May 21, 2014 (early release online). 7. Newman LA, Sahin AA, Cunningham JE, et al: A case-control study of unilateral and bilateral breast carcinoma patients. Cancer 91:1845-1853, 2001.

8. Kiely BE, Jenkins MA, McKinley JM, et al: Contralateral risk-reducing mastectomy in BRCA1 and BRCA2 mutation carriers and other high-risk women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Breast Cancer Res Treat 120:715-723, 2010. 9. Chung A, Huynh K, Lawrence C, et al: Comparison of patient characteristics and outcomes of contralateral prophylactic mastectomy and unilateral total mastectomy in breast cancer patients. Ann Surg Oncol 19:2600-2606, 2012. 10. Pesce C, Liederbach E, Wang C, et al: Contralateral prophylactic mastectomy provides no survival benefit in young women with estrogen receptor-negative breast cancer. Ann Surg Oncol 21:32313239, 2014. 11. King TA, Gurevich I, Sakr R, et al: Occult malignancy in patients undergoing contralateral prophylactic mastectomy. Ann Surg 254:2-7, 2011. 12. Peralta EA, Ellenhorn JD, Wagman LD, et al: Contralateral prophylactic mastectomy improves the outcome of selected patients undergoing mastectomy for breast cancer. Am J Surg 180:439-445, 2000. 13. Herrinton LJ, Barlow WE, Yu O, et al: Efficacy of prophylactic mastectomy in women with unilateral breast cancer: A cancer research network project. J Clin Oncol 23:4275-4286, 2005. 14. Boughey JC, Hoskin TL, Degnim AC, et al: Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer. Ann Surg Oncol 17:2702-2709, 2010. 15. Kruper L, Kauffmann RM, Smith DD, et al: Survival analysis of contralateral prophylactic mastectomy: A question of selection bias. Ann Surg Oncol 21:3448-3456, 2014. 16. Zendejas B, Moriarty JP, O’Byrne J, et al: Cost-effectiveness of contralateral prophylactic mastectomy versus routine surveillance in patients with unilateral breast cancer. J Clin Oncol 29:2993-3000, 2011. 17. Roberts A, Habibi M, Frick KD: Cost-effectiveness of contralateral prophylactic mastectomy for prevention of contralateral breast cancer. Ann Surg Oncol 21:2209-2217, 2014. 18. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569575, 2011.


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JCO Spotlight Gynecologic Oncology

Pazopanib Maintenance Improves Progression-Free Survival in Ovarian Cancer Questions arise about treatment exposure and effects in East Asian subgroup By Matthew Stenger

I

n a phase III trial reported in the Journal of Clinical Oncology, ­Andreas du Bois, MD, PhD, Professor of Gynecologic Oncology at Kliniken Essen-Mitte in Essen, Germany, and colleagues found that maintenance therapy with the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor pazopanib (Votrient) significantly prolonged progression-free survival vs placebo in women without disease progression after firstline chemotherapy.1 A second interim analysis of overall survival showed no benefit of pazopanib maintenance. Exploratory analyses suggested that the progression-free survival benefit was limited to non– East Asian patients and that treatment had a detrimental impact on survival in East Asian patients.

Study Details In this double-blind trial, 940 women from 17 countries in Europe, Asia, North America, and Australia with International Federation Gynecology Obstetrics (FIGO) stage II to IV disease, no evidence of progression after surgery, and a minimum of five cycles of platinum-taxane chemotherapy were randomly assigned between June 2009 and August 2010 to receive pazopanib at 800 mg/d (n = 472) or placebo (n = 468) for up to 24 months. The primary endpoint was investigator-assessed progression-free survival using RECIST version 1.0 criteria in the intent-to-treat population. The pazopanib and placebo groups were generally balanced for age (median, 56 and 57 years), ethnicity (77%

lopian in 3% and 4.5%), FIGO stage (II in 8.5% and 9%, III in 75% and 74%, IV in 16% and 17%), histology (eg, serous in 72% and 74%, undifferentiated in 8% and 9%), Eastern Cooperative Oncology Group performance status (0 in 76.5% and 77%, 1 in 23% and 22%), and geographic region (Europe for 68% and

Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progressionfree survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. —Andreas du Bois, MD, PhD, and colleagues

68%, Asia for 22% and 22%, and United States/Australia for 10% and 11%). The groups were also well balanced for first-line treatment outcome (complete macroscopic resection in 56% and 60%, upfront surgery in 75% and 69%, interval surgery in 25% and 31%, no evidence of disease or complete response after initial therapy in 84% and 86%), treatment duration (mean, 8.9 and 11.7 months), time from diagnosis to study entry (median, 7.0 and 7.1 months), and time from last dose of chemotherapy to study entry (median, 7.4 and 8.0 weeks).

Improved Progression-Free Survival Median follow-up was 24.3 months. Median progression-free survival was 17.9 months in the pazopanib group vs 12.3 months in the placebo group (haz-

Role of Pazopanib in Ovarian Cancer ■■ Pazopanib maintenance significantly prolonged progression-free survival in ovarian cancer patients. ■■ Exploratory analysis suggested that benefit was limited to non–East Asian patients, who received a higher mean dose than East Asian patients. ■■ No benefit in overall survival was seen in any subgroup. Decreased overall survival was seen in East Asian patients.

and 78% white, 22.5% and 22.0% Asian), primary tumor (ovarian in 90% and 88%, peritoneal in 7% and 6%, fal-

panib treatment (0.80, 95% confidence interval [CI] = 0.68–0.95). The study was designed with 80% power to detect a 27% increase in median overall survival. A second interim overall survival analysis based on events in 35.6% of the population did not show any significant difference

ard ratio [HR] = 0.77, P = .0021). On blinded central assessment, the hazard ratio was significant in favor of pazo-

between groups (HR = 1.08, 95% CI = 0.87–1.33, P =.499). Subsequent anticancer therapy was administered to 61% of placebo patients and 50% of pazopanib patients, with time to subsequent therapy being significantly longer in the pazopanib group.

Exposure and Outcome in East Asian Patients Exploratory post hoc analysis suggested that the progression-free survival benefit of pazopanib was driven by outcomes in the non–East Asian population (78% of total study population). In the non–East Asian population, pazopanib treatment was associated with a hazard ratio of 0.69 (95% CI = 0.57–0.84) and a 5.9-month increase in median progression-free survival; the hazard ratio in the East Asian subgroup (22% of population) was 1.16 (95% CI = 0.78–1.73). The second interim overall survival analysis showed no significant difference for pazopanib vs placebo in the non–East Asian population (HR = 0.98, 95% CI = 0.77–1.24, P = .859) and a significant detrimental effect in the East Asian population (HR = 1.71, 95% CI = 1.01–2.89, P = .047). Dose reductions occurred in 58% of the pazopanib group (14% in placebo group). Reductions occurred in 75% of

the East Asian subgroup vs 36% of other patients, and the mean daily doses of pazopanib were 473 mg vs 617 mg. Almost all pazopanib dose reductions were due to adverse events. Most of these occurred during the first 6 weeks of treatment, with the mean dose level remaining nearly constant thereafter.

Adverse Events The most common adverse events of any grade in the pazopanib group were hypertension (58% vs 20% in the placebo group), diarrhea (53% vs 17%), fatigue (41% vs 26%), abdominal pain (35% vs 31%), neutropenia (32% vs 8%), and liver-related toxicity (30% vs 9%). Grade 3 or 4 hypertension (30.8% vs 5.6%), neutropenia (9.9% vs 1.5%), liver-related toxicity (9.4% vs 0.7%), diarrhea (8.2% vs 1.1%), fatigue (2.7% vs 0.2%), thrombocytopenia (2.5% vs 0.7%), and palmar-plantar erythrodysesthesia (1.9% vs 0.2%) were significantly more common in pazopanib recipients (all P < .05). Treatment was discontinued due to adverse events in 33.3% vs 5.6% of patients, with pazopanib discontinuations occurring almost exclusively during the first 12 weeks of treatment. The most common reasons for discontinuation in the pazopanib group were hypertension (14% vs 2%), diarrhea (5% vs <1%), and AST (3.6% vs 0%) or ALT elevation (4.0% vs 0%). The investigators concluded: Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity. n Disclosure: The study was supported by GlaxoSmithKline Pharmaceuticals. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. du Bois A, Floquet A, Kim J-W, et al: Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32:3374-3382, 2014.


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Perspective

Maintenance Therapy in Ovarian Cancer: What’s at Stake? By Robert L. Coleman, MD

M

aintenance therapy in ovarian cancer refers to a cohort of women achieving response to initial adjuvant chemotherapy who then go on to additional therapy in the hopes of extending time to recurrence or inducing a lasting remission. The concept is not new and retains its scientific and clinical relevance when one understands the natural history of this disease. It has been long known that patients achieving clinical remission following surgery and chemotherapy (defined by normalization of CA125, negative physical exam, and frequently, normal imaging) have a 60% to 70% chance of developing recurrent disease in the next 2 years.1 This poor predictive performance of our clinical parameters spawned increasing interest in performing operative assessment: the so-called second-look procedure. Guidelines for an appropriate intraoperative assessment when doing this procedure were crafted to reduce the chance of a sampling error and dictated—in the absence of macroscopic disease—the resection of 20 to 30 random biopsies from high-risk areas of the abdomen. Despite identifying a cohort of women without macroscopically or microscopically positive disease (“pathologic” complete responders in approximately 50% of second-look procedures), the recurrence risk at 2 years was still 40%.2 This high false-negative rate both relegated routine second-look procedure to a research-only option and confirmed the need for some type of therapy to improve these sobering odds.

Randomized Trials To date, no less than a dozen and a half randomized phase III trials have been conducted in women with ovarian cancer to address this risk.3 They have evaluated not only multiple different types of agents, including chemotherapy, immunotherapy, antiangiogenesis therapy, and anti–growth Dr. Coleman is Professor and Deputy Chair, Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston.

factor therapy, but also different delivery strategies, including intraperitoneal, intravenous, and radiation. Most have not demonstrated a prolongation in any survival endpoint. The AGO-OVAR 16 trial, reported by du Bois and colleagues and reviewed in this issue of The ASCO Post, showed improvement in progressionfree survival with pazopanib (Votrient) maintenance therapy.4 Including this trial, four antiangiogenesis studies (bevacizumab [Avastin],5,6 nintedanib,7 pazopanib4) and one chemotherapy study (paclitaxel8) have improved progression-free survival

tify who these women are; for them, maintenance therapy only produces toxicity and likely diminution of quality of life. This same uncertainty can also influence investigators and patients to see treatment-related adverse events as more problematic than under conditions of treatment for existing disease. This can disproportionately drive treatment discontinuation, which occurred in the current trial in one-third of patients receiving pazopanib. Although the most common reason for discontinuation in this cohort was hypertension, it is a rate

We await the quality-of-life and genomic-profiling data to better understand how the regimen was truly tolerated and whether there are intrinsic manifestations that shed light on the adverse events and efficacy observed. —Robert L. Coleman, MD

without improving overall survival. The current trial, in addition to the trial of 1 year of paclitaxel, randomly assigned patients largely in clinical remission after induction therapy. This contrasts with the two bevacizumab trials and the nintedanib trial, in which randomization was performed before adjuvant chemotherapy was administered. Thus, AGO-OVAR 16 included the most favorable subgroup of patients, since they had reached eligibility by having a complete or near-complete clinical response to front-line therapy. Nevertheless, the result was similar to that observed in the other “positive” trials.

Study Context Before assigning a value to the treatment outcome, it is important to consider the context in which this study was conducted. While the ­population odds for progression following a complete clinical remission are high, they are not absolute; some patients (approximately 25%–30%) will be cured following surgery and adjuvant chemotherapy. Individually, we are unable to prospectively iden-

substantially higher than the rate seen in renal cancer patients treated with single-agent pazopanib.9 In addition, one could be critical of the initiating dose, as substantial modifications were required after cycle 1 (particularly in the East Asian cohort). These observations highlight that the tolerance “yardstick” is higher in the maintenance setting relative to other treatment settings.

