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ASCO Provisional Clinical Opinion

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NCCN Guidelines

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Acute Promyelocytic Leukemia

VOLUME 3, ISSUE 6

56

APRIL 15, 2012

Editor-in-Chief, James O. Armitage, MD

ASCOPost.com

Our Patients, Our Teachers

Society of Surgical Oncology Annual Symposium

Neoadjuvant Aromatase Inhibitor Therapy Converts Many Patients to Candidates for Breast-conserving Surgery By Matthew Stenger

By Richard J. Boxer, MD, FACS

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he American College of Surgeons Oncology Group (ACOSOG) Z1031 trial examined the effect of neoadjuvant aromatase inhibitor therapy on clinical response and breast-conservation rates in postmenopausal women with estrogen receptor John A. Olson, Jr, MD, PhD (ER)-rich stage  II or III breast cancer. An update of the surgical outcomes of the trial, reported by John A. Olson, Jr, MD, PhD, from The University of Maryland School of Medicine, Baltimore, at a plenary session of the Society of Surgical Oncology annual meeting,1 showed that a substantial proportion of patients who were considered at baseline to be candidates for mastectomy only or to have inoperable disease were converted to

being candidates for breast-conserving surgery after aromatase inhibitor therapy.

Study Eligibility In this randomized phase II, open-label trial, 377 patients with ER-positive (Allred score 6–8) breast cancer were randomly assigned to 16 weeks of neoadjuvant treatment with one of three aromatase inhibitors (letrozole at 2.5 mg/d, anastrozole at 1 mg/d, or exemestane at 25 mg/d). Patients had to have T2 to T4c, any N, M0 disease, with a palpable primary tumor of greater than See Page 93 2 cm, and had to agree to undergo lumpectomy or mastectomy after neoadjuvant aromatase inhibitor therapy. Patients with inflammatory breast cancer were excluded, as were patients with diagnosis established by incisional biopsy. continued on page 7

Health-care Policy

ACCC Meeting Focuses on Affordable Care Act: Its Future, and What It Might Accomplish By Margot J. Fromer

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he Association of Community Cancer Centers (ACCC) mid-March Annual Meeting devoted several sessions to the Patient Protection and Affordable Care Act: Will it still be here after the Supreme Court decides its fate? If so, how much of it will survive, and how will it affect oncology practice? In late March, the Supreme Court heard an almost unprecedented 6  hours of arguments over 3  days about the constitutionality of the law, based primarily

on Florida’s assertion that Congress cannot mandate that individuals purchase and maintain health insurance (25 other states agree). The justices may rule as soon as mid-June, or they may postpone their decision until 2014 when the law will take effect.

CMS and Innovation

The Centers for Medicare & Medicaid Services (CMS) are front and center of how the Affordable Care Act is implemented. Richard Gilfillan, MD, CMS is planning new engines to Director of the CMS Innovation Center, said, revitalize and sustain Medicare and “CMS is planning new play an even greater role in the lives of engines to revitalize and sustain Medicare and providers and patients. We have the play an even greater role will to change and we will do what the in the lives of providers country needs. and patients. We have the will to change and we — Richard Gilfillan, MD

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here is no greater professional satisfaction than the knowledge that you have cared for a patient and the care brought an improvement in the patient’s health. Regardless of the level of appreciation, whether the patient is cured or not, and even if the patient’s sense of well-being may be psychological rather than physical, we as physicians gain from the interaction. All economics aside, this is the essence of being a doctor.

The Doctor–Patient Relationship Patients have taught me so much about courage, spirituality, and dignity. Enduring surgery, chemotherapy, and radiation therapy takes a singularity of thought and a leap of faith. The lessons learned from my patients gave me the understanding and fortitude I needed when I continued on page 14

Dr. Boxer is Professor of Clinical Urology at the University of Miami, and Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin.

MORE IN THIS ISSUE Oncology Meetings Coverage Society of Surgical Oncology���������������� 1, 7 ACCC Annual Meeting��������������� 1, 17–19 GI Cancers Symposium������������������� 9, 10 GU Cancers Symposium������� 20, 22, 24 Paul A. Bunn, Jr, MD, on Lung Cancer������ 30 Direct from ASCO��������������������������������������� 43 Barbara L. Smith, MD, PhD, on Breast Cancer������������������������������������������� 52 Hematology for the Oncologist����������������� 58

continued on page 17

Fertility Preservation, see pages 26, 28, and 91

A Harborside Press® Publication


The ASCO Post  |   APRIL 15, 2012

PAGE 2

Letter to the Editor Geriatric Oncology

‘We Need an Index of Biologic Aging’ Editorial Board  James  O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

ASSOCIATE EDITORS

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland

s a retired elderly (soon to be 83-year-old) oncologist, I read the recent article on the subject of geriatric oncology, in the March 15 issue of The ASCO Post, with great interest ("Moving the Field of Geriatric Oncology Forward," by Stuart M. Lichtman, MD.) This was particularly so because I have recently been treated for two separate cancers, early in their course and hopefully cured. I have long given thought to the definition of elderly with regard to

80s, could biologically fit a group in their 50s or 60s. It seems to me that we need an index of biologic aging, just as there is a Karnofsky index for the biologic functionality of younger cancer See Page 93 patients. Such an aging or maturity index could be used in the evaluation of the applicability, intensity, and value of a given cancer treatment in such individ-

I have seen people in their 60s who could ‘biologically’ be considered to be in their late 80s, and others who, in their 80s, could biologically fit a group in their 50s or 60s. treatment of cancer. I have come to the conclusion that there is no useful definition that addresses this time of life for an individual patient. Aging has two components: chronology and biology. They do not necessarily reflect the same stage of an individual’s life. During the course of nearly 50 years of caring for patients, I have seen people in their 60s who could "biologically" be considered to be in their late 80s, and others who, in their

uals, rather than treatment decisions being made more arbitrarily. It is possible that such an index already exists, but if so, I have not read about its application to the growing problems of geriatric oncology. I hope this message may be of some value in furthering this increasingly important field of clinical investigation.

—Ernest Greenberg, MD New York, New York

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805.

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com.

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

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Correspondence: Address general inquiries to Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.


ASCOPost.com  |   APRIL 15, 2012

PAGE 3

Expert’s Corner

ASCO Releases Palliative Care Provisional Clinical Opinion A Conversation with Thomas J. Smith, MD By Ronald Piana

Central Message

Thomas J. Smith, MD

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SCO has released a provisional clinical opinion (PCO) addressing the integration of palliative care services into standard oncology care.1 The ASCO Post recently spoke with one of the PCO’s lead authors, Thomas J. Smith, MD, Director of Palliative Care for Johns Hopkins Medicine and the Johns Hopkins Sidney Kimmel Cancer Center, Baltimore.

ASCO PCO Expert Panel

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embers of the Ad hoc Expert Panel included cochairs Jamie H. Von Roenn, MD, Northwestern University, and Thomas J. Smith, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, in addition to: Amy P. Abernethy, MD, Erin R. Alesi, MD, Tracy A. Balboni, MD, MPH, Ethan M. Basch, MD, Betty R. Ferrell, RN, PhD, MA, FAAN, FPCN, Matt Loscalzo, LCSW, Diane E. Meier, FACP, MD, Judith A. Paice, PhD, RN, FAAN, Jeffrey M. Peppercorn, MD, MPH, and Ellen Stovall. See page 37 in this issue of The ASCO Post for a comprehensive summary of ASCO's provisional clinical opinion on palliative care, and visit the ASCO Connection blog discussion at http:// connection.asco.org/forums/ forumid/10/postid/492/scope/ posts.aspx#492.

What is the central message of the ASCO provisional clinical opinion on palliative care? The provisional clinical opinion highlights new clinical information that—in the context of previous data—really changes standard practice. Over the past several years, we’ve seen an increasing number of randomized controlled trials that basically come to the same conclusions about palliative care interventions: They do no harm and typically result in better quality of life, better symptom management, less depression and anxiety, less distress among caregivers, and more honoring of patients’ choices about events near the end of life.

the scant amount of data, it is premature to develop a provisional clinical opinion. What is your reaction to that review? PDQ is known to be very conservative. Although they looked at a number of trials, some of them were 10 years old, and they weighed those investigations as heavily as more recent studies. For example, in two trials they reviewed, less than one-quarter of the palliative care recommendations were followed. So it’s hard to discount the value of palliative care when it was hardly ever used. That’s like saying radiation therapy didn’t work, but only one of four patients received it. Knowing the field, and knowing the importance of an interdisciplinary palliative care team, our group concluded

The data show that when doctors have honest conversations with patients who are seriously ill, the quality of remaining life for patients and their families is far better. —Thomas J. Smith, MD

The Temel et al lung cancer trial2 was the latest randomized trial confirming the benefits of introducing palliative care concurrent with standard oncology care. Patients in the palliative care intervention arm understood their treatment and prognosis better than those receiving standard care alone. They used less IV chemotherapy in the last 60 days of life, used hospice services more often and longer (longer is better), and lived almost 3  months longer than patients receiving standard care alone. The success of the Temel study isn’t magic. It boils down to this: Having another group of health-care professionals [in addition to treating oncologists] focusing on patient symptoms and discussing goals and treatment options turns out to be very useful and highly desired.

Difference of Opinion The NCI’s Physician Data Query (PDQ) editorial board acknowledged the successes in the studies of palliative care intervention, but concluded that given

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

that the evidence supporting palliative care was increasingly compelling. We also know that we currently don’t have enough palliative care specialists. But when lumpectomy plus radiation therapy became the preferred treatment for breast cancer, we didn’t wait to make that pronouncement until everyone had access to a team that could provide the therapy. We know that we have to stimulate demand in the field as well as give physicians like me the opportunity to learn new skills.

Hospice/Palliative Care Synergy Hospice is part of palliative care. However, hospice programs will not cover chemotherapy, radiotherapy, and supportive care drugs, which disengages the valuable hospice/palliative care synergy. Is this something that can be addressed? This is the situation in nearly all communities, whether large or small, academic or not. Hospice is an integral part of palliative care, and palliative care has moved many of the core concepts of hospice into the hospital and some-

times upstream. We appreciate that nearly all hospices do not cover chemotherapy, radiation, or supportive care drugs—they simply cannot, on a per diem reimbursement of $130 to $150. But there are and will be more programs that cover “concurrent” palliative treatments and hospice. Aetna’s Compassionate Care Program and similar programs have an “expanded access” option that increasingly will let people enroll in hospice but not have to give up all treatment. The insurers know that they will save money by improving care at home, and that most people will elect not to die in the hospital, especially in the intensive care unit. And this is really honoring patients’ choices, once we make them known. There are also positions that ASCO members can take to help the process. We can have our patients talk with hospice for an informational visit when they have 3 to 6 months left to live. This brings the hospice group into the picture as part of the same team, lets them know the patient, and makes transitions easier. We can also have the “hard conversations” earlier. Data from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study—conducted mostly in community settings—showed that 60% of medical oncologists prefer not to have discussions about “do not resuscitate” orders, advance medical See Page 93 directives, or hospice until there are no treatment options left.3 No one mentioned hospice to half the patients with lung cancer within 2  months of their death. Getting hospice involved, as part of “best practice” in the continuum of care, is something we can control.

Closing Thoughts Any last thoughts about this issue? It is an incredibly important point to make that palliative care is all about honoring peoples’ choices. The only way to do that is to bring up the hard continued on page 6

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.