Progression-Free Survival Issues Another context to consider when reviewing these results is understanding the “value” of increasing progression-free survival. It is clear that one cannot make an asymptomatic patient more asymptomatic by administering therapy. Most women undergoing consideration of maintenance therapy are asymptomatic from a cancer standpoint. This fact implores investigators to carefully evaluate the impact of a prospective therapy on daily functionality. Since it is likely that therapy will differentially affect those getting drug vs placebo, the magnitude and directionality are extremely important in

understanding how an adverse event profile is tolerated. And since no measure of quality of life or patient-reported outcomes was reported in this initial analysis of AGO-OVAR 16, we are left to consider the survival data in a vacuum. Perhaps even more revealing of the primary treatment effect is how these patients do into the next line of therapy. One effect of prolonging progression-free survival is a (desired) delay in the next line of therapy for those who ultimately experience a recurrence. We know from the current trial that more patients on the placebo arm (61% vs 50%) were undergoing subsequent anticancer therapy at the time of report. However, without a measure of their quality of life, it is unknown whether this prolongation in time to initiation of subsequent therapy among the pazopanib patients actually sustained their quality of life relative to those who had started anticancer therapy in the placebo arm. It is unknown whether the toxicity experienced in patients treated with pazopanib, but who had not shown disease progression, was as bad as the toxicity in placebo-assigned patients now receiving chemotherapy. In this regard, a positive trend in quality of life would provide some context to the delay in progression.

Study Endpoints An additional lens through which one should look at this trial is that of endpoints. The primary endpoint for this trial was progression-free survival; the investigators were attempting to increase the median progressionfree survival by 47%. They largely achieved this (46% increase). However, more important than a point estimate is the hazard over exposure. In this study, exposure to pazopanib (24 months of therapy) covered about 62% of the expected progression events (those expected without treatment, or placebo). This implies that prolonging therapy would be unlikely to add benefit to the primary endpoint. In addition, while the study was initially designed to have 80% power to evaluate a 27% improvement in overall survival, the likelihood of precontinued on page 108


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Perspective

Maintenance Therapy in Ovarian Cancer continued from page 107

serving a progression-free survival benefit with an estimated 38-month postprogression survival is more likely less than 20%.10 Several factors contribute to this effect, such as uncontrolled use of additional therapy, therapeutic crossover, intent of additional therapy, subsequent treatment discovery, and surgery. In addition, confounding effects are stronger the more proximal to diagnosis the intervention is studied. This additionally highlights the need for context when assessing progression-free survival as an endpoint. The Society of Gynecologic Oncology has recently produced a white paper and a guidance document on endpoints in ovarian cancer.11,12

Closing Thoughts In all, GlaxoSmithKline has determined, despite meeting its primary endpoint, to suspend development of

the agent in this setting. The adverse event profile, particularly among East Asian patients (which was associated with a statistical detriment in overall survival), appears to tip the risk-benefit ratio away from declaring the intervention a therapeutic advance. We await the quality-of-life and genomicprofiling data to better understand how the regimen was truly tolerated and whether there are intrinsic manifestations that shed light on the adverse events and efficacy observed. n

Disclosure: Dr. Coleman reported no potential conflicts of interest.

References 1. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 21:3194-3200, 2003. 2. Greer BE, Bundy BN, Ozols RF, et al: Implications of second-look laparotomy in the context of optimally resected

stage III ovarian cancer: A non-randomized comparison using an explanatory analysis: A Gynecologic Oncology Group study. Gynecol Oncol 99:71-79, 2005. 3. Coleman RL, Monk BJ, Sood AK, et al: Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol 10:211-224, 2013. 4. du Bois A, Floquet A, Kim J-W, et al: Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32:3374-3382, 2014. 5. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484-2496, 2011. 6. Burger RA, Brady MF, Bookman MA, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473-2483, 2011. 7. du Bois A, Kristensen G, Ray-Coquard I, et al: AGO-OVAR 12: A randomized placebo-controlled GCIG/ENGOT intergroup phase III trial of standard frontline chemotherapy +/- nintedanib for advanced ovarian cancer. Int J Gynecol Cancer 23(8 suppl):Abstract, 2013.

8. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003. 9. Sternberg CN, Davis ID, Mardiak J, et al: Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 28:1061-1068, 2010. 10. Broglio KR, Berry DA: Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 101:1642-1649, 2009. 11. Herzog TJ, Alvarez RD, Secord A, et al: SGO guidance document for clinical trial designs in ovarian cancer: A changing paradigm. Gynecol Oncol 135:3-7, 2014. 12. Herzog TJ, Armstrong DK, Brady MF, et al: Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper. Gynecol Oncol 132:8-17, 2014.

Journal Spotlight Dermatologic Oncology

U.S. Skin Cancer Costs Rise From 2002 Through 2011

T

he costs associated with skin cancer increased five times as fast as treatments for other cancers between 2002 and 2011, according to a Centers for Disease Control and Prevention (CDC) study published online in the American Journal of Preventive Medicine.1 The average annual cost for skin cancer treatment increased from $3.6 billion during 2002–2006, to $8.1 billion during 2007–2011, an increase in costs of 126%. The average annual cost for treatment of all other cancers increased by 25% during the same time period. Skin cancer, the most commonly diagnosed cancer in the United States, is a major and growing public health problem. The number of skin cancer cases has been increasing, but little was known prior to this study about the costs of treating skin cancer.

Study Details “The findings raise the alarm that not only is skin cancer a growing problem in the United States, but the costs for treating it are skyrocketing relative

to other cancers,” said the lead author of the report, Gery P. Guy, Jr, PhD, MPH, of the CDC’s Division of Cancer Prevention and Control. “This also underscores the importance of skin cancer prevention efforts.” The report studied skin cancer data on adults between 2002 and 2011 using the Medical Expenditure Panel Survey.

Nearly 5 million people are treated for skin cancer every year in the United States. Most cases of melanoma, the deadliest kind of skin cancer, are caused by exposure to ultraviolet (UV) light.

Protective Measures Are Key People should take steps to protect themselves from UV exposure that

The findings raise the alarm that not only is skin cancer a growing problem in the United States, but the costs for treating it are skyrocketing relative to other cancers…. This also underscores the importance of skin cancer prevention efforts. —Gery P. Guy, Jr, PhD

The researchers created two 5-year periods of data from 2002–2006 and 2007– 2011 to allow for a comparison over time and to improve the precision of the estimates. The average annual number of adults treated for skin cancer increased from 3.4 million in 2002–2006 to 4.9 million in 2007–2011.

could lead to skin cancer by protecting their skin from the sun and avoiding indoor tanning. CDC recommends the following measures: • Stay in the shade, especially during midday hours. • Wear clothing that covers your arms and legs.

• Wear a hat with a wide brim. • Wear sunglasses that block both ultraviolet A (UVA) and ultraviolet B (UVB) rays. • Use sunscreen with SPF 15 or higher and both UVA and UVB protection. • Avoid indoor tanning. The Surgeon General’s Call to Action to Prevent Skin Cancer calls on all sectors to do more to reduce skin cancer. Examples include communities creating more opportunities for sun protection in outdoor settings, health providers counseling patients on the importance of using sunscreen, and colleges discouraging indoor tanning. Visit www.cdc.gov/cancer/skin to learn more about skin cancer prevention efforts. n

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. Guy GP, Machlin SR, Ekwueme DU, et al: Prevalence and costs of skin cancer treatment in the U.S., 2002−2006 and 2007−2011. Am J Prev Med. November 9, 2014 (early release online).


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In the Clinic Hematology

Bortezomib in Previously Untreated Mantle Cell Lymphoma By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n October 9, 2014, bortezomib (Velcade) was granted approval for use in treating previously untreated mantle cell lymphoma in combination with the combination regimen VcR-CAP (rituximab [Rituxan]), cyclophosphamide, doxorubicin, and oral prednisone).1 The drug has prior approval for previously treated mantle cell lymphoma and is approved for use in multiple myeloma.

Supporting Study Approval in previously untreated mantle cell lymphoma was based on findings in an open-label phase III trial in which adult patients with stage II to IV disease who were ineligible or not considered for bone marrow transplantation received VcR-CAP (n = 243) or R-CHOP (n = 244; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The VcR-CAP regimen consisted of bortezomib at 1.3 mg/m2 intravenously

Median progression-free survival on independent radiographic assessment, the primary endpoint, was 25 vs 14 months (hazard ratio [HR] = 0.63, P < .001). The overall response rate was 88% vs 85%, with complete response in 44% vs 34%.

How It Works Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, a protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway regulates intracellular concentrations of specific proteins, maintaining cellular homeostasis. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple intracellular signaling cascades and lead to cell death. Bortezomib is cytotoxic to a variety of cancer cell types in vitro and delays tumor growth in tumor models, including multiple myeloma models.

How It Is Given In previously untreated mantle cell lymphoma, bortezomib is given at 1.3 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period on days 12 to 21 in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin

Expanded Indication for Bortezomib ■■ Bortezomib (Velcade) has been granted approval for use in treating previously untreated mantle cell lymphoma in combination with the combination regimen VcR-CAP. ■■ In previously untreated mantle cell lymphoma, bortezomib is given at 1.3 mg/m2 twice weekly for 2 weeks followed by a 10-day rest period on days 12 to 21 in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin (50 mg/m2) on day 1 and prednisone (100 mg/m2) on days 1 to 5.

on days 1, 4, 8, and 11 (rest period, days 12–21), rituximab at 375 mg/m2 on day 1, cyclophosphamide at 750 mg/m2 on day 1, doxorubicin at 50 mg/m2 on day 1, and prednisone at 100 mg/m2 on days 1 to 5 every 21 days for six cycles. Patients in both groups with a response first documented at cycle 6 could receive two additional cycles. Patients had a median age of 66 years, 74% were male, 66% were Caucasian and 32% were Asian, 69% had positive bone marrow aspirate or biopsy, 54% of patients had an International Prognostic Index score ≥ 3, and 76% had stage IV disease.

(50 mg/m2) on day 1 and prednisone (100 mg/m2) on days 1 to 5. On day 1, bortezomib is given first, followed by rituximab. For patients with a response first documented at cycle 6, two additional VcRCAP cycles are recommended. At least 72 hours should elapse between consecutive doses of bortezomib.

OF NOTE Patients with preexisting severe neuropathy should be treated with bortezomib only after careful riskbenefit assessment.

Prior to the first day of each cycle other than cycle 1, platelet count should be ≥ 100 × 109/L, absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, hemoglobin should be ≥ 8 g/dL, and nonhema-

OF NOTE Bortezomib inhibits the 26S proteasome, which can affect multiple intracellular signaling cascades and lead to cancer cell death.

tologic toxicity should have recovered to grade 1 or baseline. Bortezomib should be interrupted for grade 3 hematologic or nonhematologic toxicities, excluding neuropathy. For hematologic toxicity, treatment should be withheld for up to 2 weeks until recovery of ANC and platelet count; the bortezomib dose should be reduced by 1 level— from 1.3 to 1.0 mg/m2 or from 1.0 to 0.7 mg/m2—if recovery occurs, and treatment should be discontinued if recovery does not occur. For peripheral neuropathy, dosing should be reduced to 1.0 mg/m2 for grade 1 with pain or grade 2, withheld until resolution and continued at 0.7 mg/m2 once per week upon resolution for grade 2 with pain or grade 3, and discontinued for grade 4. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2 during the first cycle. Subsequent escalation to 1.0 mg/ m2 or further reduction to 0.5 mg/m2 may be considered based on patient tolerance. Coadministration of bortezomib with strong CYP3A4 inhibitors (eg, ritonavir, idinavir, clarithromycin, ketoconazole, itraconazole) can increase bortezomib exposure, requiring close monitoring. Coadministration with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort) can decrease bortezomib exposure and should be avoided.

Safety Profile The most commonly reported adverse events of any grade (> 20%) in clinical trials of bortezomib include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. In the phase III trial in previously untreated mantle cell lymphoma, the most common grade ≥ 3 hematologic adverse

events in the VcR-CAP and R-CHOP groups were neutropenia (83% vs 65%), thrombocytopenia (57% vs 4%), and leukopenia (43% vs 27%). Infections occurred in 31% vs 23%, including pneumonia in 8% vs 5% (5% vs 3% grade ≥ 3). Grade ≥ 3 peripheral neuropathy occurred in 7% vs 4%. Apart from these, the most common nonhematologic grade ≥ 3 adverse events were fatigue (5% vs 2%) and diarrhea (5% vs 1%). Herpes zoster reactivation occurred in 4.6% vs 0.8% of patients; antiviral prophylaxis was mandated by protocol amendment. Grade ≥ 3 bleeding events occurred in 3 patients vs 1 patient. Adverse events led to discontinuation of treatment in 8% vs 6%, with the most common causes being peripheral sensory neuropathy in the VcR-CAP group (1%) and febrile neutropenia in the R-CHOP group (< 1%). Bortezomib carries warnings/precautions for peripheral neuropathy, hypotension, cardiac toxicity, pulmonary toxicity, posterior reversible encephalopathy syndrome, gastrointestinal toxicity, thrombocytopenia and neutropenia, tumor lysis syndrome, hepatic toxicity, and embryo-fetal risk. Patients with preexisting severe neuropathy should be treated with bortezomib only after careful riskbenefit assessment. Liver enzymes should be monitored during treatment. Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. n Reference 1. VELCADE® (bortezomib) for injection prescribing information, Millennium Pharmaceuticals, Inc, 2014. Available at www.velcade.com/Files/PDFs/ VELCADE_PRESCRIBING_INFORMATION.pdf.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).


NOW

IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. mCRC = metastatic colorectal cancer; OS = overall survival.

Boxed WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information

• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of StevensJohnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Lifethreatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. • Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package

insert for instructions on the identification of patients eligible for treatment with Vectibix®. • Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% in Study 2. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. • In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. • Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.


The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who

were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS mCRC

• Keratitis and ulcerative keratitis, known risk factors for corneal • Because many drugs are excreted into human milk and because of

perforation, have been reported with Vectibix® use. Monitor for evidence the potential for serious adverse reactions in nursing infants from of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for Vectibix®, a decision should be made whether to discontinue nursing acute or worsening keratitis. or to discontinue the drug, taking into account the importance of • In an interim analysis of an open-label, multicenter, randomized the drug to the mother. If nursing is interrupted, it should not be clinical trial in the first-line setting in patients with mCRC, the resumed earlier than 2 months following the last dose of Vectibix®. addition of Vectibix® to the combination of bevacizumab and ® chemotherapy resulted in decreased OS and increased incidence • Women who become pregnant during Vectibix treatment are of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC encouraged to enroll in Amgen’s Pregnancy Surveillance Program. grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- Women who are nursing during Vectibix® treatment are encouraged treated patients included rash/acneiform dermatitis (26% vs 1%), to enroll in Amgen’s Lactation Surveillance Program. Patients or diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring their physicians should call 1-800-77-AMGEN (1-800-772-6436) in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/ to enroll. mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). ® • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix in Vectibix®-treated patients (7% vs 3%) and included fatal events were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in three (< 1%) Vectibix®-treated patients. • As a result of the toxicities experienced, patients randomized to in the Vectibix® arm were general physical health deterioration and Vectibix®, bevacizumab, and chemotherapy received a lower mean intestinal obstruction. relative dose intensity of each chemotherapeutic agent (oxaliplatin, • In Study 3, the most commonly reported adverse reactions (≥ 20%) irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first in patients with wild-type KRAS mCRC receiving Vectibix® 24 weeks on study, compared with those randomized to bevacizumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were and chemotherapy. • Advise patients of the need for adequate contraception in both males diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, and females while receiving Vectibix® and for 6 months after the last anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, dose of Vectibix® therapy. Vectibix® may be transmitted from the pruritus, and dry skin. Serious adverse reactions (≥ 2% difference mother to the developing fetus, and has the potential to cause fetal between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. harm when administered to pregnant women. References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aflibercept) prescribing information, sanofi-aventis. Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 05/14 80389-R1-V1

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Vectibix® (panitumumab) Brief Summary of full PreScriBing information Warning: Dermatologic toXicity Dermatologic toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (nci-ctc grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. inDicationS anD uSage metastatic colorectal cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies 14.2 in Full Prescribing Information]. • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. limitation of use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information]. DoSage anD aDminiStration Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)]. Dose modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose. • Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at 80% of the original dose. • Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose. • Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®. Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. Preparation and administration Do not administer Vectibix® as an intravenous push or bolus. contrainDicationS None. WarningS anD PrecautionS Dermatologic and Soft tissue toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. increased tumor Progression, increased mortality, or lack of Benefit in Patients with KRAS-mutant mcrc Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®. electrolyte Depletion/monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. infusion reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. acute renal failure in combination with chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary fibrosis/interstitial lung Disease (ilD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed. In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered. Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. ocular toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. increased mortality and toxicity with Vectibix® in combination with Bevacizumab and chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. aDVerSe reactionS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] clinical trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most frequently reported (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). table 1: adverse reactions (≥ 5% Difference) observed in Patients treated with Vectibix® monotherapy and Best Supportive care compared to Best Supportive care alone (Study 1)

SyStem organ claSS Preferred Term eye DiSorDerS Growth of eyelashes gaStrointeStinal DiSorDerS Nausea Diarrhea Vomiting Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Fatigue Mucosal inflammation infectionS anD infeStationS Paronychia reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Dyspnea Cough SKin anD SuBcutaneouS tiSSue DiSorDerS Erythema Pruritus Acneiform dermatitis Rash Skin fissures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive care Best Supportive care (n = 234) (n = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)]. In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. table 2: adverse reactions (≥ 5% Difference) observed in Patients with Wild-type (Wt) KRAS tumors treated with Vectibix® and folfoX chemotherapy compared to folfoX chemotherapy alone (Study 3)

SyStem organ claSS Preferred Term eye DiSorDerS Conjunctivitis gaStrointeStinal DiSorDerS Diarrhea Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Mucosal inflammation Asthenia infectionS anD infeStationS Paronychia inVeStigationS Weight decreased metaBoliSm anD nutrition DiSorDerS Anorexia Hypomagnesemia Hypokalemia Dehydration reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Epistaxis

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) n (%)

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

116 (36) 96 (30) 68 (21) 26 (8)

46 (14)

14 (4) 21 (7) 32 (10) 8 (2)

SyStem organ claSS Preferred Term SKin anD SuBcutaneouS tiSSue DiSorDerS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1) 10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

24 (7)

30 (9)

4 (1)

9 (3)

1 (< 1)

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing experience The following adverse reactions have been identified during post-approval use of Vectibix ®. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] Drug interactionS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. uSe in SPecific PoPulationS Pregnancy Pregnancy category c. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. nursing mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)]. Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll. Pediatric use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. geriatric use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy. Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. oVerDoSage Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. Patient counseling information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

22 (7)

85 (26) 26 (8) 42 (13) 10 (3)

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14. Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. v20 05/14


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Inside the Black Box Top 10 Myths About FDA’s Office of Hematology and Oncology Products By Gideon Blumenthal, MD, and Tatiana Prowell, MD

INSIDE THE BLACK BOX is an occasional column providing insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, FDA oncologists Gideon Blumenthal, MD, and Tatiana Prowell, MD, discuss 10 common myths about FDA’s Office of Hematology and Oncology Products. Dr. Blumenthal is Clinical Team Leader of the Thoracic and Head and Neck Oncology Team in the Division of Oncology Products 2, and Dr. Prowell is a Medical Officer and Breast Cancer Scientific Lead in the Division of Oncology Products 1. Both divisions are in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research.

O

ver the years, clinical reviewers in the FDA’s Office of Hematology and Oncology Products (OHOP) have heard many urban legends about FDA and the oncology approval process from the media, industry, and academia alike. In this article, we will attempt to dispel some of these myths with facts. Myth #1: FDA takes longer to approve oncology drugs than other countries. Fact: Although the drug approval process is not a race and different regulatory bodies must adhere to different laws, a recent study published in Health Affairs1 found that from 2003 to 2010, FDA approved 32 new anticancer drugs while the European Medicines Agency (EMA) approved 26. Of the 23 drugs approved by both agencies, the median time from marketing application submission to approval was 6 months for the FDA vs 11.5 months for the EMA. When an oncology drug has definitively demonstrated safety and efficacy, FDA reviewers work diligently to approve the drug as expeditiously as possible. Myth #2: FDA’s OHOP only lets you study drugs at their approved doses and schedules. Fact: This myth has two facets— doses of approved drugs in the experimental arm and in the control arm of a study. In the experimental arm, you can study a different dose and schedule of an already approved drug. An example of this is sunitinib (Sutent), which was initially studied and approved in renal

cell carcinoma at a dose of 50 mg daily, 4 weeks on and 2 weeks off, and was subsequently studied and approved in pancreatic neuroendocrine tumor at a dose of 37.5 mg daily continuously. In addition, if you are adding an experimental drug to an FDA-approved drug, in many settings (such as advanced incurable cancer with limited treatment options) it would be acceptable to reduce the dose of the backbone therapy. For example, if you were to combine a MEK inhibitor with docetaxel in the second-line metastatic lung cancer set-

vival as the endpoint, requires enrollment of U.S. patients, and does not permit crossover. Fact: Actually, there are at least three myths embedded in this one statement. In oncology, as opposed to other therapeutic areas, FDA approves most drugs based on a single trial due to the challenges involved in repeating a positive trial given the high unmet medical need in oncology. Although randomized controlled trials are the gold standard design, and overall survival is considered the ultimate clinical benefit endpoint because it captures critical efficacy and safety data, OHOP has repeatedly approved drugs on the basis of single-arm trials with high objective response rates and long durations of response. For randomized trials, OHOP has approved numerous drugs based on clinically meaningful improvements in progression-free survival with a favorable risk-benefit profile. For example, in the past decade, six drugs to treat renal cell carcinoma were approved based upon a progression-free survival endpoint. Drug development in this day and age is an international endeavor, and FDA accepts trial data from outside the United States so long as the population studied reflects the U.S. population and

Contrary to popular belief, FDA allows, and indeed often encourages, crossover at the time of disease progression. —Gideon Blumenthal, MD, and Tatiana Prowell, MD

ting, FDA would not object to lowering the dose of docetaxel to 60 mg/m2 from the approved dose of 75 mg/m2. With respect to the control arm, as long as the dose represents an established practice in the community, it is acceptable to use a different dose from that in the label. For example, in a randomized study in advanced breast cancer, it would be acceptable to treat control patients with 1,000 mg/m2 of capecitabine on days 1 through 14 every 21 days, a dose and schedule commonly used in clinical practice. Myth #3: FDA’s OHOP requires randomized trials with overall sur-

is treated according to standard U.S. clinical practice. For example, it would not be acceptable in 2014 to study patients with metastatic breast cancer without assessing HER2 and hormone receptor status. Finally, contrary to popular belief,2 FDA allows, and indeed often encourages, crossover at the time of disease progression. The 2013 approvals of dabrafenib (Tafinlar) and trametinib (Mekinist) in metastatic melanoma, and erlotinib (Tarceva), afatinib (Gilotrif), and crizotinib (Xalkori) in non– small cell lung cancer are examples of approvals based on progression-free

FDA Clinical Reviewers

Gideon Blumenthal, MD

Tatiana Prowell, MD

survival where crossover was allowed at the time of progression.3 Myth #4: FDA advisory committees, such as the Oncologic Drugs Advisory Committee (ODAC), are the final decision-makers in drug approval. Fact: Although some in the lay press interpret an ODAC vote as akin to a U.S. Supreme Court vote, ODAC’s role is not to render a decision on approval but rather to provide the FDA with scientific advice. Typically, when we ask ODAC a question on a particularly complicated new drug application or policy issue, we are more interested in the members’ thought process and rationale for their votes than the vote tally. Myth #5: FDA staff lack scientific and clinical expertise. Fact: When a drug is submitted as a new drug application or biologics license application, the FDA review team is multidisciplinary and includes, among others, experts in chemistry and manufacturing, microbiology, pharmacology/toxicology, clinical pharmacology, biostatistics, and clinical medicine. In OHOP, all clinical continued on page 114