In Advanced Renal Cell Carcinoma...

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of

electrolytes within the normal range should be performed. • Hemorrhagic Events: Fatal hemorrhagic events have been reported (all Grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. • Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all Grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events. • Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. • Hypertension: Hypertension, including hypertensive crisis, has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite


Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology . These Guidelines also include therapies other than VOTRIENT as first-line treatment options

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information.

VOTRIENT: Safety Profile Summary1 • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% of patients — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% of patients • For any individual adverse reaction in the VOTRIENT arm, the rate of Grade 3/4 adverse events is ≤4%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% of patients • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

anti-hypertensive therapy and dose reduction of VOTRIENT. • Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. • Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. • CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. • CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

• Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%). • Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); and leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%). • VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%). Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2012. © National Comprehensive Cancer Network, Inc 2011. All rights reserved. Accessed November 17, 2011. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com


The ASCO Post  |   APRIL 15, 2012

PAGE 6

Expert’s Corner

Thomas J. Smith, MD continued from page 3

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

issues early and often in quality discussions. All the data show that when doctors have honest conversations with patients who are seriously ill, the quality of remaining life for patients and their families is far better.

References 1. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol. February 6, 2012 (early release online).

2. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010. 3. Huskamp HA, Keating NL, Malin JL, et al: Discussions with physicians about hospice among patients with metastatic lung cancer. Arch Intern Med 169:954-962, 2009.

BRIEF SUMMARY VOTRIENT (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

See page 37 for more on ASCO's provisional clinical opinion on palliative care.

5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension : In clinical studies, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 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. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hemorrhagic events, arterial thrombotic events, gastrointestinal perforation and fistula, and hypertensive crisis [see Warnings and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and


ASCOPost.com  |   APRIL 15, 2012

PAGE 7

Society of Surgical Oncology Breast Cancer

Neoadjuvant Aromatase Inhibitors

analysis (3 withdrew consent), clinical T stage was T2 in 74.6%, T3 in 19.5%, and T4a-c in 5.9%, and 71.4% were clinically node-negative at baseline. Prior to treatment, surgeons categorized patients as marginal for breast-conserving surgery (53.2%), candidate for mastectomy only (45.7%), or inoperable (1.1%).

continued from page 1

No prior treatment for invasive breast cancer, including radiotherapy, endocrine therapy, chemotherapy, or investigational agents, was permitted. Among 374 patients included in the

vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebocontrolled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

VOTRIENT

Placebo

(N = 290)

(N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290)

Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

41

<1

0

33

1

0

36

3

<1

10

1

<1

34

4

0

11

0

0

31

4

1

24

4

0

26

<1

1

14

0

0

17

0

<1

3

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Key Results Clinical response to aromatase inhibitor treatment (by World Health Organization criteria) occurred in 258 (69.0%) of 374 patients across all arms, with no significant difference observed among aromatase inhibitor arms. Of 352 patients who underwent surgery

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) of full prescribing information and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT has been associated with hypertensive crisis in patients with various cancer types including RCC. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.2).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.3).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any post-baseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.8).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. [See Warnings and Precautions (5.9).] Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)].

after aromatase inhibitor treatment, 241(68.5%) had breast-conserving surgery, including 84 of 163 (51.5%) who were assessed as candidates for mastectomy only or inoperable at baseline. Baseline clinical T stage and final tumor size after neoadjuvant aromatase continued on page 8


The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; APRIL 15, 2012

PAGE 8

Society of Surgical Oncology Neoadjuvant Aromatase Inhibitors continued from page 7

inhibitor therapy were significantly associated with increased likelihood of conversion from mastectomy candidacy or inoperable status to ability to undergo breast-conserving surgery.

After aromatase inhibitor therapy, 27 (24.3%) of 111 patients undergoing mastectomy had pathologic T1 disease (<  2  cm), suggesting that mastectomy was also unnecessary in these patients. The final decision on surgery was surgeon recommendation in 75% of cases and patient preference in 25%.

7.2 Effects of Pazopanib on CYP Substrates Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of â&#x2030;Ľ3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossiďŹ cation. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses â&#x2030;Ľ3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses â&#x2030;Ľ30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses â&#x2030;Ľ100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses â&#x2030;Ľ3 mg/kg/day (AUC not calculated). 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 of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug 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 VOTRIENT, 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: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses â&#x2030;Ľ3 mg/ kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged â&#x2030;Ľ65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identiďŹ ed differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin â&#x2030;¤1.5 X ULN and AST and ALT â&#x2030;¤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/ moderate renal impairment (creatinine clearance â&#x2030;Ľ30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to signiďŹ cantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/ min) did not inďŹ&#x201A;uence clearance of pazopanib. Therefore, renal impairment is not expected to inďŹ&#x201A;uence pazopanib exposure, and dose adjustment is not necessary.

Implications of Findings Thus, the use of neoadjuvant aromatase inhibitor in patients with ERrich tumors enabled half of patients who would have required mastectomy to have tumors downstaged sufficiently to permit lumpectomy, with the evidence further suggesting that mastec-

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no speciďŹ c antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not signiďŹ cantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages â&#x2030;Ľ30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses â&#x2030;Ľ10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given â&#x2030;Ľ100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given â&#x2030;Ľ300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses â&#x2030;Ľ3 mg/kg/day, epididymal sperm concentrations at doses â&#x2030;Ľ30 mg/kg/ day, and sperm motility at â&#x2030;Ľ100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaďŹ&#x201A;et that accompanies the product. However, inform patients of the following: t5IFSBQZXJUI7053*&/5NBZSFTVMUJOIFQBUPCJMJBSZMBCPSBUPSZ abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the ďŹ rst 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. tZFMMPXJOHPGUIFTLJOPSUIFXIJUFTPGUIFFZFT KBVOEJDF tVOVTVBMEBSLFOJOHPGUIFVSJOF tVOVTVBMUJSFEOFTT tSJHIUVQQFSTUPNBDIBSFBQBJO t(BTUSPJOUFTUJOBMBEWFSTFSFBDUJPOTTVDIBTEJBSSIFB OBVTFB BOEWPNJUJOH have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. t8PNFOPGDIJMECFBSJOHQPUFOUJBMTIPVMECFBEWJTFEPGUIFQPUFOUJBMIB[BSE to the fetus and to avoid becoming pregnant. t1BUJFOUTTIPVMECFBEWJTFEUPJOGPSNUIFJSIFBMUIDBSFQSPWJEFSTPGBMM concomitant medications, vitamins, or dietary and herbal supplements. t1BUJFOUTTIPVMECFBEWJTFEUIBUEFQJHNFOUBUJPOPGUIFIBJSPSTLJONBZ occur during treatment with VOTRIENT. t1BUJFOUTTIPVMECFBEWJTFEUPUBLF7053*&/5XJUIPVUGPPE BUMFBTUIPVS before or 2 hours after a meal). VOTRIENT is a trademark of GlaxoSmithKline.

Š2011, GlaxoSmithKline. All rights reserved. Revised 10/2011 VTR:4BRS Š2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT274R0 November 2011

Neoadjuvant Therapy and Breast-conserving Surgery â&#x2013; â&#x2013;  Sixteen weeks of

neoadjuvant aromatase inhibitor therapy permitted breastconserving surgery in half of patients with estrogen receptorâ&#x20AC;&#x201C;rich breast cancer who were initially considered to be candidates for mastectomy only or to have inoperable disease.

â&#x2013; â&#x2013;  Pathologic findings

after surgery indicated that tumors in a quarter of women who had undergone mastectomy after neoadjuvant therapy had been downstaged sufficiently to permit breast-conserving surgery.

â&#x2013; â&#x2013;  Improved techniques

to accurately determine tumor burden after neoadjuvant aromatase inhibitor therapy and willingness to attempt breast-conserving surgery in patients with tumor response could improve rates of successful breastconserving surgery.

tomy was not necessary in a quarter of the patients who did undergo mastectomy after neoadjuvant therapy. As stated by Dr. Olson, â&#x20AC;&#x153;Women with strongly ER-positive tumors who are facing mastectomy have a low toxicity tablet therapy that may permit them to spare their breast by having lumpectomy and radiation. Better techniques to determine residual tumor burden and a willingness to attempt [breast-conserving surgery] in patients with responsive tumors could improve the rates of successful [breastconserving surgery] after neoadjuvant [aromatase inhibitor therapy].â&#x20AC;?

â&#x2013; 

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

Reference 1. Olson JA, Gildy BV, Unzeitig G, et al: Neoadjuvant aromatase inhibitor therapy permits breast conservation in postmenopausal women with large, estrogen receptor (ER)-rich breast cancer facing mastectomy: Results from the American College of Surgeons Oncology Group (ACOSOG) Z1031Trial. Society of Surgical Oncology 65th Annual Cancer Symposium. Abstract 3. Presented March 23, 2012.


ASCOPost.com  |   APRIL 15, 2012

PAGE 9

2012 Gastrointestinal Cancers Symposium Targeting KRAS in GI Cancers: The Hunt for the Holy Grail in Cancer Research By Caroline Helwick

T

he RAS oncogenes are the most frequently mutated class of oncogenes in human cancers, and this has prompted a search for Ras inhibitors to effectively treat tumors with these mutations. Despite intensive efforts, however, none has materialized clinically because K-Ras is proving to be a very vexing target, according to Channing J. Der, PhD, of the University of North Carolina at Chapel Hill, who gave an invited lecture on the topic at the 2012 Gastrointestinal Cancers Symposium.1,2 The search for K-Ras inhibitors, he said, is like the hunt for the Holy Grail in cancer research. “It has not been easy, though lessons have been learned from our research, some of them bitter and disappointing,” he noted. “Targeting effector signaling is our best hope. However, a cocktail of inhibitors hitting pathways at multiple

points will be needed, and this cocktail will be different, depending upon the Ras isoform, the particular mutation, and the cancer type. This is much more complicated than we had previously envisioned,” Dr. Der said.

Lessons Learned about K-Ras Four main “lessons” have emerged from almost 3 decades of research: 1. The three RAS genes (KRAS, NRAS, and HRAS) are not identical in function. KRAS is the most important isoform mutated in colorectal cancer. 2. The K-Ras protein is considered “undruggable.” Current efforts target K-Ras indirectly. 3. Signal transduction pathways are not simple linear unidirectional pathways, but are complex, dynamic networks that are difficult to fully comprehend.

K-Ras4B

ARRY-162/MEK162 ARRY-300 AS703026/MSC1936369B AS703988/MSC2015103B AZD8330/ARRY-424704 E6201 GDC-0973/XL518 GSK1120212 PD-0325901 BAY86-9766/RDEA119 RO4987655 Selumetinib/AZD6244 TAK-733

GSK2118436 Vemurafenib/ PLX4032+ RAF265 RO5126766‡ Sorafenib* XL281

Raf

MEK

BGT226 BEZ235 GDC-0980 GSK2126458 PF-04691502 PF-05212384/PKI-587 SF1126 XL765/SAR245409

PK13

Protein kinase inhibitors Lipid kinase inhibitors

GSK2141795 MK-2206 Perifosine SR13668

AKT

AZD2014 AZD8055 CC-223 Everolimus/RAD001¶ Ridaforolimus/MK-8669 OSI-027 Sirolimus/Rapamycin Temsirolimus/CCI-779

ERK

BKM120 BYL719 CAL-101 GDC-0941 PX-866 XL147/SAR245408

mTOR

‡Also MEK inhibition *Multikinase inhibitor ¶Approved for RCC +Approved for BRAFmutant melanoma

Dual lipid/protein kinase inhibitors

Fig. 1: Inhibitors of Raf or PI3K effector signaling under phase 1-III clinical evaluation. Courtesy of Channing J. Der, PhD.