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PAGE 114

Inside the Black Box Top 10 OHOP Myths continued from page 113

reviewers are trained in hematology and/or oncology, and 20 of our clinicians are still practicing medicine. FDA reviewers also publish in high-impact journals, speak at national and international meetings, organize diseasespecific workshops, write guidance and policy papers to further science and drug development, teach, and conduct independent research. Myth #6: FDA rejects most requests for expanded access to investigational drugs (aka compassionate use), and adverse events observed in an expanded access program could jeopardize approval. Fact: The first step in requesting compassionate use of an investigational drug is to have the treating physician contact the company that makes the drug. The reason for this is that FDA has no legal authority to mandate companies to provide patients investigational drugs outside of clinical trials. Since treatment with an investigational drug is only possible if the drug is available, a singlepatient investigational new drug (IND) application should only be submitted to FDA once the company has agreed to provide the drug to the patient. The goal of FDA’s review of a singlepatient IND is to make sure that no appropriate standard therapy or clinical trial has been overlooked and to ensure that adequate safety measures are being taken. Over the past 4 years, FDA has allowed more than 99% of single-patient expanded access requests to proceed, and most compassionate use requests are processed by OHOP within 1 to 2 business days. It is always challenging to determine causality of adverse events in patients with advanced cancer. This is particularly the case in the compassionate use setting, where patients generally have late-stage disease, are heavily pretreated, and there is no control group for comparison. As a result, although reporting of adverse events from singlepatient INDs is required and monitored by FDA for the safety of the patients being treated, OHOP is unaware of any drug applications for which adverse event information obtained from expanded access use of the drug has resulted in denial of approval. Myth #7: FDA determines the cost of anticancer agents. Fact: Regulatory decisions in the United States are made solely on the basis of a clinical risk-benefit determi-

nation and are cost-blind. We have no knowledge of a drug’s cost at the time of review or approval and no control over drug pricing at any point. There is growing societal attention to cost-benefit considerations in American health care, reflected in such initiatives as the American Board of Internal Medicine’s Choosing Wisely campaign and the American Society of Clinical Oncology’s Value Initiative, but decisions based on cost-benefit analyses rest with insurers, physicians, patients, and society, not with the FDA. Myth #8: The FDA is responsible for all of the recent drug shortages due to changes in manufacturing standards that impose burdens on companies. Fact: Actually, FDA has been part of the solution. While the most common reasons for drug shortages have been issues related to manufacturing and quality, FDA’s standards have not recently changed. A number of alarming drug quality incidents have been highlighted in the lay press.4 In addition to these issues, many companies have halted production of older drugs, including many sterile injectable agents, to devote greater resources to newer drugs that are more profitable, leaving fewer manufacturers to make older drugs and rendering them more vulnerable to shortages. The FDA has no authority to require a company to produce any drug, and prior to 2012, manufacturers were not required to report anticipated drug shortages to us. In 2012, Title X of the FDA Safety & Innovation Act was passed, which required manufacturers to notify FDA about potential manufacturing interruptions or discontinuations for all drugs and biologics, including the reasons and expected duration. This has enabled us to intervene proactively with strategies such as expediting review processes for new sources of raw materials or production lines for use by alternate manufacturers, as well as temporary redirection of drugs available outside the United States into the U.S. market. In 2012, FDA successfully prevented 282 anticipated drug shortages. FDA has developed a strategic plan for preventing and mitigating drug shortages that is available on its website.5 Myth #9: FDA does not take the voice of the patient into account in approval decisions and discourages use of patient-reported outcome measures.

Fact: The FDA is very interested in the patient perspective and has long supported use of patient-reported outcome measures in clinical trials. ODAC has a voting patient representative, and FDA first drafted a Guidance on use of patient-reported outcomes in trials nearly a decade ago. The final Guidance was published in 2009 after considerable discussion with all stakeholders, including patient advocates. Patient-reported outcomes can provide the basis for both efficacy and safety claims and have been used successfully, but we do believe that patient-reported outcome data should be as rigorously collected and analyzed as any other data being used to support regulatory approval. There is an entire team known as the Study Endpoints and Labeling Development Staff at FDA dedicated to helping companies develop and validate novel patient-reported outcome tools for use in clinical trials. A familiar example is ruxolitinib ( Jakafi) for myelofibrosis. The company originally had a development strategy that would have relied upon splenic response rate as the basis for accelerated approval. FDA worked with the company to develop a simple six-item patientreported outcome tool called the Myelofibrosis Total Symptom Score that documented meaningful symptomatic improvements in patients receiving ruxolitinib and served, along with splenic response rate, as the basis for regular approval. Myth #10: The FDA chooses to withhold its reasons for a negative review and nonapproval of a drug. Fact: For drugs that are approved by the FDA, the reviews and approval letters are posted on the Drugs@FDA website6 and are subject to Freedom of Information Act requests. For drugs that are not approved, we are prohibited by law from releasing either our reviews or the letters issued to the drug company that explain the rationale for the negative decision, as well as from discussing the application publicly. The only exception to this rule is in the setting of presentation of the application at an ODAC meeting. In fact, a common reason to convene an ODAC meeting is not only to hear the Committee’s thoughts but also to discuss problematic issues in the application in a public forum. Without a public discussion at ODAC, the reasons for a negative decision may not be apparent. It would be

GUEST EDITOR

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. impossible to present every application at an ODAC meeting due to constraints on time and resources, but we have identified numerous errors in oncology drug development that would likely be less common if FDA could release its reviews of every application, whether approved or not. This cannot happen in the absence of a change in the law. However, two of our colleagues are currently researching the common errors in drug development and plan to publish these results without identifying specific drugs or applications. n

Disclosure: Drs. Blumenthal and Prowell reported no potential conflicts of interest.

References 1. Roberts S, Allen JD, Sigal EV: Despite criticism of the FDA review process, new cancer drugs reach patients sooner in the United States than in Europe. Health Affairs 30:1375-1381, 2011. 2. O’Brien S: Ibrutinib CLL trial: Where is the equipoise? ASCO Post 4:1, 2013. 3. de Claro R, Kaminskas E, Farrell A, et al: FDA on CLL drug approval and expanded access (letter to the editor). ASCO Post 4:111, 2013. 4. Harris G: Medicines made in India set off safety worries. NY Times. February 14, 2014. Available at nyti.ms/1duVUbc. Accessed October 24, 2014. 5. Food and Drug Administration: Strategic Plan for Preventing and Mitigating Drug Shortages. October 2013. Available at www.fda.gov/downloads/Drugs/ DrugSafety/DrugShortages/UCM372566 .pdf. Accessed October 24, 2014. 6. Food and Drug Administration: Drugs at FDA: FDA Approved Drug Products. Available at www.accessdata.fda .gov/Scripts/cder/drugsatfda/index.cfm. Accessed October 24, 2014.


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FDA Update

FDA Approves Ramucirumab in Combination With Paclitaxel for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

T

he U.S. Food and Drug Administration (FDA) has approved ramucirumab (Cyramza) for use in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma. Ramucirumab was approved in April 2014 as a single agent for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma refractory to or progressive following first-line therapy with platinum or fluoropyrimidine chemotherapy. The combination of ramucirumab with paclitaxel was approved earlier this month.

neutropenia and febrile neutropenia (3.7% and 2.4%, respectively). The recommended dose and schedule for ramucirumab in combination with paclitaxel for advanced gastric or

gastroesophageal junction adenocarcinoma are ramucirumab at 8 mg/kg intravenously administered every 2 weeks and paclitaxel at 80 mg/m2 intravenously once a week for 3 weeks of every 28-

day cycle. Treatment should continue until disease progression or unacceptable toxicity. For additional information on use of the combination, see page 208. n

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC)...

Improved Overall Survival The approval of ramucirumab in combination with paclitaxel was based on the demonstration of improved overall survival in a multicenter, double-blind, placebo-controlled study (I4T-IE-JVBE) that enrolled 665 patients with previously treated advanced or metastatic gastric or gastroesopha-

Go with FASLODEX. Now Availa b

p d ate d D

Primary Endpoint: Progression-Free Survival (PFS)1,*

A Secondary Endpoint: Overall Survival (OS)1

Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg in CONFIRM2,†

Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg in CONFIRM2

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006) 2

m .c o

ta

xU

le

Safety data were evaluated in 656 patients who received at least one dose of study drug. The most frequently reported adverse reactions with ramucirumab plus paclitaxel (incidence ≥ 30%) were fatigue/asthenia, neutropenia, diarrhea, and epistaxis. The most common serious adverse reactions with ramucirumab plus paclitaxel were

de

o

Safety and Toxicity

w w w.F asl

geal junction adenocarcinoma. Patients were randomly assigned to receive either ramucirumab at 8 mg/kg every 2 weeks in combination with paclitaxel at 80 mg/m2 once a week for 3 weeks of every 28-day cycle (n = 330) or matching placebo plus paclitaxel (n = 335). A statistically significant prolongation of overall survival was demonstrated (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.68–0.96, P = .017). Median overall survival was 9.6 and 7.4 months in the ramucirumabplus-paclitaxel arm and placebo-pluspaclitaxel arm, respectively. Progressionfree survival was also significantly longer for patients receiving ramucirumab plus paclitaxel (HR = 0.64, 95% CI = 0.54– 0.75, P < .001).

Final O Analy S sis From CONFI RM*

a

• Not statistically signifcant as no adjustments were made for multiplicity2

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96) 2

Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on following pages. * PFS is defned as the time between randomization and the

earliest evidence of progression or death from any cause. 2 † COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Go with Confdence Learn more at www.FaslodexUpdatedData.com


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PAGE 116

Journal Spotlight

Study Sheds Light on Factors That May Contribute to Pancreatic Cancer

N

ew research that provides a better understanding of pancreatic cancer may help identify individuals at increased risk. The findings were recently published early online in Cancer.1 Pancreatic cancer is usually detected at a very late stage and has a 5-year

survival rate of less than 5%. Strategies that might help identify which individuals have an increased risk of developing the disease are needed. Some cases seem to run in families, but the genes that are responsible for such inherited predisposition remain

largely unknown. To get a better understanding of the disease, corresponding author Andrew Biankin, MBBS, PhD, of the University of Glasgow, in Scotland, and his colleagues studied 766 patients who had been diagnosed with pancreatic

cancer. Patients were thought to have an inherited predisposition if they had one or more affected first-degree relatives. Otherwise, their cancer was considered sporadic. Nearly 9% of patients who were diagnosed with pancreatic cancer had at

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer (mBC) in postmenopausal women with disease progression following antiestrogen therapy. See more a t

FASLODEX 500 mg vs 250 mg in the Updated OS Analysis in CONFIRM2,§ • Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2 • Not statistically signifcant as no adjustments were made for multiplicity.2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically signifcant difference in OS between the 2 treatment groups2 * The CONFIRM trial was a randomized, double-blind, controlled phase III

study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † PFS was the primary endpoint.1 ‡ ORR is defned as the number of patients with complete response or partial response.2 § OS was a secondary endpoint.1

em FASLODEX 500 mg Showed 4 b er 01 9-1 3, 2 a Comparable Safety Profle to FASLODEX 250 mg in CONFIRM1 c

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2 • Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2 — Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

De

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

SABC BoothS #465

Additional Important Safety Information About FASLODEX

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX • The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Please read brief summary of full Prescribing Information for FASLODEX on following pages.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Go with Confdence FASLODEX is a registered trademark of the AstraZeneca group of companies.

©2014 MedImmune, Specialty Care Division of AstraZeneca.

All rights reserved.

3017912

8/14


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Journal Spotlight

least one parent or sibling who was also diagnosed with pancreatic cancer. When Dr. Biankin and his team examined the pancreatic tissue adjacent to the cancer in all study participants, they found more precancerous tissue in those whose first-degree relatives also had pancreatic cancer. They also found that members of these families appeared to be at higher

risk of developing other cancers including melanoma and endometrial cancer. Importantly, active smoking was associated with a significantly younger age at diagnosis in all patients. “These findings are important because they suggest that the genes we inherit from our parents likely play a significant role in our lifetime risk of

FASLODEX® (fulvestrant) Injection

developing pancreatic cancer,” said Dr. Biankin. “Secondly, they emphasize that when assessing someone’s individual risk of developing pancreatic cancer, it may be important to assess not just family history of pancreatic cancer but other malignancies too. Finally, our data emphasize the importance of smoking abstinence.” n Disclosure: For a full list of contributors

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

BRIEF SUMMARY For full Prescribing Information, see package insert. INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged. 2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.” 4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap. 5. Twist to lock the needle to the luer connector. 6. Remove needle sheath. 7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock. 9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered. 10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector. 11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX.

WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration]. FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].

Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and wellcontrolled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

and Adverse Reaction Body as a Whole

Vascular System

Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms. Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis. Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2). Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day. Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0

—continued

and disclosure information, see http://www. pancreaticcancer.net.au/apgi/collaborators).