K-Ras*

*Mutated in human cancer

PI3K*

PIP2

PIP3

PIP2

IP3 + DAG Ca2+

PTEN*

Raf*

PLCɛ

AKT

P

PKC

MEK

Elk-1

Phospholipid and second messenger metabolism

P

Ral GEF

Tiam1

P Rac GTP

Ral GDP

Ral GTP

P

P

Kinase cascade

PAK

P

TBK1

GTPase cascades

Fig. 2: Effectors implicated in mutant K-Ras–driven cancer growth. Concurrent inhibition of multiple effectors may be required for effective inhibition of mutant K-Ras function. Courtesy of Channing J. Der, PhD.

cade, and the lipid kinase PI3K, which activates the AKT and mTOR protein kinases. At least three other functionally distinct classes of Ras effectors exist, with validated roles in Ras trans-

We found that most KRAS-mutant cell lines were refractory to growth inhibition with MEK inhibitors, despite the fact that MEK inhibition did block the activation of this pathway. — Channing J. Der, PhD

“In colorectal cancer, many mutations are identified (approximately 80 per tumor), but most are harmless, and the development of cancer is driven by about 15. KRAS is the key oncogene and the most attractive for targeting. But while 40% of tumors have KRAS mutations, they also share—at a much lower frequency—other mutations, and as a consequence are genetically heterogeneous,” Dr. Der noted. Targeting all the necessary mutation combinations within one tumor will be problematic. And should this be accomplished—that is, should the KRAS defect be “corrected”—will this alone have a positive clinical impact? While this remains unknown, it is clear that colorectal cancer cells are “addicted” to K-Ras—ie, they require its presence, making it a validated target. Refining the target and developing drugs for it should have significant therapeutic consequences, he predicted.

Future Therapeutic Options

Rac GDP ERK

4. The 40% of KRAS mutant colorectal cancers are genetically and biologically heterogeneous. One therapeutic approach alone will not work.

“Ideally, what needs to be done is to target K-Ras directly, but we have not succeeded in this. As a result, there is a perception that Ras is an undruggable target,” he said. For complex biochemical reasons, it is essentially impossible to develop a small-molecule antagonist that will block GTP binding, which is critical for Ras function. Ras is a signaling molecule that stimulates a cascade of cytoplastic signaling pathways. Activated Ras binds preferentially to a spectrum of functionally diverse downstream effectors. These include the protein kinases Raf, MEK, and ERK of the MAPK cas-

formation. Significant evidence now suggests the potential importance of these less studied effectors for antiRas drug discovery, Dr. Der said. “Most of the effort in developing Ras inhibitors is focusing on the inhibition of downstream effector signaling,” he said. “If we block these pathways successfully, we should be able to cripple Ras.” Approximately 40 small-molecule inhibitors of different components of these effector pathways are now in clinical trials (Fig. 1). However, targeting Ras effector signalSee Page 93 ing is not simple . It is now known that Raf inhibition and MEK inhibition do not produce the same effect and that Ras does not rely exclusively on the MAP kinase pathway, accentuating the concept that “multiple effectors are necessary for Ras-dependent cancer growth,” Dr. Der noted.

Further Complications In addition, mutant KRAS does not correlate with ERK activation, and inhibition of B-raf in colorectal cancer does not produce the same clinical effect as it does in melanoma. “This suggests that the same genetic mutation in two different cancer types is not susceptible to the same treatment approach,” he said. Furthermore, MEK inhibitors do not reduce the growth of KRAS mutant colorectal cancer cells. “This was surprising and disappointing,” he said. “We found that most KRAS-mutant cell continued on page 10


The ASCO Post  |   APRIL 15, 2012

PAGE 10

2012 Gastrointestinal Cancers Symposium Survival Analysis by Gastric Cancer Subtypes in AVAGAST Phase III Trial Distal nondiffuse subtype associated with best prognosis By Caroline Helwick

Manish A. Shah, MD

S

ubset analysis of the AVAGAST trial, which evaluated the benefit of bevacizumab (Avastin) in advanced gastric cancer, has demonstrated distinct differences in outcomes according to disease subtype, reported Manish A. Shah, MD, of Weill Cornell Medical College and New York Presbyterian Hospital, at the 2012 Gastrointestinal Cancers Symposium.1 “In all geographic regions of the study, distal gastric cancer had a better prognosis than diffuse gastric cancer,” Dr. Shah noted. “In clinical practice, gastric cancer is treated as a single disease. However, it appears to be more than one disease, and its subtypes have different prognoses,” he added.

Study Findings AVAGAST was a global, randomized, phase  III trial evaluating the efficacy of bevacizumab plus chemotherapy (capecitabine [Xeloda]/cisplatin) as first-line treatment for patients with advanced See Page 93 gastric cancer.1 The superiority of bevacizumab over placebo

Targeting KRAS continued from page 9

lines were refractory to growth inhibition with MEK inhibitors, despite the fact that MEK inhibition did block the activation of this pathway,” Dr. Der said. Compensatory mechanisms take over, he explained, saying “This is not the only pathway that Ras depends on for initiating oncogenic consequences.

was not demonstrated (P = .1002), but regional differences were noted. In particular, patients from Europe and the Americas derived more benefit from bevacizumab than patients from the Asia-Pacific region. “Several analyses have been performed to better understand the regional differences,” he said. These showed that Asia-Pacific patients had better outcomes, independent of other prognostic variables, and patients from Europe/ Americas with one or more unfavorable prognostic factors derived a survival benefit from bevacizumab.2 The current study (n = 773) exam-

cancer had worse outcomes than those with type  3, with a median overall survival of 10.3 vs 11.7 months. Non-Asian patients had the most dismal prognosis, with a median overall survival of 8.0 vs 11.1 months in non-Asians. A treatment effect with bevacizumab was also related to subtype. Non-Asian patients with type 2 and type 3 tumors (diffuse/distal) appeared to benefit most from the drug, achieving a median overall survival of 11.4 months with bevacizumab, compared with only 7.3 months with placebo, which was a 33% reduction in risk with bevacizumab, Dr. Shah noted.

AVAGAST Subtype Analysis ■■ Although bevacizumab provided no benefit in the overall AVAGAST population of patients with advanced gastric cancer, it appeared to improve survival in the subset of non-Asian patients with diffuse or distal tumor subtypes.

■■ Favorable outcomes were associated with high plasma VEGF-A levels and low tumor NRP-1 expression, and these biomarkers were most common in distal and diffuse tumors, respectively.

ined survival data according to cancer subtype and region and examined the distribution of angiogenic biomarkers (plasma vascular endothelial growth factor [VEGF]-A and tumor markers neuropilin [NRP]-1, VEGF-A, VEGFR1, VEGFR2) across subtypes. The subtypes were classified as proximal, nondiffuse (type 1); diffuse (type 2); and distal, nondiffuse (type 3). Type 2 gastric cancer (52% of study patients) was found to be more common than type 1 (10%) or type 3 (38%). Irrespective of treatment, patients with type  2

Differences in Biomarker Distribution

Concurrent inhibition of two or more pathways will be needed to effectively ablate oncogenic KRAS-driven growth (Fig. 2).” Additionally, the core effector signaling pathways are probably different among the cancer types. All KRAS mutants “are not created equal”—ie, the frequency of specific mutations varies across cancer types—and clini-

cal response varies according to the specific mutation. All things considered, Dr. Der predicted that inhibitors of effector signaling will ultimately be effective against KRAS-mutant cancers, but therapeutic “cocktails” unique to the Ras isoform, the particular RAS mutant, and the cancer type will be needed for full therapeutic efficacy.

“The addition of bevacizumab to chemotherapy especially appeared to improve outcomes in patients from Europe and the Americas with diffuse and distal gastric cancer,” he noted.

There also appeared to be differences in the pattern of biomarker expression among gastric cancer subtypes. In general, high plasma VEGF-A levels and low tumor NRP-1 levels were associated with treatment efficacy in

AVAGAST.3 Plasma VEGF-A levels were highest in patients with type 3 tumors, and NRP-1 was lowest in patients with type 2 tumors. Proximal (type 1) gastric cancer appears to have the “worst” profile for treatment with bevaciziumab, as it is generally associated with low levels of plasma VEGF-A and generally high expression of NRP-1. Patients with diffuse or distal (type 2 or 3) disease appear to have at least one biomarker that is supportive of a benefit from antiangiogenic therapy, Dr. Shah concluded. “These candidate biomarkers, tumor NRP-1 and plasma pVEGF-A, provide a rationale for gastric cancer and/or subtype-specific outcomes with bevacizumab,” he suggested.

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

References 1. Shah M, Van Cutsem E, Kang Y, et al: Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer. 2012 Gastrointestinal Cancers Symposium. Abstract 5. Presented January 19, 2012. 2. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29:3968-3976, 2011. 3. Kang Y, Ohtsu A, Van Cutsem E, et al: Survival analysis by pooling risk factors in AVAGAST: First-line capecitabine plus bevacizumab or placebo in patients with advanced gastric cancer. 2011 ASCO Annual Meeting. Abstract 4119. Presented June 4, 2011. Disclosure: Dr. Der reported no potential conflicts of interest.

References 1. Der CJ: Targeting KRAS for the treatment of gastrointestinal cancers: Mission impossible? Invited lecture. 2012 Gastrointestinal Cancers Symposium. Presented January 21, 2012. 2. Cox AD, Der CJ: Ras history: The saga continues. Small GTPases 1:2-27, 2010.


Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

1


The first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation, then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.


EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9 mo) for ZELBORAF patients vs 4.5 months (95% CI, <0.1-11.7 mo) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of analysis.

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 months vs 1.6-1.7 months) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%)3 There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

0.294 inrash, alopecia, fatigue, photosensitivity The most common adverse reactions of any grade (≥30%) reported were arthralgia, reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. Use in Pregnancy: Pregnancy Category D ZELBORAF may 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 ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) 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 predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. http://f1000.com/reports/m/3/8. Published April 1, 2011. Accessed July 14, 2011. 3. 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.

© 2012 Genentech USA, Inc. All rights reserved. BRF0000653201 Printed in USA.

zelboraf.com


The ASCO Post  |   APRIL 15, 2012

PAGE 14

Opinion

Our Patients, Our Teachers continued from page 1

was ill.1 Being with a patient who has accepted the inevitable end of life with dignity and resolve has taught me how to help others in the same situation. These experiences cannot be taught in medical school lectures or books. There is a pal-

Dignity I remember an elderly patient with widespread metastatic prostate cancer who tearfullySafety:7" told me that he could not af-

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 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. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported 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. 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.

ford the copay on the LHRH agonist that I prescribed. He did not want to spend the money that his wife would need once he was gone, and he did not want to sully his memory by her thinking that the copay for the medication he was receiving was causing her to struggle. Even though I beseeched him to continue and offered

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 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 3 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

-

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were  ≥ 65 years. Elderly disorders patients (≥  65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 †# pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

8

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-

7

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12

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10

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*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

programs through various agencies or the pharmaceutical company, his determination and pride resulted in him no longer accepting the medication. This man embodied resolve and dignity. He lived and died as he wanted to be remembered.

Compassion I remember a bedridden man who had aphasia due to a stroke. I saw him and his wife of 65 years engage in See Page 93 a lifetime of memories and conversation simply by looking into each other’s eyes. The nonverbal communication was more than a thousand words could have conveyed. That experience taught me that how I present myself to my patients can enormously impact the confidence they have and the words I speak. Patients who donate their organs, whether as living or deceased donors, have impacted my understanding of selfless love for the future. Living related donors are remarkable, but living unrelated donors are awe-inspiring. And those who donate organs upon their death demonstrate an immeasurable sense of hope for the future. Patients whose emotions and personalities have evolved from childhood innocence to adult maturity and to fighting critical illness have taught me about the necessity of embracing friends and family.

Wisdom Safety:10"

ZELBORAF ® (vemurafenib) tablet, oral 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 recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced  >  1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc  >  500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both  >  500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may 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)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

pable connection that clearly defines the doctor–patient relationship. Nothing else in professional life can match it.

A doctor is an aggregate of experiences. Wisdom is knowledge plus experience. The thousands of interactions I have had resulted in the development of my personality, philosophy, and a measure of wisdom. I have gained enormously from listening to my patients. Their stories— landing on Normandy, living through the hell of Iwo Jima, suffering through the jungles of Vietnam, losing a loved one or a job, enjoying life to its fullest, or not being able to enjoy even one minute—these are the stories that make up the tapestry of life. I am a better person and physician to have been in the privileged position of confidant and doctor to so many people. I am very fortunate to have been on the receiving end of my patients’ teachings. It has made me who I am today.

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

Reference 1. Boxer RB: Physician as patient: A personal perspective. The ASCO Post 1(3):1, 2010. BRF0000422001 Initial U.S. Approval: August 2011 © 2012 Genentech, Inc


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JCO Spotlight

Controlled Study Links ‘Chemobrain’ to Longitudinal Changes in Brain By Caroline McNeil

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he phenomenon called “chemobrain”—impaired cognitive functioning following chemotherapy— correlates with longitudinal changes in the brain’s white matter, according a recent study in the Journal of Clinical Oncology.1 Structural changes in the white matter, measured by magnetic resonance diffusion tensor imaging before and after treatment, correlated with the results of neuropsychologic assessments. Moreover, the objective assessments were associated with patient self-reports of cognitive problems in this small, controlled study. Previous imaging studies have found changes in the brain following chemotherapy. But this study, unlike most others, used imaging and neuropsychologic tests before and after treatment in chemotherapy patients as well as in two control groups.

This study used imaging and neuropsychologic tests before and after treatment in chemotherapy patients as well as in two control groups. “What is good about this study are the control groups and the fact that patient self-reports correlated with the neuropsychologic testing,” said Patricia Ganz, MD, Director of the Division of Cancer Prevention and Control Research at the University of California, Los Angeles, Jonsson Comprehensive Cancer. Dr. Ganz, who was not involved in the study, wrote an editorial accompanying the report (see sidebar).2

First Longitudinal Evidence The study authors, led by Sabine Deprez, MSc, of University Hospital Gasthuisberg, Leuven, Belgium, concluded that the findings “provide the first longitudinal evidence that [diffusion tensor imaging]– based assessment of the microstructural properties of [white See Page 93 matter] may be suf-

EXPERT POINT OF VIEW

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Sabine Deprez, MSc

ficiently sensitive to investigate the neuronal substrate of chemotherapyinduced cognitive complaints.” Diffusion tensor imaging is a technique that allows researchers to visualize and characterize the architecture of white matter via the self-diffusion of water molecules. The investigators used a diffusion tensor imaging measure called fractional anisotropy. This parameter reflects the organization of white matter, which is important to communication among various regions of the brain; damage to the white matter can affect cognitive performance. To determine whether fractional anisotropy values would fall after chemotherapy, the researchers compared 34 young premenopausal women with earlystage breast cancer who had chemotherapy with 16 matched patients who did not have chemotherapy and 19 age-matched healthy controls. The chemotherapy patients had diffusion tensor imaging and neuropsychologic assessments before and after treatment while both control groups underwent the tests at matched intervals. In all three groups, the baseline, prechemotherapy diffusion tensor imaging, and neuropsychologic assessments were similar. The neuropsychologic test battery measured attention, concentration, memory, executive functioning (eg, distraction), and cognitive/psychomotor processing speed. After adjusting for IQ and depression, which can be expected in cancer patients, there were no significant differences among participants at baseline. However, 3 to 4 months after chemotherapy, diffusion tensor imaging revealed differences in the white matter among the treated patients, including significantly decreased fractional anisotropy compared to baseline. No differences were found in the two control groups.

Neuropsychologic Tests Correlate The same pattern was reflected in the

ommenting on the study by Deprez et al, Patricia Ganz, MD, noted the importance of the finding for clinicians. “This study tells us that self-reported complaints mapped onto the neuropsychologic tasks; this has not been shown very often,” said Dr. Ganz, who is Director of the Division of Cancer Prevention and Control Research at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center. “It’s one of the first studies to show that what patients are saying is backed up by test abnormalities,” she said. “It shows we have to believe the patient.”

Patricia Ganz, MD

Evolving Acceptance of Chemobrain as ’Real’ In an editorial accompanying the study, Dr. Ganz traces three stages in the evolution of our understanding of cognitive impairment following chemotherapy. Early on, few patients reported problems and doctors tended to dismiss any possibility that such problems were caused by chemotherapy, believing that the drugs couldn’t cross the blood-brain barrier. As chemotherapy regimens became more intensive and complaints multiplied, the phenomenon that women were calling chemobrain was often attributed to depression. More recently, advancements in neuroimaging, greater understanding of the immune system, and other factors have led to wider acceptance of chemobrain as “real,” and the mechanisms are being actively investigated.

It’s one of the first studies to show that what patients are saying is backed up by test abnormalities…It shows we have to believe the patient. Research on the topic has expanded, with a number of studies showing changes in the brain and decreases in cognitive function following treatment. But researchers have had trouble correlating these changes with patient reports of problems. This study, however, used an established self-reporting instrument, the Cognitive Failures Questionnaire, and focused on specific problems within the questionnaire, such as word and name finding, rather than looking at the total score. By doing so, the researchers were able to associate specific self-reported complaints to a decrease in the neuropsychologic test results for the same kind of cognitive function.

Mechanisms Remain Unclear The study supports the idea that in studying chemobrain and other cancer survivor issues, “it’s important to ask specific questions about quality of life, like depression, concentration, memory,” Dr. Ganz said. “If you just ask about global quality of life, you don’t get to the problem.” While this and other studies provide evidence that chemotherapy can impair cognitive functioning, at least temporarily, the mechanisms involved are still unclear. Some evidence suggests that the immune system and/or host factors, such as particular single nucleotide polymorphisms (SNPs), may be involved in making some individuals more susceptible to the problem.  Disclosure: Dr. Ganz reported no potential conflicts of interest.

neuropsychologic test results. The chemotherapy patients performed significantly worse after treatment on attention and concentration tests, psychomotor

speed, and memory. Performance on the neuropsychologic tests did not decline in the control groups over the same period. continued on page 16


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JCO Spotlight

‘Chemobrain’ continued from page 15

Finally, patient-reported complaints correlated with the neuropsychologic tests. For instance, chemotherapy patients reported significantly more problems with verbal memory, and these self-reported problems with name and word finding correlated significantly with decreased performance on the controlled word association test. The authors noted that the correlation between self-reports and neuropsychologic tests conflicts with the results of other studies. The reason for the difference, they suggested, may be the use of two time points in their study; that is, correlating changes over time in self-reports and objective test results may be more sensitive than correlating one-time scores.

Qualifying Remarks One limitation of this study is its small size. Another, the authors pointed out, is that a majority of the patients had hormonal treatment with tamoxifen, a possible confounding factor since tamoxifen has been shown in some studies to impair cognition. There is also the possibility that early

Cognitive Function after Chemotherapy ■■ Impaired cognitive functioning

following chemotherapy correlated with longitudinal changes in the structure of the brain’s white matter, as measured by magnetic resonance diffusion tensor imaging before and after treatment.

■■ Patients who had

chemotherapy did worse on neuropsychologic tests after treatment, compared to baseline tests before treatment. Matched control groups measured over the same time interval had no significant declines from baseline results.

■■ Neuropsychologic test results

also correlated with patient self-reports of specific cognitive problems.

■■ Longitudinal changes in

diffusion tensor imaging— specifically in a measure called fractional anisotropy—may serve as a biomarker for chemotherapy-induced cognitive impairment.

menopause due to chemotherapy influenced cognitive performance, although studies differ on the cognitive effects of menopause. More research is needed, said the authors, on whether the white matter changes are long-term or temporary and whether the difference in cogni-

Disclosure: Ms. Deprez and Dr. Ganz reported no conflicts of interest.

Reference 1. Deprez S, Amant F, Smeets A, et al:

Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol 30:274-281, 2012. 2. Ganz PA: “Doctor, will the treatment you are recommending cause chemobrain?” J Clin Oncol 30:229-231, 2012.

CD30-directed therapy Important Safety Information BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS™ (brentuximab vedotin).

Contraindication: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions: • Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.

■■ The results may be confounded by hormonal changes in the chemotherapy group.

tion before and after chemotherapy is related to the degree of change in the brain's white matter.

855.4SEAGEN (855.473.2436) SeaGenSecure.com

CT SCANS confirmed responses in relapsed patients Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9 120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/Lin:DCM/id:ID W:200 L25

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ACCC 37th Annual National Meeting Affordable Care Act continued from page 1

will do what the country needs.” The Affordable Care Act funds the Innovation Center, which was established to find new and better ways to provide health care to the growing number of Medicare and Medicaid

beneficiaries. He added that although the United States spends more than any other country on health care, it still lags far behind in longevity, infant mortality, and other parameters of successful health outcomes. “Our goals of better health, better health care, and

lower costs remain to be achieved,” he said. CMS now pays for health care in expensive and inefficient fragments. “We should pay for coordinated care, and providers ought to deliver it. In other words, we need to come up with and test innovative payment and service

After multiple failures,

single-agent response Indicated for the treatment of:

Important Safety Information (continued)

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

1

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

sALCL: 86% ORR (95% CI: 77%-95%)

1

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

Adverse Reactions:

2011 August 19

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

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• Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken. • Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)– treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with newonset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Drug Interactions:

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Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. US/BVP/2011/0104c

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

delivery models that will decrease expenditures while preserving quality,” Dr. Gilfillan said. This means that providers will have to be open to change as CMS provides new alternative payment models from which to choose. continued on page 18


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ACCC 37th Annual National Meeting Affordable Care Act continued from page 17

Ten billion dollars has been appropriated for CMS over the next 9 years, which the agency will use to streamline the way it does business, regardless of what the Supreme Court decides. “The system has to be changed regardless,

Medicare patients. “The purpose is to give the right care at the right time while avoiding unnecessary duplication of services and preventing medical errors. [Accountable care organizations] are designed to save money and will share those savings with Medicare,” explained Dr. Gilfillan. And there is more than one

and the funds are in the bank,” said Dr. Gilfillan.