Reference 1. Humphris JL, et al, and the Australian Pancreatic Cancer Genome Initiative: Clinical and pathologic features of familial pancreatic cancer. Cancer. October 14, 2014 (early release online).


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Announcements

ACCC to Develop Comprehensive Program on Immuno-Oncology for Community‐Based Providers

T

he Association of Community Cancer Centers (ACCC) has been provided with a contribution to develop a comprehensive program in immuno-oncology for community-

based providers. The funding, provided by Bristol-Myers Squibb, will enable ACCC to establish the Institute for Clinical Immuno‐Oncology to educate providers about immuno-oncology and

its implementation and delivery in the community setting. The Institute for Clinical ImmunoOncology will be a catalyst in assuring the availability of and access to inno-

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

FASLODEX 250 mg N=423 (%) Metabolic and Nutritional Disorders 18.2 Peripheral Edema 9.0 Musculoskeletal System 25.5 Bone Pain 15.8 Arthritis 2.8 Nervous System 34.3 Dizziness 6.9 Insomnia 6.9 Paresthesia 6.4 Depression 5.7 Anxiety 5.0 Respiratory System 38.5 Pharyngitis 16.1 Dyspnea 14.9 Cough Increased 10.4 Skin and Appendages 22.2 Rash 7.3 Sweating 5.0 Urogenital System 18.2 Urinary Tract Infection 6.1

Anastrozole 1 mg N=423 (%) 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered. Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26. Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known. Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis. In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic Impairment FASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8). The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

2

SafetyGlide™ is a trademark of Becton Dickinson and Company. FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2355400 2/13

vative immune-oncology agents and therapies for patients in need. Immuno-oncology, a transformational paradigm in cancer treatment, focuses on developing therapies that put the body’s own immune system to work to fight cancer. “We are thrilled about the opportunity to help our members adopt innovations,” said Becky L. DeKay, MBA,

ACCC is pleased to have the opportunity to help ensure [that] cutting-edge therapies can be delivered in the community setting. —Becky L. DeKay, MBA

President of ACCC. “There have been exciting advancements in understanding the immune system over the last 5 years, and this has led to newly emerging immunotherapy treatments. ACCC is pleased to have the opportunity to help ensure these cutting-edge therapies can be delivered in the community setting.”

Advisory Committee to Be Assembled The Institute for Clinical ImmunoOncology will engage community thought leaders and providers to advance the science and clinical applications of immune-oncology therapeutics in the community setting through the collective expertise, experience, and insights of leading providers. The initial phase of the program will involve the establishment of the project infrastructure, including staffing, project planning, and marketing, and identification of potential partner organizations. An Advisory Committee consisting of ACCC members and other immune-oncology leaders will be created to oversee the planning and development of the Institute. Early phases of the program will include the identification and engagement of clinician scholars and thought leaders, an educational needs assessment of the ACCC membership, a 1‐day national conference, a monthly series of e‐courses and e‐newsletters for clinicians and fellows, and multiple scientific and policy publications highlighting the project findings and ­outcomes. n


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In the Clinic Supportive Care

Fixed-Combination Netupitant/Palonosetron for Prevention of Chemotherapy-Induced Nausea and Vomiting By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n October 10, 2014, oral fixedcombination netupitant and palonosetron (Akynzeo) was approved for use in prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy including, but not limited to, highly emetogenic chemotherapy.1,2 Palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phases after cancer chemotherapy.

Supporting Trials Approval was based on results of two randomized trials in which the key efficacy endpoints were complete response (no emetic episode and no use of rescue medication) for the delayed phase at 25 to 120 hours, for the acute phase at 0 to 24 hours, and within 120 hours (overall phase) after the start of chemotherapy. In the first trial,2,3 conducted in patients receiving a chemotherapy regimen including cisplatin (median dose of 75 mg/m2), 135 patients received a single dose of netupitant (300 mg)/palonosetron (0.5 mg) plus dexamethasone (12 mg), and 136 patients received a single dose of palonosetron (0.5 mg) plus dexamethasone (20 mg) prior to the start of chemotherapy. All patients received dexamethasone at 8 mg on days 2 to 4. Complete response was observed in 90.4% vs

80.1% in the delayed phase (P = .032), 98.5% vs 89.7% in the acute phase (P = .002), and 89.6% vs 76.5% in the complete phase (P = .003). In the second trial,2,4 conducted in patients receiving an anthracycline and cyclophosphamide-based regimen, 724 patients received a single dose of netupitant (300  mg)/palonosetron (0.5 mg) plus dexamethasone (12 mg), and 725 received a single dose of palonosetron (0.5 mg) plus dexamethasone (20 mg). No antiemetic treatment was given on days 2 or 3. Complete response was observed in 76.9% vs 69.5% in the delayed phase (primary endpoint, P = .001), 88.4% vs 85.0% in the acute phase (P = .047), and 74.3% vs 66.6% in the complete phase (P = .001).

How It Works Palonosetron (available in single-agent form as Aloxi) is a 5-HT3 receptor antagonist that exhibits strong binding affinity for this receptor and little or no affinity

OF NOTE Palonosetron/netupitant carries warnings/precautions for hypersensitivity reactions including anaphylaxis and serotonin syndrome.

for other receptors. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. Development of

Combination Drug for Chemotherapy-Related Nausea/Vomiting ■■ Oral fixed-combination netupitant/palonosetron (Akynzeo) was approved for use in prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy. ■■ In patients receiving highly emetogenic chemotherapy, the recommended dosage in adults is one capsule (300 mg of netupitant, 0.5 mg of palonosetron) given approximately 1 hour prior to the start of chemotherapy, with dexamethasone at 12 mg given 30 minutes prior to chemotherapy on day 1 and at 8 mg once daily on days 2 to 4. Dexamethasone administration is not necessary on days 2 to 4 for chemotherapy not considered highly emetogenic.

acute emesis depends on serotonin, and its 5-HT3 receptors have been shown to selectively stimulate the emetic response. Netupitant is a selective antagonist of substance P/neurokinin 1 receptors. Delayed emesis is largely associated with substance P activation of tachykinin family neurokinin 1 receptors, distributed in the central and peripheral nervous systems. Netupitant inhibits substance P– mediated responses.

How It Is Given A capsule of the new product contains 300 mg of netupitant and 0.5 mg of palonosetron. In patients receiving highly emetogenic chemotherapy, including cisplatin-based therapy, the recommended dosage in adults is one capsule given approximately 1 hour prior to the start of chemotherapy, with dexamethasone at 12 mg given orally 30 minutes prior to chemotherapy on day 1 and dexamethasone at 8 mg given once daily on days 2 to 4. In those receiving anthracycline- and cyclophosphamide-based chemotherapy or other chemotherapy not considered highly emetogenic, the recommended dosage in adults is one capsule approximately 1 hour prior to the start of chemotherapy with dexamethasone at 12 mg given 30 minutes prior to chemotherapy on day 1. Administration of dexamethasone on days 2 to 4 is not necessary. The palonosetron/netupitant combination should be used with caution in patients receiving CYP3A4 substrates (eg, tacrolimus, imatinib, anastrozole, paclitaxel), since inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug that can last at least 4 days. Concomitant use with CYP3A4 inducers (eg, carbamazepine, phenobarbital, pioglitazone) should be avoided, since they decrease plasma concentrations of netupitant. Use of the combination should be avoided in patients with severe hepatic impairment and those with severe renal impairment or end-stage renal disease. The safety and efficacy of the combination have not been evaluated in patients aged < 18 years.

Safety Profile The most common adverse events of any grade with palonosetron/netupitant vs palonosetron in the single cycle of the first trial were dyspepsia (4% vs 2%), fatigue (4% vs 2%), constipation (3% vs 1%), and erythema (3% vs 2%). The most

OF NOTE Palonosetron is a selective 5-HT3 receptor antagonist that blocks the serotonin-activated acute emetic response; netupitant is a selective antagonist of substance P/neurokinin 1 receptors that inhibits substance P–mediated delayed emesis.

common adverse events in the first cycle of the second trial were headache (9% vs 7%), asthenia (8% vs 7%), and fatigue (7% vs 5%), with similar adverse events occurring during subsequent treatment cycles. Among all patients, liver function abnormalities consisting of aspartate transaminase (AST) or alanine transaminase (ALT) > 3 times upper limit of normal with total bilirubin > upper limit of normal occurred in 0.3% vs 0.6%, AST or ALT > 10 times upper limit of normal with total bilirubin > upper limit of normal occurred in 0% vs 0.2%, and AST or ALT > 3 times upper limit of normal with total bilirubin ≥  2 times upper limit of normal occurred in 0.1% vs 0.1%. Palonosetron/netupitant carries warnings/precautions for hypersensitivity reactions including anaphylaxis, which have been reported in patients receiving palonosetron with or without known hypersensitivity to other 5-HT3 receptor antagonists, and serotonin syndrome, which has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. n References 1. U.S. Food and Drug Administration: FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy. Available at www.fda.gov. 2. AKYNZEO® (netupitant and palonosetron) capsules prescribing information. Eisai, October 2014. Available at www.akynzeo.com. 3. Hesketh PJ, Rossi G, Rizzi G, et al: Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 25:1340-1346, 2014. 4. Aapro M, Rugo H, Rossi G, et al: A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 25:1328-1333, 2014.


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State of the Art Gastrointestinal Oncology

Pancreatic Cancer in 2014 A Conversation With Margaret Tempero, MD By Ronald Pi­­­ana

A

denocarcinoma of the pancreas is the fourth leading cause of cancer death in men and women in the United States. This year, about 46,000 people in this country will be diagnosed with pancreatic cancer, and more than 39,000 will die of the disease. The ASCO Post recently spoke with Margaret A. Tempero, MD, Director of the University of California, San Francisco (UCSF) Pancreas Center, whose research career has focused on pancreatic cancer, especially in the area of investigational therapeutics. Dr. Tempero shed light on the current state of pancreatic cancer therapy and research.

able to try some of the newer strategies that we’ve only dreamed of trying in pancreatic cancer. The other major advance, which has accelerated our ability to understand the biology of this disease, has been the introduction of cutting-edge genetically engineered mouse models, a technology that has evolved over the past 10 years or so. These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer, and they will have a huge impact on our approach to developing new therapies as we move forward.

Major Advances

Early Detection

What have been the biggest advances in pancreatic cancer seen during your career? The recent introduction of some reasonably effective combination chemotherapies is an important advance. Considering where we were a decade ago, having the opportunity to treat patients now and see them go into remission and then be able to take them off treatment for observation is nothing short of miraculous. Now that we have diseasestabilizing chemotherapy, it will allow us to go to the next level, where we’ll be

Early detection in pancreatic cancer is very uncommon. Is this something we have to accept, or are there any markers forthcoming that may show promise? The disease is somewhat diverse in its biology, and there are patients who seem to have a very early propensity for metastases even with very small primary tumors. Then there are other patients who don’t have a propensity for metastatic involvement and instead have slower-growing locally invasive disease. So in this subset of patients that have

‘Dream Team’ Principal

S

tand Up To Cancer is a groundbreaking initiative created to accelerate innovative cancer research that will rapidly bring new therapies to patients. In 2014, Margaret A. Tempro, MD, was selected to join a multidisciplinary Stand Up To Cancer “dream team” of pancreatic cancer researchers from nine institutions. Dr. Tempero will lead the University of California, San Francisco, portion of research, collaborating nationally to study vaccines and other immune-based strategies. The project, titled “Transforming Pancreatic Cancer to a Treatable Disease,” is being funded by the Lustgarden Foundation and the Fox Family Cancer Research Funding Trust, along with administrative support and oversight from Stand Up To Cancer’s scientific partner, the American Association for Cancer Research. n

localized, slow-growing disease, early detection would have clinical benefit. We need to come up with a detection marker on the molecular level with a cost-effective, high-throughput assay for patients at average risk and an imaging tool that could be used to screen patients at high risk. That said, risk stratification is something we don’t know how to do very well in this disease, and it remains a very important research area.

Risk Factors Cigarette smoking is related to pancreatic cancer. Are there other lifestyle drivers of this disease that we know about?