Accountable Care Organizations One major innovation is accountable care organizations—groups of providers giving coordinated care to

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. 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. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin 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 ADCETRIS 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

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

Although the United States spends more than any other country on health care, it still lags far behind in longevity, infant mortality, and other parameters of successful health outcomes. —Richard Gilfillan, MD

Pregnancy

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

way to run an accountable care organization program. The Advance Payment Model will test whether and how prepaying a portion of anticipated costs could increase participation in the Medicare Shared Savings Program. Provider organizations would receive an advance on anticipated shared savings as a monthly stipend for each Medicare beneficiary. There has been interest in the program, but some providers are concerned about being able to afford the required infrastructure and staff.

General dosing information

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150b

The Pioneer Model will be used with providers already experienced in coordinating patient care. It allows groups to move rapidly from a shared payment model to a population-based one on a track separate from the Shared Savings Program. It is designed to coordinate with private payers, which should improve quality and health outcomes, as well as save money for everyone.

The ‘Medical Home’ Concept “Medical home” is a buzzword engendered by the Affordable Care Act and is defined as the coordination of comprehensive care by primary providers, the oncology team, and accountable care organizations. Its primary goal is to improve outcomes. According to a survey conducted by the ACCC, 63% of administrators, oncologists, and oncology nurses who work in a hospitalbased cancer program believe that an oncology medical home model could work in their practices (see related story on page 38). Almost half the respondents were worried about start-up costs and negotiations with payers, but some thought that a medical home could provide better quality collaborative care at lower cost. Half said that they don’t anticipate their practice or hospital becoming part of a medical home within the next


ASCOPost.com  |   APRIL 15, 2012

PAGE 19

ACCC 37th Annual National Meeting 2 years because they don’t foresee a shift away from the traditional “buy and bill” model. The other half think that moving away from traditional billing practices can result in improved patient care.

Thomas L. Whittaker, MD

Thomas L. Whittaker, MD, ACCC President, said “there is tremendous value in strong connections between oncology and primary care and in educating the entire oncology community about the structure and benefit of the oncology medical home. I believe it could fit nicely into an [accountable care organization], carving out the oncology care and ownership of that care. Medical home and [accountable care organizations] can complement each other.”

Bundled Payments The CMS Bundled Payments for Care Improvement initiative will combine payments for services delivered across one episode of care—for example, heart bypass or cancer diagnosis and treatment—rather than paying for each service separately. Bundled payments will give providers incentives to

coordinate care, improve quality, and save money for Medicare, said Dr. Gilfillan. It also can reduce duplication of services and medical errors, help patients heal without harm, and lower costs. When payment is bundled, CMS will create a “package” of services for a specific condition, such as a hospital stay and its recovery. “Providers will have the flexibility to determine which episodes of care and which services will be bundled. Thus, they can choose what works best for them based on the size and characteristics of their practice. We are responding to an overwhelming need on the part of hospitals and physicians for a flexible approach to patient care improvement. Already, many healthcare institutions have implemented this initiative with positive results,” said Dr. Gilfillan.

Sharp Divide on Health-care Improvement “The current system of providing health care in this country is rife with bad outcomes,” said Deborah E. Trautman, PhD, RN, Executive Director, Center for Health Policy and Healthcare Transformation, Johns Hopkins Medicine. “It’s expensive, ineffective, and unjust,” she said. Almost everyone agrees that there’s a serious problem, but there is little agreement about solutions and what, if anything, the Affordable Care Act can do to improve things. Many people, including health-care providers, do not fully understand

Deborah E. Trautman, PhD, RN

what is in the 900+ page legislation. In essence, it aims to make health insurance more accessible and affordable, enabling 32 million more people to purchase health care coverage in the United States. Approximately 50  million people in the United States do not have health insurance, according to a U.S. Census Report issued in 2010. Other provisions include: ■■ Dependent children remaining on their parents’ plans until age 26 ■■ Making insurance carriers justify a rate hike of 10% or more per year ■■ Requiring that at least 80% of insurance premiums be spent on health care rather than on administrative costs and advertising ■■ Removal of lifetime benefit limits and a ban on exclusion for preexisting conditions ■■ Increased access to free preventive services ■■ An increase in the number of healthcare providers ■■ A major effort to crack down on Medicare and private insurance fraud ■■ Ease of access to state health insur-

ance exchanges, 13 of which have already been established and 5 of which are in progress ■■ Coverage of essential health benefits, a comprehensive package of items and services, such as ambulatory care, emergency services, hospitalization, mental health and substance abuse treatment, chronic disease management, and others. “The health-care reform train has left the station, and we are going to be at this for quite some time,” said Dr. Trautman. She added that the United States is a nation divided about what to do, much of which is due to lack of information. For example, according to a Kaiser Health See Page 93 Tracking Poll from last year,1 22% of Americans thought the Affordable Care Act had already been repealed, and another 26% did not know what its legal status was. The federal government is not the only stakeholder in this endeavor. “Much will be happening at the local level, and there is a lot of opportunity for health professionals to have their voices heard,” Dr. Trautman said.

Disclosure: Dr. Gillifan, Whittaker, and Trautman reported no potential conflicts of interest.

Reference 1. Henry J. Kaiser Family Foundation: Kaiser Health Tracking Poll, February 2011. Available at http://www.kff.org/kaiserpolls/upload/8156-F.pdf. Accessed March 21, 2012.

George Kovach, MD, Named as President of the Association of Community Cancer Centers

George Kovach, MD

George Kovach, MD, became President of the Association of Community Cancer Centers (ACCC) at its 38th Annual National Meeting in March 2012. Dr. Kovach is the medical director of the Genesis Cancer Center, Davenport, Iowa, and one of the founding members of the Iowa Oncol-

ogy Society (IOS). “I am honored to serve as President of the Association of Community Cancer Centers,” said Dr. Kovach. “As health-care reform takes center stage this year, ACCC must continue to define quality cancer care, be a strong national advocate with a seat at the discussion table, and represent the needs and goals of the multidisciplinary cancer care team. The Affordable Care Act’s uncertain future offers us an opportunity to shape policy rather than react to it.” Dr. Kovach has been active in ACCC for many years. He served as ACCC Treasurer and as Co-chair for ACCC’s Subcommittee on Reimbursement.

He has also been a member of the American Society of Clinical Oncology Clinical Practice Committee, through his positions in the Iowa Oncology Society. In addition, as a board-certified hematologist, he is on the Medicare Carrier Advisory Committee, representing the subspecialty of hematology. Dr. Kovach participates in NCIsponsored clinical trials through the Southwest Oncology Group, the National Surgical Adjuvant Breast and Bowel Project (NSABP), and the National Cancer Institute’s Cancer Trials Support Unit (CTSU). Dr. Kovach succeeds Thomas L. Whittaker, MD, FACP, of Central Indiana Cancer Centers in Indianapolis,

Indiana, who served as ACCC President during 2011-2012.

ACCC Honors Albert B. Einstein, Jr, MD In other news from the ACCC Annual National Meeting, Albert B. Einstein, Jr, MD, was honored with the ACCC David King Community Clinical Scientist Award for his outstanding service, leadership, and commitment to the oncology community. Recently retired, Dr. Einstein was the Executive Director of the Swedish Cancer Institute in Seattle, Washington, and a medical oncologist. The award was presented at the ACCC 38th Annual National Meeting last month.


The ASCO Post  |   APRIL 15, 2012

PAGE 20

2012 Genitourinary Cancers Symposium Study Shows Concurrent Chemoradiation Therapy to be a Viable Strategy for Muscle-invasive Bladder Cancer By Alice Goodman

C

ombined-modality therapy provides a bladder-sparing alternative to radical cystectomy with comparable outcomes in patients with muscle-invasive bladder cancer, according to a pooled analysis of six Radiation Therapy Oncology Group (RTOG) trials.1 The study included 468 patients and showed that clinical T stage and complete response are important predictors of long-term survival in patients with muscle-invasive bladder cancer who undergo combined-modality therapy. “Combined-modality therapy can spare the bladder, but the optimal [chemoradiation] regimen for [this approach] remains to be defined. The small sample sizes of these [six] studies do not allow comparisons between these trials to determine optimal combined-modality therapy,” said

Combined-modality Therapy for Muscle-invasive Bladder Cancer ■■ A pooled analysis of six RTOG trials including 468 patients validates combined-modality therapy as a bladder-sparing strategy for patients with muscle-invasive bladder cancer.

■■ Clinical T stage and complete response are important predictors of long-term survival with this strategy.

Raymond H. Mak, MD

Raymond H. Mak, MD, of the Harvard Radiation Oncology Program, Boston, at the 2012 Genitourinary Cancers Symposium. The six trials were RTOG 8802, 8903, 9506, 9706, 9906, and 0233; five were phase II trials and one was a phase III study. These small trials all utilized combined-modality therapy with a variety of neoadjuvant and/ or adjuvant regimens. Two trials in-

EXPERT POINT OF VIEW

A

ccording to Seth P. Lerner, MD, Professor in the Scott Department of Urology at Baylor College of Medicine, Houston, and Co-chair of the session at the Genitourinary Cancers Symposium where the study by Mak and colleagues was presented, the data clearly demonstrate proof of principle that the combined-modality approach to therapy is safe and effective in selected patients with muscle-invasive bladder cancer. However, he Seth P. Lerner, MD cited several caveats, including the small number of patients accrued over 14 years, and the exclusion of patients with hydronephrosis, anemia, and large T3 or T4 tumors. Moreover, even though locoregional control was achieved in the majority (over 70%) of patients and a minority of patients require salvage cystectomy, a significant percentage experienced a non–muscle invasive recurrence in the bladder, necessitating salvage intravesical therapy. Further, cystectomy is often required in patients who fail to achieve a complete response, as well as in those who develop a recurrence with high-grade non–muscle invasive disease, leaving at most 35% to 40% of patients who are long-term disease-free survivors and have an intact bladder. The chemotherapy regimens used are effective as radiosensitizers and optimize locoregional control but are unlikely to sterilize occult systemic visceral and N2 or N3 nodal metastatic disease. Finally, this is intensive therapy, requires meticulous coordination with the multidisciplinary team, and be can be costly as a result of both the treatment and follow-up intensity, Dr. Lerner noted. “Despite these limitations, it is hard to argue against the benefit to the patient for bladder preservation. So, can we identify the patients most likely to respond among those without locally advanced disease or those who are not medically fit or refuse cystectomy?” he asked.

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

■■ The 5-year rate of non–muscle invasive local failure was 31%, and

the 5-year muscle-invasive failure rate was 13%, underscoring the need for careful post-treatment surveillance via cystoscopy and prompt salvage cystectomy for patients with muscle-invasive local recurrences.

cluded two cycles of neoadjuvant chemotherapy, one trial had no neoadjuvant or adjuvant chemotherapy, and three incorporated adjuvant chemotherapy.

Study Details The analysis was based on a total of 468 patients with a median age of 66 years; 64% were younger than age 70, 19% were aged 70 to 75, and 17% were older than age 75. Among all patients, 82% were male. Approximately 94% had transitional cell carcinoma; 61% had clinical stage T2 tumors, and 35% had clinical stage T3. Median followup was 4.3 years for all patients and 7.8 years among 205 survivors. Seventy-two percent of patients had a complete response to combinedmodality therapy. The 5- and 10-year estimated overall survival rates were 57% and 36%, respectively; 5- and 10year estimated disease-specific survival rates were 71% and 65%. The majority of local failures in the bladder were non–muscle invasive, with an estimated 5- and 10-year incidence of 31% and 36%. The 5- and 10-year estimates for muscle-invasive failure rates were 13% and 14%, and 5- and 10-year estimates of distant metastases were 31% and 35%. “This recurrence pattern underscores the need for careful post-treatment surveillance via cystoscopy [with prompt salvage cystectomy for invasive tumor recurrences] and further study for novel systemic therapies,” Dr. Mak told listeners. Patients with a complete response to combined-modality therapy had improved 5-year survival vs

nonresponders: 79% vs 56%. Multivariate analysis adjusted for age and histology found that higher clinical T stage (cT3/4 vs cT2) was associated with decreased overall and disease-specific survival. Elderly (age ≥ 75) patients did not have significantly different disease-specific survival compared with younger (age 70-75 and age < 70) patients (64% vs 61% vs 67% at 10 years, respectively), Dr. Mak explained. Thus, the pooled data from these multi-institutional prospective See Page 93 trials indicate that bladder-preser ving chemoradiation is a good treatment option for elderly patients, and satisfies an unmet need for treatment options in this group of patients, many of whom (30%-40% are not receiving curative treatment).2

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

References 1. Mak RH, Hunt D, Shipley WU, et al: Long-term outcomes in patients with muscle-invasive bladder cancer after bladder preserving combined-modality therapy: A pooled analysis of RTOG 8802, 8903, 9706, 9906, and 0233. Genitourinary Cancers Symposium. Abstract 264. Presented February 3, 2012. 2. Gray PJ, Fedewa SA, Shipley WU, et al: Receipt of aggressive therapies for muscle-invasive bladder cancer: Results from the National Cancer Data Base. Genitourinary Cancers Symposium. Abstract 272. Presented February 3, 2012.


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The promise of Dendritic Cell Mediated Immunotherapy (DCMI) in advanced NSCLC

BINDS

PROPOSED MECHANISM OF ACTION: Orally administered DCMIs bind in the gut epithelium and interact with dendritic cells in the gut wall1,2

STIMULATES

Binding produces an immunostimulatory cytokine cascade in the gut, triggering the migration and maturation of tumor antigen-presenting dendritic cells2,3

ACTIVATES Matured dendritic cells present tumorassociated antigens to T lymphocytes and activate them2,3

INFILTRATES These T lymphocytes then make their way to distal tumors where they infiltrate and inhibit tumor growth2,3

There is an unmet need for treatments in advanced NSCLC that work in a broad range of patients regardless of tumor histology or mutation status.4 Agennix is investigating a novel oral DCMI to potentially fulfill this need.4 Learn more at www.discoverDCMI.com

DCMI

REFERENCES: 1. Suzuki YA et al. Biochem. 2001;40:15771-15779. 2. Spadaro M et al. Cancer Res. 2007;67:6425-6432. 3. Varadhachary A et al. Int J Cancer. 2004;111:398-403. 4. Kelly RJ, Giaccone G. Expert Opin Biol Ther. 2010;10:1379-1386.

©2012 Agennix All rights reserved 4/12 TLF-JA05-3-2012


The ASCO Post  |   APRIL 15, 2012

PAGE 22

2012 Genitourinary Cancers Symposium Short-term Hormone Therapy Did Not Increase Risk of Cardiovascular Death in Men with Localized Prostate Cancer, RTOG 94-08 Trial Finds By Alice Goodman

S

hort-term androgen deprivation therapy does not appear to increase cardiovascular mortality in men with clinically localized prostate cancer, according to a post hoc analysis of a large Radiation Therapy Oncology Group (RTOG)-sponsored clinical trial.1

Jason A. Efstathiou, MD, DPhil

“Our study analyzes data from a large randomized trial with long followup showing that short-term androgendeprivation therapy improves overall survival but does not increase cardiac mortality in men with localized prostate cancer. The vast majority of men included in the trial were at a lower risk for prostate cancer–specific mortality. These findings are consistent with other analyses of large randomized controlled trials lookSee Page 93 ing at cardiac mortality and androgen deprivation therapy in men with higher-risk locally advanced disease,” said lead author Jason A. Efstathiou, MD, DPhil, of Massachusetts General Hospital, Boston. Since October 2010, labeling for gonadotropin-releasing hormone ago-

nists has included a black box warning to the effect that these agents increase the risk of diabetes mellitus and certain cardiovascular diseases. “Significant controversy remains surrounding the potential effects of hormonal therapy on cardiovascular death, especially in men with localized prostate cancer who are expected to live a long time,” Dr. Efstathiou explained. Last year, RTOG 94-08 investigators reported that short-term androgen-deprivation therapy added to radiation therapy improved overall and disease-specific survival in men with intermediate-risk prostate cancer.2 That study randomly assigned more than 1,800 men with localized prostate cancer to radiotherapy plus 4 months of androgen-deprivation therapy vs radiotherapy alone and showed a survival benefit in men at intermediate risk. “This was a practice-defining trial,” Dr. Efstathiou noted. “Whether androgen deprivation therapy adds to contemporary high doses of radiation in intermediate-risk disease continues to be investigated in RTOG 0815.”

RTOG 94-08 Analysis The present analysis, reported at the 2012 Genitourinary Cancers Symposium, showed no statistical difference in cardiovascular mortality between the two arms. Cardiovascular death occurred in 92 patients in the androgen deprivation–plus–radiotherapy arm vs 99 patients in the radiotherapy-alone arm. In a multivariate analysis, the following traditional cardiac risk

Androgen-deprivation Therapy and Cardiovascular Risk ■■ Androgen-deprivation therapy improves overall and disease-specific survival when added to radiation therapy in men with localized intermediate-/high-risk and/or locally advanced prostate cancer.

■■ Use of androgen-deprivation therapy in conjunction with radiation

therapy does not appear to increase the risk of cardiovascular death in men with prostate cancer.

■■ In RTOG 94-08, older men (age 70 or above), men with preexisting

cardiovascular disease, and men with diabetes mellitus at baseline are also not at increased risk of cardiovascular death with short-term hormonal therapy. However, in a large study of men undergoing androgen deprivation and brachytherapy, a small subgroup of highrisk patients with a history of heart failure or myocardial infarction had worse outcomes.

EXPERT POINT OF VIEW

O

liver Sartor, MD, Medical Director of Tulane Cancer Center, New Orleans, said that in his opinion, RTOG 94-08 had some flaws because outdated radiotherapy doses were employed. “The utility of hormone therapy is questionable with today’s doses,” Dr. Sartor said. “Using standard radiation doses at the time the study was conducted, androgen-deprivation therapy unequivocally added a survival benefit to the intermediate-risk Oliver Sartor, MD patients, but not for low-risk patients. It is still open to question whether [androgen deprivation] is necessary with contemporary radiation doses and techniques,” he said. Dr. Sartor added, “The cardiac findings are reassuring, since they demonstrate that short courses of androgen-deprivation therapy are not associated with an elevated risk of cardiovascular morbidity.”

Recent Meta-analysis Dr. Sartor noted that a recent study1 suggests that patients who have a poor outcome after hormonal therapy are those with a prior history of heart failure or myocardial infarction. “For a patient without this history, 4 months of hormones appears safe in terms of cardiovascular mortality.” The study Dr. Sartor referred to was an analysis of 14,594 men undergoing androgen deprivation and brachytherapy. The authors found that (other than in the high-risk subgroup with a history of heart failure or myocardial infarction) there was no association between use of androgen-deprivation therapy and risk of cardiovascular death, and androgen deprivation was associated with a lower risk of disease-specific and all-cause mortality.

Disclosure: Dr. Sartor is a consultant to Tolmar.

Reference 1. Nguyen PL, Chen MH, Beckman JA, et al: Influence of androgen deprivation therapy on all-cause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction. Int J Radiat Oncol Biol Phys 82:1411-1416, 2012.

factors were significantly related to cardiovascular mortality: age (HR = 1.06; P  < .0001), existing cardiovascular disease (HR= 2.04; P < .0001), and prevalent diabetes mellitus (HR = 1.04; P = .03). Multivariate results were similar (ie, no increased cardiovascular death with androgen-deprivation therapy) when analysis was limited to the 22% of patients at high risk for cardiovascular mortality, as defined as age ≥ 70 and presence of baseline cardiovascular disease or diabetes mellitus (HR = 1.04; P = .79). “These findings should allay some of the concern surrounding risk of cardiovascular mortality with androgen-deprivation therapy in men with localized prostate cancer. With long

follow-up in a large trial, we found no such increased risk,” he stated. “All treatment decisions should ultimately be based on risk vs benefit,” he added.

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

References 1. Efstathiou JA, Paulus R, Smith MR, et al: Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: An analysis of RTOG 94-08. 2012 Genitourinary Cancers Symposium. Abstract 18. Presented February 2, 2012. 2. Jones CU, Hunt D, McGowan DG, et al: Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med 365:107-118, 2011.


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The ASCO Post  |   APRIL 15, 2012

PAGE 24

2012 Genitourinary Cancers Symposium SELECT Trial Update: Vitamin E Fails to Prevent Prostate Cancer in Healthy Men, Appears to Increase Risk By Alice Goodman

S

upplements touted as preventing prostate cancer may turn out to be dangerous, as is evident from updated results of the largest long-term prevention trial, called the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Final analysis of SELECT showed that, compared to placebo, vitamin E alone increased the risk of developing prostate cancer in otherwise healthy men by 17%. After an average of 7 years (5.5 years on supplements and 1.5 years off of them), vitamin  E was associated with a statistically significant increased risk of prostate cancer, whereas selenium alone was not. For every 1,000 men who took placebo, there were 65 cases of prostate cancer over 7 years, and for every 1,000 men who took vitamin E, there were 76 cases of prostate cancer. These findings were published in JAMA on October 12, 2011,1 and pre-

Supplements in Prostate Cancer Prevention ■■ Supplements taken by healthy individuals to prevent cancer can be potentially harmful.

■■ Vitamin E at 400 IU/d taken over 5.5 years by healthy individuals to

prevent prostate cancer was associated with a 17% increased risk of developing prostate cancer.

■■ Selenium at 200 μg/d did not increase the risk of prostate cancer but Eric Klein, MD

sented at the 2012 Genitourinary Cancers Symposium.2

Trial Halted Early “Healthy men who took a common dose of vitamin E [400 IU/d] supplementation alone for 7 years had a 17% increased risk of developing cancer vs the other three intervention arms. In men who developed cancer on either treatment, there was no difference between intervention arms for tumor ag-

EXPERT POINT OF VIEW

A

ccording to Adam Kibel, MD, Urology Chair at Brigham and Women’s Hospital in Boston, it would appear to be logical that increasing the doses of vitamin E and selenium would decrease the risk of prostate cancer, since the preponderance of evidence demonstrates that these supplements do so. “The SELECT trial has demonstrated that not only isn’t this true, but that it might actually increase Adam Kibel, MD the risk. What can the prostate cancer community take home from this? That well designed clinical trials like SELECT are needed before we firmly endorse lifestyle changes, even those as mundane as taking a vitamin,” he commented. Dr. Kibel believes that nutraceuticals should be subject to the same rigorous testing as drugs. “Does this mean that dietary changes cannot influence risk of disease? Of course they can, but it is harder to predict than we would have expected. Physicians seeking to advise patients on ways to prevent disease should certainly advocate lifestyle changes. I think we can safely say, though, that vitamin E should not be one of those recommendations,” Dr. Kibel stated. Disclosure: Dr. Kibel reported no potential conflicts of interest.