Newer Approaches In this era of biologics and the rise of immunotherapy, please discuss how we currently approach this disease and which, if any, of the newer approaches hold promise. There are several areas that hold promise. For one, studying the microenvironment in this disease and how it influences its biologic behavior is pretty high on our research priority list. One such strategy is being explored by Halozyme Therapeutics, which has developed a form of hyaluronidase that diminishes the hyaluronan component

Considering where we were a decade ago, having the opportunity to treat patients and see them go into remission and then be able to take them off treatment for observation is nothing short of miraculous. —Margaret Tempero, MD

Cigarette smoking is a risk factor in pancreatic cancer but not nearly at the ratio we see in lung cancer and head and neck cancer. Obesity is also a risk factor for pancreatic cancer, at about the same ratio as cigarette smoking. These are two environmental risks based on lifestyle that we can modify and thereby ultimately reduce disease incidence. That said, in the overall picture of pancreatic cancer, this impact would be small. Outside of familial disease, the biggest risk factor is something we don’t want to change, and that is successful aging. Pancreatic cancer, like most cancers, is a disease associated with aging. Since we have an expanded aging population, we are going to see an increase in this disease in patients over the age of 75, so our real challenge is in developing better ways to treat and manage this growing population of older patients.

of the stroma. In doing so, it reduces interstitial pressure and may allow for more effective drug delivery. This approach is already being studied in randomized phase II trials. The other area of the microenvironment that is being tackled by our Stand Up To Cancer team [see sidebar] is immunomodulation, which seeks to change the immunoenvironment from a protumor to an antitumor environment. To do this, we’re looking at a variety of strategies. For one, we’ve found a connection between B cells and tumorpromoting myeloid cells, so reprogramming B cells with a Bruton’s tyrosine kinase inhibitor plus chemotherapy is one approach. Also, we are exploring some vaccines in combination with checkpoint inhibitors. In fact, there are some vaccines already in very late-stage development in randomized phase III trials.


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State of the Art

The early signals are encouraging, and as I said before, finally having chemotherapy agents that stabilize our patients allows this groundbreaking work to move forward.

with clean margins following preoperative treatment. We need rigorous trials to help us translate this into better outcomes, but the anecdotal information we have is encouraging.

Surgical Setting

Editorial Position

Please touch on the current role of surgery in pancreatic cancer. Obviously, if you have an organ-confined lesion, surgery plays an important role in the treatment of pancreatic cancer. And another benefit of the new chemotherapy regimens is to improve the outcome with surgery. We are seeing more reports now on successful surgery

Congratulations on being named Editor-in-Chief of the Journal of the National Comprehensive Cancer Network (JNCCN). What does this new opportunity mean to you? The JNCCN is a powerful tool for disseminating the latest information that clinicians can readily translate into their patient care. As someone who has

devoted a career largely to one disease site, being the Editor-in-Chief of this journal that so carefully covers malignancies is a real honor. It is also a great way for me to keep up to speed with progress in cancer care.

Closing Thoughts Please share some last thoughts on this disease, which you have dedicated so much of your career to. I’ve been involved in treating patients with pancreatic cancer for over 30 years. Frankly, a lot of people thought I was nuts to devote my career to this dreadful disease. But what I learned ear-

ly on from my mentors was to focus and never let go of my goal. And I’ve come to look at this very vulnerable patient population as my professional mission in life. When I think about how this disease affects my patients, it just makes me want to work harder and harder. I also feel fortunate to direct the Pancreas Center at UCSF, a very prestigious university with teams of incredible scientists, all of whom are dedicated to the mission of curing pancreatic cancer or turning it into a manageable chronic disease. n

Disclosure: Dr. Tempero reported no potential conflicts of interest.

Journal Spotlight Melanoma

Ipilimumab/Sargramostim Improves Overall Survival vs Ipilimumab Alone in Patients With Advanced Metastatic Melanoma By Jo Cavallo

A

randomized clinical trial of patients with advanced metastatic melanoma treated with ipilimumab (Yervoy), an immune checkpoint inhibitor, in combination with sargramostim (Leukine), an immune stimulant, vs ipilimumab alone, has found a 1-year survival rate of 68.9% vs 52.9% in the ipilimumab-only group. In addition, patients treated with the combination therapy experienced fewer serious adverse side effects than those treated with ipilimumab alone. The study by F. Stephen Hodi, MD, Director of the Melanoma Treatment Center and Director of the Center for Immuno-Oncology at Dana-Farber Cancer Institute, and colleagues is published in JAMA.1

Study Methodology The Eastern Cooperative Oncology Group (ECOG) conducted a phase II randomized clinical from December 2010 to July 2011, enrolling 245 patients with stage III/IV metastatic melanoma who had received at least one prior therapy. The patients were randomly assigned to receive ipilimumab plus sargramostim (granulocyte-macrophage colony-stimulating factor) vs ipilim-

umab alone. The primary end point was a comparison of length of overall survival. The secondary endpoint was progression-free survival, response rate, safety, and tolerability. The patients were followed for a median of 13.3 months.

This [study] opens the possibility of improving clinical outcomes and decreasing serious side effects in treating advanced melanoma with ipilimumab.

Key Findings The researchers found that the median overall survival for the ipilimumab-plus-sargramostim group was 17.5 months vs 12.7 months for the ipilimumab-only group. The 1-year survival rate for the combination therapy was 68.9% compared to 52.9% for ipilimumab alone (P = .01). In both groups, however, the median progression-free survival was similar, at 3.1 months. In addition, grade 3 to 5 adverse events occurred in 44.9% of patients in the

—F. Stephen Hodi, MD

ipilimumab-plus-sargramostim group vs 58.3% of patients in the ipilimumab-alone group. “Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer [overall survival] and lower toxicity, but no difference in [progression-free

Ipilimumab Plus Sargramostim in Melanoma ■■ Median overall survival was 17.5 months for the ipilimumab-plussargramostim group vs 12.7 months for the ipilimumab-only group. Median progression-free survival was similar in both groups. ■■ The 1-year overall survival rate for the ipilimumab-plus-sargramostim group was 68.9% compared to 52.9% for ipilimumab alone. ■■ Grade 3 to 5 adverse events occurred more often in the ipilimumab-alone group (58.3% vs 44.9% in the combination group).

survival]. These findings require confirmation in larger studies with longer follow-up,” concluded the researchers. “This [study] opens the possibility of improving clinical outcomes and decreasing serious side effects in treating advanced melanoma with ipilimumab,” said Dr. Hodi in a statement. n

Disclosure: The research was supported by Public Health Service Grants, the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Hodi FS, Lee S, McDermott DF, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014.


Kyprolis速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.


KYPROLIS is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma. • Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria. References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100603 October 2014


The ASCO Post  |   NOVEMBER 15, 2014

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Announcements

NIH Awards Aim to Improve Understanding of Cell Pathways, Development of New Therapies

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uilding on a successful 3-year pilot project, the National Institutes of Health (NIH) has awarded more than $64 million to six individuals at five research institutions to create a database

of human cellular responses—the Library of Integrated Network-based Cellular Signatures (LINCS). Discovering such cell responses will improve scientists’ understanding of cell pathways

and aid in the development of new therapies for many diseases. LINCS data will be freely available to any scientist. The funding establishes six centers, collectively called the Data and Signature

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing a Cycles 2 and Beyond Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 Dosing Dosing Dosing Dosing (27 mg/m2): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250  mL  to 500  mL of intravenous  fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2. Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

Recommended Action • Withhold dose. • If fully recovered before next scheduled dose, continue at same dose level. • If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline. Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to • congestive heart failure; 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • decreased left ventricular • If tolerated, the reduced dose may be escalated to the function; previous dose at the discretion of the physician. • or myocardial ischemia

[see Warnings and Precautions] Pulmonary Hypertension [see Warnings and Precautions]

Pulmonary Complications • Grade 3 or 4 [see Warnings and Precautions]

Hepatic Toxicity • Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions)]

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• Withhold until resolved or returned to baseline. • Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

Generating Centers. The National Human Genome Research Institute (­ NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) administer the program. The LINCS program aims to catalog

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function. • Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If not attributable to KYPROLIS, restart at the dose used prior to the event. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Other • Grade 3 or 4 non‑hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

a

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2  mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs.  DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2  to 5  minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The  reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50  mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS Storage Conditions of Reconstituted KYPROLIS

a

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

24 hours

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

4 hours

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade  4 events, and 1  death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in <  1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day  8 of each 28‑day cycle and recovery to baseline by the start of the next 28‑day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

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6.75”

6.25”

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and analyze cellular function and molecular activity in response to perturbing agents such as drugs and genetic factors. LINCS researchers then will measure the cells’ molecular and biochemical responses and use computer analyses to uncover “signatures.” “The simplest way to think about signatures is as broad common patterns, as

Event

All Gradesa

well as uncommon behavior, in how cells respond to various small molecules or genetic changes,” said Ajay Pillai, PhD, Program Director in NHGRI’s Division of Genome Sciences, and Co-Coordinator of the LINCS program, along with Albert Lee, PhD, Program Director in NHLBI’s Division of Cardiovascular ­Sciences.

Patients (N = 526) [n (%)] Grade 3 Events

Grade 4 Events

Recipients of the new LINCS grants (pending available funds) are: • Harvard Medical School, Boston, $12.87 million over 6 years—Principal Investigator: Peter Sorger, PhD This center will develop new measurement methods and computer algorithms to detect and analyze perturbations induced by therapeutic drugs in

B:11.25”

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T:10.875”

healthy and diseased human cells. • Oregon Health and Science University (OHSU), Portland, $10.29 million over 6 years—Principal Investigator: Joe Gray, PhD The OHSU team will study how both malignant and nonmalignant cells are controlled by the microenvironments in which they live. The researchers will provide measurements of the impacts of thousands of different microenvironments on cellular phenotypes, protein makeup, and geneexpression readouts in cell lines. • Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge $12.56 million over 6 years—Principal Investigator: Todd Golub, MD The Golub team will study up to 50 cell types perturbed by a large number of chemical compounds and genetic reagents. Each perturbation will produce about 1,000 gene-expression readouts. By the project’s end, Dr. Golub expects to have generated more than 1 million profiles of how genes are expressed in different cells. $8.9 million over 6 years—Principal Investigator: Jacob D. Jaffe, PhD Dr. Jaffe’s LINCS Center for Proteomic Characterization of Signaling and Epigenetics will study cell disruption at the most basic levels: phosphorylationmediated signaling and epigenetics. These latter signals are transmitted in part by modifications to histone proteins, around which the DNA in cells is wrapped. • Icahn School of Medicine at Mount Sinai, New York City, $11.39 million over 6 years—Principal Investigator: Srinivas (Ravi) Iyengar, PhD Dr. Iyengar’s Drug Toxicity Signature Center aims to develop cell signatures that will predict adverse events that might be caused by drugs and will identify other drugs that might lessen these side effects. The researchers will leverage the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System database to identify drugs that produce adverse events in heart, liver, and neuronal function and to search for drugs that may mitigate these events. • University of California, Irvine, $8 million over 6 years—Principal Investigator: Leslie M. Thompson, PhD The Thompson team will concentrate on human brain cells. By applying LINCStype perturbations to studying an array of human brain cells, the researchers hope to identify targets for developing drugs against neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and Huntington’s disease. The National Institute of Neurological Disorders and Stroke (NINDS) is funding Dr. Thompson’s grant. n


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Palliative Care in Oncology Survivorship

Addressing Patients’ Sexual Dysfunction Throughout Survivorship A Conversation With Patricia A. Ganz, MD By Jo Cavallo

Patricia A. Ganz, MD

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tudies show that all cancers and related treatments have the potential to affect sexuality and sexual function. Surgery, chemotherapy, hormonal therapy, bone marrow transplantation, and radiation therapy can physically impact sexual health in myriad ways, including vaginal dryness, dyspareunia, and chemically induced menopause in women; erectile dysfunction in men; and reduced libido in both sexes. The psychological distress of a cancer diagnosis and treatment, caused by changes in body image, depression, and anxiety, can further conspire to tamp down sexual desire and patients’ ability to achieve arousal and orgasm. Despite study findings1-3 showing that sexual dysfunction is an important quality-of-life issue for many patients throughout all phases of survivorship, including end of life, the subject remains a neglected component in palliative care. Because oncologists rarely broach the subject with their patients and patients are often hesitant to raise the issue themselves, fearing embarrassment and the possibility of interfering with their cancer treatment, sexual dysfunction remains largely undiagnosed and untreated. The ASCO Post talked with Patricia A. Ganz, MD, Director of the Division of Cancer Prevention and Control Research at UCLA’s Jonsson Comprehensive Cancer Center and Director of the UCLALIVESTRONG Survivorship Center of Excellence, about how a cancer diagnosis and treatment affect the sexual health of men and women, and how oncologists can start a dialogue about sexual dysfunction with their patients.