Visit

had no beneficial effect on prevention.

gressiveness. Increased screening or biopsy did not account for the increased risk of prostate cancer in the vitamin E arm,” said Eric Klein, MD, of the Glickman Urological and Kidney Institute of the Cleveland Clinic. An interim analysis of SELECT showed that selenium at 200 μg/d and vitamin E at 400 IU/d, alone or in combination, had no beneficial effect on prevention of prostate cancer in otherwise healthy men. In 2008, the trial was halted early due to these results, but subjects continued to be followed. SELECT enrolled 35,434 men aged 55 or older (or age 50 or older if they were African-American) at more than 400 study sites across the United States, Puerto Rico, and Canada. All men stopped taking the study supplements (selenium at 200 μg/d, vitamin E at 400  IU/d, the combination, or placebo) when the study was halted prematurely. They continued to be monitored to determine the longterm effects of their study medications.

SELECT Biorepository Dr. Klein emphasized the potential dangers of taking supplements that have not been subject to rigorous study. “This study illustrates that supplements are biologically active and may be harmful. Half of the adult U.S. population take supplements, and it is a $23  billion a year industry. An estimated 50% of men over age 60 take vi-

tamin E, and 23% take 400 IU per day. For agents with biology we don’t understand, postintervention follow-up is critical. We wouldn’t have found this if we didn’t continue our follow-up,” Dr. Klein told listeners. The SELECT investigators are maintaining a biorepository of tissues from participants that includes blood, toenails, and prostate tissues. Blood samples will be used in extensive molecular analysis to understand the effects of the study agents and See Page 93 other hypotheses. Dr. Klein said that researchers interested in obtaining tissues should visit the Southwest Oncology Group website at www.swog.org/ SELECT.

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

References 1. Klein EA, Thompson IM Jr, Tangen CM, et al: Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306:1549-1556, 2011. 2. Klein EA, Thompson I, Tangen CM, et al: Vitamin E and the risk of prostate cancer: Updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). 2012 Genitourinary Cancers Symposium. Abstract 7. Presented February 2, 2012.

website at ASCOPost.com


CURRENTLY ENROLLING for METASTATIC PANCREATIC CANCER

A Randomized Phase III Study of Weekly ABI-007 Plus Gemcitabine Versus Gemcitabine Alone in Patients With Metastatic Adenocarcinoma of the Pancreas Primary Objective To evaluate the efficacy of the combination of ABI-007 and gemcitabine versus gemcitabine alone in improving overall survival in patients with metastatic adenocarcinoma of the pancreas Key Eligibility Criteria* • Confirmed, measurable metastatic pancreatic adenocarcinoma diagnosed 6 weeks prior to randomization • ≥1 metastatic tumor measurable by CT scan • No prior therapy for treatment of metastatic disease • Karnofsky performance status ≥70 • No brain metastases • No prior malignancy in last 5 years

Albumin-bound Paclitaxel + Gemcitabine Arm† • Albumin-bound paclitaxel 125 mg/m2 IV weekly x 3 • Gemcitabine 1000 mg/m2 IV weekly x 3 • 28-day cycles N=842 Randomization (1:1) Gemcitabine Arm† • Cycle 1 (56-day cycle): Gemcitabine 1000 mg/m2 IV weekly x 7 • Cycles 2+ (28-day cycles): Gemcitabine 1000 mg/m2 IV weekly x 3

* Additional criteria apply. †

Patients continue treatment until disease progression or unacceptable toxicity, palliative radiotherapy to a target lesion is required, consent is withdrawn, or physician’s choice. End-of-study assessments will be performed for all patients who are removed from study.

Visit www.thempactstudy.com to learn more. Investigational use of paclitaxel protein-bound particles for injectable suspension (albumin-bound).

©2011 Celgene Corporation 11/11 US-CELG110064a

For more information, please contact Study Manager Tammy Davis at tadavis@celgene.com or call 910-791-2301.


The ASCO Post  |   APRIL 15, 2012

PAGE 26

National Comprehensive Cancer Network Annual Conference

NCCN Announces New Guidelines for Adolescent and Young Adult Oncology

T

he National Comprehensive Cancer Network (NCCN) announced that it has issued new NCCN Clinical Practice Guidelines in Oncology for Adolescent and Young Adult (AYA) Oncology.1 Adolescent and young adult patients are defined in the guidelines as individuals 15 to 39 years of age at initial cancer diagnosis. The guidelines address the critical issues that adolescent and young adult patients with cancer and their caregivers encounter at diagnosis, during treatment, and after therapy. According to the American Cancer Society’s CA: A Cancer Journal for Clinicians, remarkable progress has been made in the treatment of children under the age of 15 and in adults over 40 years of age in the past 35 years. However, there has been minimal improvement in the survival rate in the 70,000 new adolescent and young adult patients with invasive cancer diagnosed yearly.2

Medical Center, Chair of the NCCN Adolescent and Young Adult Oncology Panel, and a member of the NCCN Board of Directors. “Patients in this age group with pediatric types of cancers such as acute lymphoblastic leukemia and bone and soft tissue sarcomas have better outcomes when treated with aggressive therapies utilized by pediatric oncologists. We also see worse outcomes for adolescent and young adult patients diagnosed with adult onset cancers such as breast and colon cancer. We hope and believe that the new NCCN Guidelines for Adolescent and Young Adult Oncology will make a difference in how these patients are managed throughout the course of their disease.” The NCCN Guidelines address the many factors responsible for the disappointing results in adolescent and young adult patients. In the United States, only about 10% of 15- to

We hope and believe that the new NCCN Guidelines for Adolescent and Young Adult Oncology will make a difference in how these patients are managed throughout the course of their disease. — Peter F. Coccia, MD

Urgent Need “There is an urgent need for increased awareness of the many unique issues responsible for these poor outcomes in the adolescent and young adult oncology patients,” noted Peter F. Coccia, MD, of the UNMC Eppley Cancer Center at The Nebraska

19-year-old patients and 1% to 2% of 20- to 39-year-old patients enroll in clinical trials. Conversely, more than 90% of children under 15 years of age are managed in centers that participate in the Children’s Oncology Group protocols or clinical trials. In addition, adolescent and young

Adolescent and Young Adult Oncology ■■ Each year 70,000 new cases of invasive cancer are diagnosed in adolescent and young adults.

■■ The new NCCN guidelines define adolescents and young adults as patients between 15 and 39 years of age.

■■ The guidelines include recommendations for fertility preservation,

screening for late effects, psychosocial issues, palliative care and endof-life considerations, and details about online resources for patients and survivors.

■■ The NCCN Guidelines Adolescent and Young Adult Oncology Panel

advises that adolescent and young adult patients be referred to cancer centers with expertise and experience in treating patients in this age group and the cancers that affect them.

These patients face serious problems related to loss of fertility, disruptions in their education or their careers, and their social interactions—in addition to the threat to their mortality. — Bradley J. Zebrack, PhD, MSW, MPH

adult patients more often lack adequate health insurance, and may not have access to either routine health care—which leads to earlier diagnosis—or to state-of-the-art care once diagnosed. Moreover, adolescent and young adult patients tend to be less compliant with their prescribed treatments.

Referral to Experienced Cancer Centers The NCCN Guidelines Panel, made up of experts in adolescent and young adult oncology from the 21 NCCN Member Institutions, strongly advises that adolescent and young adult patients be referred to cancer centers with expertise and experience in treating patients in this age group and the cancers that affect them. They cite improved enrollment in clinical trials, the need for a multidisciplinary approach to treatment, and specific attention to the special physical and psychosocial issues that adolescent and young adult patients face as critical components in delivering state-of-the-art care. The NCCN Guidelines include recommendations for fertility preservation, screening recommendations for late effects after successful completion of therapy, palliative care and endof-life considerations when curative therapy fails, and details about available online resources for adolescent and young adult patients and cancer survivors.

Psychosocial Issues Bradley J. Zebrack, PhD, MSW, MPH, of the University of Michigan Comprehensive Cancer Center, a member of the NCCN Adolescent and Young Adult Oncology Panel, stresses the importance of understanding and managing psychosocial issues for these patients.

“Psychological distress is significantly greater among adolescent and young adult patients as compared to younger children or older patients with cancer,” he said. “These patients face serious problems related to loss of fertility, disruptions in their education or their careers, and their social interactions—in addition to the threat to their mortality. These issues—and the isolation that accompanies them—can affect their lives for many years. Managing these patients medically and communicating effectively with them can be challenging, and requires that the full team of See Page 93 health-care providers be knowledgeable about adolescent behavior. The team must also be well trained in how to communicate with teens and young adults, as well as their families and peers. The new NCCN Guidelines include a comprehensive psychosocial assessment to assure that these issues are fully addressed.” The NCCN Guidelines for Adolescent and Young Adult Oncology were presented at the NCCN 17th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care. Access to the NCCN Guidelines for Adolescent and Young Adult Oncology or any of the NCCN Guidelines are available free of charge at NCCN.org.

References 1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Adolescent and Young Adult (AYA) Oncology. Version 1.2012. Available at http:// www.nccn.org/professionals/physician_gls/pdf/aya.pdf. Accessed March 16, 2012. 2. Bleyer A: Young adult oncology: The patients and their survival challenges. CA Cancer J Clin 57:242-255, 2007.


NOW APPROVED!

For more information, visit www.Erivedge.com

Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS Erivedge (vismodegib) capsule can result in embryo-fetal death or severe birth defects. Erivedge is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of Erivedge exposure through semen.

Boxed Warning and Additional Important Safety Information Embryo-Fetal Death and Severe Birth Defects • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555 Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on the following page.

© 2012 Genentech USA, Inc. All rights reserved. HED0000916900 Printed in USA.


The ASCO Post  |   APRIL 15, 2012

PAGE 28

News Adolescent and Young Adult Oncology

Radiation Oncologists Are Discussing Infertility Risks with Young Patients

M

ore than 80% of radiation oncologists discuss the impact of cancer treatments on fertility with their patients of childbearing age. This can lead to improved quality of life for young patients with cancer, according to a study in Prac-

tical Radiation Oncology.1 In the past, the clinical focus for young patients with cancer was strictly survival. The success of today’s treatment options has shifted the clinical focus from strictly survival, to survival

Table 1: Adverse Reactions Occurring in ≥  10% of Advanced BCC Patients (cont) All aBCC Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%) 1

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150  mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 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 clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138  patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10  months (305  days; range 0.7  to  36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥  10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥  10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

-

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

-

2

35 (25.4%)

3 (2.2%)

-

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

-

76 (55.1%) 15 (10.9%)

-

-

88 (63.8%)

-

-

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade  3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE 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 embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

plus long-term quality-of-life issues. A patient’s risk for infertility increases after chemotherapy, radiation therapy, and sometimes surgery. For the large percentage of patients with cancer who are of reproductive age, this is an impor-

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, 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 The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7  months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540  mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7  months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

tant quality-of-life issue. There have been great advances in the field of fertility preservation, but these options must be considered before cancer treatment begins.