Incidence and Causes How prevalent is sexual dysfunction after a cancer diagnosis and treatment? There are no exact data available, but sexual dysfunction is very common in both men and women following a cancer

diagnosis. For women, the literature suggests that having good emotional wellbeing and being in a good-quality partnered relationship are very important in maintaining sexual health and function after a cancer diagnosis. For both men and women, changes in body image that are caused by surgery, radiation, and chemotherapy, such as alopecia, scars, and deformities, can affect the sense of sexual attractiveness and reduce interest in sexual activity and intimacy. More prominent culprits are side effects of cancer and its treatment such as fatigue, pain, and physical impairment, all of which can interfere with arousal and interest in resuming normal sexual activity in both women and men. Low testosterone levels, especially in men, can also hinder sexual interest. Damage to the pelvic area from treatment for any type of cancer in that region—including testicular, prostate, rectal, colon, and bladder cancers—such as radical prostatectomy, radiation therapy, and orchiectomy, as well as stem cell or bone marrow transplant, can lead to erectile dysfunction. For women, surgery for breast cancer can cause loss of nipple sensation, and removal of the whole breast can cause prolonged pain, discouraging the desire

for physical contact. Systemic therapy, radiation therapy, and surgical treatment for gynecologic cancers can cause vaginal dryness and a narrowing of the vagina, causing intercourse to be painful and provoking anxiety, making it difficult for women to want to resume sexual activi-

patients may not feel comfortable talking about these issues with their oncologist, but asking the question lets them know that the oncologist is aware that sexual dysfunction is a potential problem during and after cancer treatment and that it is okay to talk about it.

Sexual health is an important issue for many patients— even those with advanced disease—and we have to acknowledge their concerns and provide solutions. —Patricia A. Ganz, MD

ties. Hormonal therapies, such as aromatase inhibitors, can also cause severe vaginal dryness and pain with intercourse.

Raising the Issue Why is so little medical attention paid to a health issue affecting virtually every cancer survivor? Oncologists have a sort of “don’t ask, don’t tell” policy when it comes to sexual health. I usually raise the issue during adjuvant therapy and will ask patients, “How is your sex life?” And if patients want to talk about any problems they may be having, the question gives them an entrée and permission to respond. Some

My experience is that most patients respond positively to that question and will give you information about their sexual health concerns if there is an issue for them.

Addressing the Problem How should sexual health be addressed in the palliative care setting? Any physical and psychosocial symptom, including pain, fatigue, sexual dysfunction, anxiety, and depression, should be managed throughout the continuum of oncology care. The mental and physical health of the whole person should be evaluated from the get-go, whether the

Key Solutions to Sexual Concerns in Cancer Survivors

E

valuating a Patient’s Sexual Health—The National Cancer Institute suggests designating and training a member of the oncology team, such as an oncology nurse or social worker, as the expert on sexual

Sage Bolte, PhD, LCSW, OSW-C

health issues. When assessing general quality-of-life concerns, relationship and sexuality should be included in the questions asked, such as: “Many cancer survivors notice changes or problems in their sex lives after cancer treatment. Do you have any problems or concerns related to sexuality?”

Encouraging Patients to Discuss Sexual Dysfunction—In an interview with The ASCO Post (“Sexual Health After Cancer: Communicating With Your Patients,” April 15, 2013), Sage Bolte, PhD, LCSW, OSW-C, suggested including sexual side effects of treatment in the informed consent process and discussing them with the same level of detail as other possible side effects. “The informed consent process should include the informational component of potential side effects of treatment and normalizing language to explain them,” said Dr. Bolte. “For example, you might say, “Some patients may experience changes in their sexual desire, the way they feel about their body, changes in erectile function, or vaginal changes. If you notice any changes, please feel free to talk to one of us about your concerns.” Providing Patients With Useful Resources —Many sexual problems associated with cancer and cancer treat-

ment can be mitigated with proper intervention. These websites provide helpful information for patients seeking solutions to sexual dysfunction: • American Association of Sexuality Educators, Counselors and Therapists—aasect.org • American Cancer Society—Sexuality for the Woman With Cancer; Sexuality for the Man With Cancer: cancer.org • ASCO—cancer.net • Leukemia & Lymphoma Society—Sexuality and Intimacy Fact Sheet: lls.org • LIVESTRONG—Male Sexual Functioning After Cancer; Female Sexual Functioning After Cancer: livestrong.org • National Cancer Institute—Facing Forward: Life After Cancer Treatment: cancer.org • The Institute for Sexual Medicine —theinstituteforsexualmedicine .com n


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Palliative Care in Oncology patient has curable or advanced disease. I see sexual health as a survivorship issue and our experience suggests the sooner you address the problem the more likely it is to be resolved. We conducted an intervention study4 for breast cancer several years ago. In that study, we initiated a group intervention for sexual dysfunction in women with breast cancer who were at least a year away from completing treatment. Although we saw some benefit, we found that many women had settled into a new routine of sexual inactivity and they were not always sure they wanted to try to resume intimacy. In my opinion, interventions such as vaginal lubricants and moisturizers for vaginal dryness and pelvic muscle exercises for vaginal pain in women, and erectile dysfunction medications and penile rehabilitation for men, have to be introduced during or immediately at the end

of treatment, because once people get set in a pattern of limited intimacy or find that they can’t do what they used to do, it is difficult to change that pattern. Discussions and remedies for sexual health need to be included in the posttreatment care plan of every cancer survivor. For a long time, palliative care was more focused on end-of-life care and symptom management. But now oncologists and palliative care specialists are starting to address patients’ quality-of-life concerns from the moment of diagnosis. I would advise clinicians to ask their patients, “What are the most important issues you need help with right now?” And if the patient raises sexual dysfunction as a big concern, it clearly has to be addressed. Sexual health is an important issue for many patients—even those with advanced disease—and we have to ac-

knowledge their concerns and provide solutions. n

GUEST EDITOR

Disclosure: Dr. Ganz reported no potential conflicts of interest.

References 1. Howlett C, Swain M, Fitzmaurice N, et al: Sexuality: The neglected component in palliative care. Int J Palliat Nurs 3:218, 1997. 2. Katz A: The sounds of silence: Sexuality information for cancer patients. J Clin Oncol 23:238-241, 2005. 3. Redelman MJ: Is there a place for sexuality in the holistic care of patients in the palliative care phase of life? Am J Hosp Palliat Care 25:366-371, 2008. 4. Rowland JH, Meyerowitz BE, Crespi CM, et al: Addressing intimacy and partner communication after breast cancer: A randomized controlled group intervention. Breast Cancer Res Treat 118:99-111, 2009.

Jamie H. Von Roenn, MD

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

JCO Spotlight Survivorship

Vigorous Exercise Lowers Risk of Cardiovascular Events in Adult Survivors of Childhood Hodgkin Lymphoma By Matthew Stenger

I

n a report from the Childhood Cancer Survivor Study published in the Journal of Clinical Oncology,1 Lee W. Jones, PhD, of Memorial Sloan Kettering Cancer Center, and colleagues

the response to the following question: “On how many of the past 7 days did you exercise or do sports for at least 20 minutes that made you sweat or breathe hard (eg, dancing, jogging,

[O]ur findings indicate that adoption of regular exercise consistent with national vigorous exercise recommendations in currently sedentary survivors could confer substantial public health benefits in the rapidly growing population of survivors of childhood cancer. —Lee W. Jones, PhD, and colleagues

found that vigorous exercise reduces the risk of major cardiovascular events in adult survivors of childhood Hodgkin lymphoma.

Study Details In the study, 1,187 survivors of childhood Hodgkin lymphoma with a median age of 31.2 years completed a questionnaire evaluating vigorousintensity exercise behavior, based on

basketball, and so on).” Data on cardiovascular events were collected in follow-up questionnaires. The primary endpoint was incidence of any major (grade 3 to 5) cardiovascular event. Over a median follow-up of 11.9 years (range, 1.7–14.3 years), a total of 135 cardiovascular events were reported, including 21 cardiovascular-related deaths. Mean vigorous-intensity exer-

cise behavior was 6.1 metabolic equivalent (MET) h/wk-1 ; 36% of survivors reported having participated in no vigorous-intensity exercise behavior.

Dose-Dependent Effect The cumulative incidence of any cardiovascular event was 12.2% at 10 years for patients reporting 0 MET h/ wk-1 vs 5.2% for those reporting ≥ 9 MET h/wk-1. In multivariate analysis adjusting for attained age, age at diagnosis, sex, race, smoking, education, cardiovascular risk factors, baseline grade 3 to 4 (noncardiovascular) chronic conditions, and anthracycline and chest radiation exposures, the incidence of cardiovascular events decreased across increasing MET categories (P = .002 for trend). Compared with survivors reporting 0 MET h/wk-1, the adjusted rate ratio for any cardiovascular event was 0.87 (95% confidence interval [CI] = 0.56–1.34) for 3 to 6, 0.45 (95% CI = 0.26–0.80) for 9 to 12, and 0.47 (95% CI = 0.23– 0.95) for 15 to 21 MET h/wk-1. Meeting the national vigorous-intensity exercise guideline for cancer of ≥ 9 MET h/wk-1 (ie, ≥ 3 sessions of vigorous intensity exercise/wk of ≥ 20

minutes in duration) was associated with a 51% reduction in risk of any cardiovascular event compared with not meeting the guideline (P = .002). The investigators concluded: “Vigorous exercise was associated with a lower risk of [cardiovascular] events in a dose-dependent manner independent of [cardiovascular] risk profile and treatment in survivors of [Hodgkin lymphoma]…. [O]ur findings indicate that adoption of regular exercise consistent with national vigorous exercise recommendations in currently sedentary survivors could confer substantial public health benefits in the rapidly growing population of survivors of childhood cancer.” n

Disclosure: The study was supported by the National Cancer Institute grants and American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Jones LW, Liu Q, Armstrong GT, et al: Exercise and risk of major cardiovascular events in adult survivors of childhood Hodgkin lymphoma: A report from the Childhood Cancer Survivor Study. J Clin Oncol. October 13, 2014 (early release online).


The ASCO Post  |   NOVEMBER 15, 2014

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Journal Spotlight Hematology

Impact of High-Dose Melphalan/Autologous Stem Cell Transplant and Lenalidomide Maintenance in Myeloma Patients ≤ Age 65 By Matthew Stenger

I

n a phase III trial reported in The New England Journal of Medicine, Antonio Palumbo, MD, Chief of the Myeloma Unit at the University of Turin, Italy, and colleagues found that high-dose melphalan plus autologous stem cell transplantation improved progression-free survival and overall survival compared with MPR (melphalan, prednisone, and lenalidomide [Revlimid]) consolidation. They also found that lenalidomide maintenance vs no maintenance improved progression-free survival in multiple myeloma patients aged ≤ 65 years.1

Study Details In this open-label trial, 402 patients aged ≤ 65 years with newly diagnosed multiple myeloma from 62 centers in Israel and Italy received induction therapy consisting of four 28-day cycles of lenalidomide at 25 mg/d on days 1 to 21 plus dexamethasone at 40 mg/d on days 1, 8, 15, and 22 and were randomly assigned between November 2007 and July 2009 to high-dose melphalan plus autologous stem cell transplant or MPR consolidation and to lenalidomide maintenance vs no maintenance. Cyclophosphamide and granulocyte colony-stimulating factor (Neupogen) were used for stem cell mobilization. At the end of induction, randomization was revealed for the total of 273 patients without progressive disease during induction/mobilization who remained eligible for consolidation therapy and received high-dose melphalan 200 mg/m2 for two 4-month cycles followed by autologous stem cell transplant (n = 141) or MPR consolidation (n = 132). Of these, a total of 251 received randomized treatment with lenalidomide maintenance after high-dose melphalan consolidation (n = 67) or MPR consolidation (n = 59) or no lenalidomide maintenance after high-dose melphalan (n = 68) or MPR (n = 57). MPR consolidation consisted of six

28-day cycles of melphalan at 0.18 mg/ kg on days 1 to 4, prednisone at 2 mg/ kg on days 1 to 4, and lenalidomide at 10 mg on days 1 to 21. Lenalidomide maintenance consisted of 10 mg on days 1 to 21 of each 28-day cycle. Patients with progressive disease during induction or consolidation were treated according to local standards and remained in the trial for outcome evaluations. The primary endpoint was progression-free survival.

Survival From Diagnosis Median follow-up was 51.2 months. Among all enrolled patients, median progression-free survival from time of

the MPR consolidation group (hazard ratio [HR] = 0.44, P < .001) and 4-year overall survival was 81.6% vs 65.3% (HR = 0.55, P = .02). The progressionfree survival benefit associated with high-dose melphalan was consistent across all patient subgroups.

Survival From Start of Lenalidomide Maintenance Among the 251 patients eligible for the maintenance period, median progression-free survival from the start of maintenance was 41.9 months with lenalidomide maintenance vs 21.6 months without maintenance (HR =

Our findings confirm that high-dose melphalan remains the more effective therapeutic option in patients with newly diagnosed multiple myeloma. —Antonio Palumbo, MD, and colleagues

■■ High-dose melphalan plus autologous stem cell transplantation improved progression-free and overall survival compared with melphalan/ prednisone/lenalidomide consolidation.

0.47, P < .001). Three-year overall survival was nonsignificantly prolonged with lenalidomide maintenance (88.0% vs 79.2%, HR = 0.64, P = .14). The beneficial effect of lenalidomide maintenance on progression-free survival was consistent in all subgroups except patients with stage III disease (P = .04 for interaction between stage and treatment). The investigators found no significant differences in progression-free survival between the lenalidomide maintenance and no-maintenance groups in the comparison of high-dose melphalan vs MPR (P = .99 for interaction) or between the high-dose melphalan and MPR groups in the comparison of lenalidomide maintenance vs no maintenance (P = 0.93 for interaction). Among patients with relapse, 3-year overall survival from time of relapse was similar in the four treatment groups. In the MPR group, 63% of patients received high-dose melphalan at relapse.

■■ Lenalidomide maintenance was associated with significantly improved progression-free survival but not overall survival.

Toxicity

diagnosis was 54.7 months in patients who received high-dose melphalan plus lenalidomide maintenance, 37.4 months in those receiving high-dose melphalan without maintenance, 34.2 months in those receiving MPR plus lenalidomide maintenance, and 21.8 months in those receiving MPR without maintenance. The respective 5-year overall survival rates were 78.4%, 66.6%, 70.2%, and 58.7%.

Survival From Start of Consolidation Among the 273 patients eligible for the consolidation phase, median progression-free survival from the start of consolidation was 43.0 months in the high-dose melphalan/autologous stem cell transplant group vs 22.4 months in

Treating Multiple Myeloma

Grade 3 or 4 adverse events that

were significantly more common with high-dose melphalan (all P < .001) included neutropenia (94.3% vs 51.5%), thrombocytopenia (93.6% vs 8.3%), gastrointestinal events (18.4% vs 0%), infections (16.3% vs 0.8%), and systemic events (12.8% vs 1.5%). Grade 3 or 4 adverse events that were more common with lenalidomide maintenance vs no maintenance included neutropenia (23.3% vs 0%, P < .001), infections (6.0% vs 1.7%, P = .09), and dermatologic events (4.3% vs 0%, P = .03). Treatment was discontinued due to adverse events in 4% of patients during induction and in 0.7% during high-dose melphalan treatment and 3.0% during MPR treatment. Adverse events led to lenalidomide dose reduction in 14.7% of patients and discontinuation in 5.2%. Second primary cancers were observed in 0.3% of patients during induction, in no patients during high-dose melphalan or MPR consolidation, and in 4.3% of both the lenalidomide maintenance and no-maintenance groups during the maintenance period.

Conclusions The investigators concluded: [W]e found that consolidation therapy with high-dose melphalan, as compared with MPR, improved progression-free and overall survival, although at a cost of increased toxicity. Our findings confirm that high-dose melphalan remains the more effective therapeutic option in patients with newly diagnosed multiple myeloma. We also found that maintenance therapy with lenalidomide, as compared with no maintenance therapy, significantly reduced the risk of disease progression. n Disclosure: The study was funded by Celgene. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Palumbo A, Cavallo F, Gay F, et al: Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895-905, 2014.

See commentary by Paul Richardson, MD, on page 132.

G.


FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There was a 53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (hazard ratio [HR]=0.47; 95% confidence interval [CI], 0.35-0.62; P<0.0001). There were 78 deaths and 122 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2


EXTEND SURVIVAL WITH ZELBORAF Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)† 100

HR=0.47 (95% CI, 0.35-0.62), P<0.0001

Percentage surviving

80 60 40 20 0

0

1

2

3

4

5

6

7 8 OS (months)

9

10

ZELBORAF (n=337)

11

12

13

Dacarbazine (n=338)

14

*Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Patients were not censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months for ZELBORAF patients.

53% reduction in risk of death from any cause in patients treated with ZELBORAF vs dacarbazine (HR=0.47; 95% CI, 0.35-0.62; P<0.0001) —78 (23%) deaths and 122 (36%) deaths in the ZELBORAF and dacarbazine arms, respectively In an updated analysis, median OS was reached at 13.6 months with ZELBORAF: 3.3-month improvement over median OS of 10.3 months with dacarbazine (95% CI, 12.0-15.3 months vs 9.1-12.8 months) —Updated based on 478 deaths (ZELBORAF median follow-up 13.4 months)

Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

© 2014 Genentech USA, Inc. All rights reserved. BRF0000653206

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT substudy in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.


Significant improvement in PFS ≈4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis. Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE


The ASCO Post  |   NOVEMBER 15, 2014

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Perspective

High-Dose Melphalan, Early Stem Cell Transplant, and Lenalidomide Maintenance in Myeloma: One Size Still Does Not Fit All By Paul G. Richardson, MD

I

n an important recent study by Dr. Antonio Palumbo and colleagues,1 reviewed in this issue of The ASCO Post

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in  ≥  10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

8 3 <1 1 1 2 0 0 <1 0

2 4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

5

3

1

0

15

6

18

0

8

<1

21

0

8

0

7

0

12

0

10

0

0

0

14

0

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

ing MPR (melphalan, prednisone, and lenalidomide [Revlimid]) after successful induction with lenalidomide

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)]. • ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)]. • Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)]. • Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)]. • ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)]. • Liver laboratory abnormalities can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)]. • ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)]. • Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)]. • ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422005 Initial U.S. Approval: August 2011 © 2014 Genentech, Inc

and dexamethasone, with a further 251 patients assigned to lenalidomide maintenance or no maintenance treatment. This study is of considerable interest in terms of guiding principles but also has certain limitations in the context of application to U.S. practice in particular.

Short Follow-up First, the median follow-up period of 51.2 months is relatively short in this setting. That being said, both progression-free survival and overall survival proved longer with high-dose melphalan compared to MPR, with the difference in median progression-free survival being particularly in favor of early transplant. Encouragingly, in the same study, median progression-free survival proved significantly longer with lenalidomide maintenance, with almost a doubling of clinical benefit seen with lenalidomide maintenance given until either time of progression or intolerance. With relatively short follow-up, 3-year overall survival was not significantly prolonged, although a trend in favor of lenalidomide maintenance is noted, and with longer follow-up, this may indeed achieve significance, consistent with other studies in this setting. Interestingly, the clinical benefit associated with lenalidomide maintenance was independent of the consolidation regimen. Specifically, response rates improved during maintenance therapy in both the high-dose melphalan and MPR groups. As compared with no maintenance, low-dose lenalidomide maintenance until progression delayed relapse by approximately 2 years at the time of this analysis. As the authors comment, longer follow-up clearly will be needed to better evaluate the benefit of a de-

Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased >  60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table  2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

(page 128), 273 patients aged ≤ 65 years were randomly assigned to early Safety:7" transplant or consolidation therapy us-

continued on page 133

Dr. Richardson is Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and the R.J. Corman Professor of Medicine, Harvard Medical School, Boston.


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layed clinical relapse and the risk of chemoresistance after maintenance therapy. Moreover, the benefit of maintenance therapy was seen in all subgroups except those with highrisk disease by International Staging System assessment, where additional agents as part of maintenance may be needed.

Toxicity Considerations In terms of toxicities, transplant was clearly associated with more frequent hematologic and nonhematologic adverse events, but toxicity proved manageable and did not affect the rate of early death, treatment discontinuation, or patients’ ability to proceed to the maintenance phase. One major limitation is that only 63% of patients in the MPR group at the time of relapse were able to go on to stem cell transplantation. The reasons for this require greater explanation, but obviously the availability of effective salvage regimens and their timely use are key in making any comparison of early vs late stem cell transplant. In terms of the side effects of maintenance treatment with lenalidomide, more frequent grade 3 or 4 adverse events including neutropenia and infections were seen with lenalidomide than without. Encouragingly, however, the rate of secondary primary cancers was low, and no between-group differences were seen.

Other Strengths and Weaknesses This study has strengths and weaknesses. Importantly, with initial induction treatment, only two-thirds of the enrolled patients were eligible to undergo first randomization. This was primarily because of disease progression or patient decision to choose an alternative therapy because of a suboptimal response after induction, presumably as the doublet of

These benefits have been seen not only in the setting of stem cell transplant but also in non–transplant eligible patients. Therefore, this critical aspect of both induction and consolidation requires further evaluation.

Unanswered Questions In aggregate, the principles from this study of novel therapy induction and maintenance contributing to clinical benefit are clear, but in the

In the absence of availability of a clinical trial, a personalized approach to induction treatment followed by consolidation is justified, with the use of transplantation early in the course supported by these data, but subject to caveats… . —Paul G. Richardson, MD

lenalidomide-dexamethasone proved ­inadequate. As the authors acknowledge, the absence of bortezomib (Velcade)based induction and consolidation regimens in this setting is a substantial limitation. Bortezomib-based induction and consolidation regimens in combination with both alkylating and/or immunomodulatory agents have been associated with unprecedented rates of high-quality response and clinical benefit both in terms of progression-free and overall survival.

absence of proteasome inhibition, the question of actual benefit and best timing of transplantation as we help guide choices for our patients going forward are not yet answered. Although the maintenance-untilprogression data are encouraging, the relatively short follow-up limits their interpretability, and again the absence of a proteasome inhibitor in consolidation leaves the question of early vs late transplantation open. With that in mind, various ongoing studies will hopefully address these

key questions both in North America and Europe. The geographic distinction is critical, not least because differing salvage regimens can impact upon both the feasibility and efficacy of salvage. Furthermore, differences in the duration of maintenance are being assessed as part of these ongoing trials, and that, too, will be very helpful in assessing the impact of continuous therapy on clinical benefit.

Practical Implications From the standpoint of the practicing oncologist, participation of patients in randomized, ongoing, prospective clinical trials is a top priority. In the absence of the availability of a clinical trial, a personalized approach to induction treatment followed by consolidation is justified, with the use of transplantation early in the course supported by these data, but subject to the important caveats already ­outlined. Specifically, a one-size-fits-all approach to initial treatment and consolidation with the mandatory use of stem cell transplantation is very difficult to support. Once again, the priority of participation in prospective clinical trials remains of the utmost importance going forward. n

Disclosure: Dr. Richardson reported no potential conflicts of interest.

Reference 1. Palumbo A, Cavallo F, Gay F, et al: Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 371:895-905, 2014.

News Hematology

Initiative Aims to Accelerate Development of Targeted Therapies for Multiple Myeloma

T

he Multiple Myeloma Research Foundation (MMRF) has announced an initiative designed to accelerate the evaluation of new investigational therapies for multiple myeloma. The MMRF, in collaboration with the U.S. Food and Drug Administration (FDA), the National Cancer Institute (NCI), pharmaceutical, biotech, and diagnostic industry members, academic center leaders, and patients, initiated the formal development of a Master Protocol to allow patients to participate in clinical trials evaluating several investigational therapies at once.

At a workshop held last month in Washington, DC, participants from the FDA, NCI, industry, academia, and the patient community endorsed a plan to move forward with the development of the complete master study protocol.

Critical Targeted Therapies “We have made real progress in the battle against multiple myeloma, but