Referral Patterns Studied Recent research suggests that less than 50% of adult patients with cancer who are of childbearing age receive adequate education about their options before cancer treatment. Moreover, less than 35% of women recall discussing the risks of infertility during or after cancer treatment. Researchers in this study sought to determine the fertility preservation discussion and referral patterns among oncology specialists (ie, medical oncologists, radiation oncologists, and surgical oncologists). Physicians were See Page 93 asked if they always/ often, sometimes, or rarely/never discussed the impact of cancer treatments on future fertility with their patients. Among radiation oncologists who responded to the survey, 82% always/often discussed fertility and 17% sometimes did; none answered rarely/never. Among medical oncologists, 84% discussed fertility options and 4% admitted to never discussing the subject. Among surgical oncologists, 51% always discussed fertility and 20% never discussed it. All specialties referred patients to a reproductive endocrinologist for fertility preservation at approximately the same low rate: 40% of radiation oncologists, compared with 45% of medical oncologists and 46% of surgical oncologists. “These findings are important particularly for radiation oncologists, who may have a unique role in communicating fertility preservation options to their patients, since their patients have daily interaction with staff and weekly treatment exams with the radiation oncology physician and nurse,” said Gwendolyn P. Quinn, PhD, senior author of the study and an Associate Member and Director of the Survey Methods Core Facility at Moffitt Cancer Center in Tampa, Florida.

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

Reference 1. Gwede CK, Vadaparampil ST, Hoffe S, et al: The role of radiation oncologists and discussion of fertility preservation in young cancer patients. Pract Radiat Oncol. January 27, 2012 (early release online).


ASCOPost.com  |   APRIL 15, 2012

PAGE 29

News

Surgeon General Releases New Report on Youth Smoking

Regina M. Benjamin, MD, MBA

T

he fight against tobacco use among young people was accelerated recently by Surgeon General Regina M. Benjamin, MD, MBA, with the release of the Surgeon General’s Report, Preventing Tobacco Use Among Youth and Young Adults. This report details the scope, health consequences, and influences that lead to youth tobacco use and proven strategies that prevent its use. To help communicate the report findings and steps anyone can take to join the fight against youth tobacco use, the Surgeon General also unveiled a guide with practical information on addressing tobacco use in young

people, Preventing Tobacco Use Among Youth and Young Adults: We Can Make the Next Generation Tobacco-Free. In addition, the Centers for Disease Control and Prevention’s Office on Smoking and Health will launch the Surgeon General’s Video Challenge to engage youth and young adults in developing original videos that feature one or more of the report’s findings. More information can be found at www.Challenge.gov.

‘Replacement Smokers’ Tobacco is the leading cause of preventable and premature death, killing more than 1,200 Americans every day. For every tobacco-related death, two new young people under the age of 26 become regular smokers. Nearly 90% of these replacement smokers try their first cigarette by age 18. Approximately 3 out of 4 high school smokers continue to smoke well into adulthood. “Targeted marketing encourages more young people to take up this deadly addiction every day,” said U.S. Department of Health and Human

Major Conclusions of the Surgeon General’s Report on Youth Tobacco Use 1. Cigarette smoking by youth and young adults has immediate adverse health consequences, including addiction, and accelerates the development of chronic diseases across the full life course. 2. Prevention efforts must focus on both adolescents and young adults because among adults who become daily smokers, nearly all first use of cigarettes occurs by 18 years of age (88%), with 99% of first use by 26 years of age. 3. Advertising and promotional activities by tobacco companies have been shown to cause the onset and continuation of smoking among adolescents and young adults. 4. After years of steady progress, declines in the use of tobacco by youth and young adults have slowed for cigarette smoking and stalled for smokeless tobacco use. 5. Coordinated, multicomponent interventions that combine mass media campaigns, price increases including those that result from tax increases, school-based policies and programs, and statewide or community-wide changes in smoke-free policies and norms are effective in reducing the initiation, prevalence, and intensity of smoking among youth and young adults. From Preventing Tobacco Use Among Youth and Young Adults: A Report of the Surgeon General, Executive Summary. U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, Rockville, Maryland, 2012.

Services (HHS) Secretary Kathleen Sebelius. “This administration is committed to doing everything we can to prevent our children from using tobacco.”

The younger individuals are when they start using tobacco, the more likely they are to become addicted and the more heavily addicted they will become. This administration has taken historic steps to protect children from the dangers of tobacco use, including the passage of the Family Smoking Prevention and Tobacco Control Act, which gives the FDA authority to regulate tobacco products to prevent use by minors. The Tobacco Control Act prevents tobacco use through activities such as age and identification verification at retailers, restrictions on the sale of single cigarettes, and a ban on certain candy and fruit-flavored cigarettes. Other activities include support for state quitlines and implementation of Web- and mobile-based interventions aimed at reaching young people. 

Nicotine’s Addictive Power The Surgeon General’s Report provides further scientific evidence on the addictive nature of nicotine. The younger individuals are when they start using tobacco, the more likely they are to become addicted and the more heavily addicted they will become. “The addictive power of nicotine makes tobacco use much more than a passing phase for most teens. We now know smoking causes immediate physical damage, some of which is permanent,” said Dr. Benjamin. “Today, more than 600,000 middle school students and 3  million high school students smoke. We don’t want our children to start something now that they won’t be

able to change later in life.” While the long-term health effects of tobacco use are well known, this report concludes that smoking early in life is associated with substantial health risks that begin immediately in young smokers. These include serious early cardiovascular damage, a reduction of lung functionality, and increased risk of pulmonary diseases later in life. Expenditures for marketing and promotion of tobacco products exceed $1  million an hour—over $27  million a day—in the United States alone. Targeted messages and images that portray smoking as an acceptable, appealing activity for young people are widespread, and advertising for tobacco products is prominent in retail stores and online. 

Howard Koh, MD, MPH

Toward Ending the Tobacco Epidemic “We can and must continue to do more to accelerate the decline in youth tobacco use,” said Howard Koh, MD, MPH, Assistant Secretary for Health at HHS, “Until we end the tobacco epidemic, more young people will become addicted, more people will die, and more families will be devastated by the suffering and loss of loved ones.” Copies of the full Report, executive summary, and easy-to-read guide can be downloaded at http://www.surgeongeneral.gov. To order printed copies of these documents, go to http://www. cdc.gov/tobacco and See Page 93 click on the Publications Catalog link under Tools & Resources. For access to quitting resources, visit www.smokefree.gov.


The ASCO Post  |   APRIL 15, 2012

PAGE 30

Expert’s Corner Thoracic Oncology

An Expert Shares Insight into the Future of Lung Cancer Treatment A Conversation with Paul A. Bunn, Jr, MD By Ronald Piana tify. That’s why we need more definitive data on cost per life year gained and on improving diagnostic accuracy before widespread community adoption.

Paul A. Bunn, Jr, MD

D

espite growing national focus on early detection, prevention, and new molecular-based treatments, lung cancer persistently remains the number 1 cause of cancer death for men and women in the United States. The ASCO Post spoke to lung cancer specialist Paul A. Bunn, Jr, MD, Executive Director, International Association for the Study of Lung Cancer (IASLC), about current and future developments in the detection and treatment of lung cancer.

Lung Cancer Screening The National Lung Screening Trial (NLST) provoked strong reactions. Is there more clarity about what the trial results mean for clinicians and their patients? Currently, no. However, answers will come from further analyses of patients who participated in the National Lung Screening Trial and from numerous ongoing lung cancer CT screening trials that will ultimately bring insight into the value of lung cancer screening. A 20% reduction in lung cancer mortality in heavy smokers over the age of 55 is incredibly important. However, 26% of patients in the National Lung Screening Trial had a suspicious nodule found on low-dose spiral CT, but only 4% of those nodules were cancer. So considering that the trial found 96% of suspicious nodules were benign, the major question is, how do we discern a benign nodule from one destined to become malignant? The characteristics of the nodule (eg, solid, spiculated, calcified, ground glass) can help determine its potential for cancer, but with not nearly enough specificity. A study from Pittsburgh found that 30% of nodules removed for biopsy were benign, which is a lot of unnecessary workup and surgery. Add monetary costs and psychological toll on the patients, and it is difficult to jus-

What do we do in the interim period, while we wait for better predictive capabilities? Many organizations, like the U.S. Preventive Services Task Force, have been silent on this issue, indicating they don’t have enough information to make informed suggestions. The International Association for the Study of Lung Cancer suggests that patients who are concerned about developing lung cancer—for instance, those who have more than 20 to 30 pack-years of smoking and are over 55 years of age—should have a thorough conversation with their doctors to make an educated decision about the pros and cons of screening. As the National Lung Screening

We’ve also learned that in many tumors—although they have an average of 300 mutations—one of those mutations might be driving the oncogenic process. If we can match the mutation with the tumor, we can give a pill that actually has better outcomes than chemotherapy. We’ve identified two mutations for which there are FDA-approved pills—EGFR mutations that respond to gefitinib (Iressa) or erlotinib (Tarceva), and EML4ALK fusion, for which we would use crizotinib (Xalkori) therapy. If we looked at 10 genes known to be oncogenic drivers for which there is a pill (only 2 are FDA-approved, but the 8 others are under investigation), 60% of these patients have 1 of these 10 genetic triggers. This tells us that patients are going to be getting different treatments based on the genetic properties of their tumor. The Lung Cancer Mutation

We are primed to make a difference in this deadly disease. In the past, one could argue that there was a dearth of scientific avenues to explore, but that’s certainly not the case today. So the question remains: Why is the nation’s deadliest cancer given the least amount of federal funding? —Paul A. Bunn, Jr, MD

Trial showed, the great proportion of suspicious nodules end up benign, but there was also a 20% reduction in mortality in screened populations. So, at this point, screening is a patient-bypatient decision.

Treatment Advances Switching topics to treatment, is there anything in the current clinical landscape that seems promising, such as targeted biologics? Also, are we arriving at a better understanding of tumor markers? Lung cancers are heterogeneous, and there are four major histologic types, with some tumors having a mixture of histologies. We now have biomarkers to identify tumor histology. For example, if it’s adenocarcinoma, it usually has the protein TTF1, and squamous cell cancer usually carries the p63 protein. And if there’s an undifferentiated tumor, these two proteins help identify the histology.

Consortium tests for these 10 tumor markers and then puts patients on clinical trials based on individualized markers. So we are indeed making progress.

Smokers vs Never-smokers Are we learning about the genomic differences in the tumors between neversmokers and smokers who develop lung cancer that will affect therapeutic strategies moving forward? Yes and no. Smokers have more genetic changes in their tumors than neversmokers. However, the driver oncogenes identified so far are more common in never-smokers. Never-smokers have a better overall clinical outcome, and it’s likely that they have fewer mutations. Smokers can have the same driver mutations as well, so we are still going to have to test everyone. Put simply, if we determine that a particular mutation occurs in perhaps

30% of the tumors in never-smokers but in only about 5% of smokers, and if it’s the best treatment for a particular cancer, we’re not going to exclude the 5% from testing. Genetic differences between smokers and never-smokers who develop lung cancers provide an interesting scientific issue, but the clinical relevance is not as high as one might think. That said, further research is necessary.

Preventive Strategies Do any current drugs look promising as preventive agents? Foremost among preventive strategies is an aggressive national smokingcessation message. However, half of U.S. lung cancers are in former smokers, so smoking cessation is not going to help that population. The best strategy for former smokers would be a fairly nontoxic chemoprevention pill. But getting approval for this indication would require lengthy clinical trials, and in reality we would need a biomarker to predict whether an agent is likely to prevent lung cancer. We actually think that bronchial histology is an intermediate biomarker. In other words, smoking causes changes in the epithelial cells—hyperplasia, dysplasia, and some carcinoma in situ. Select lesions regress with smoking cessation, but many persist and subsequently undergo another genetic transformation and develop a cancer. The challenge is to develop a pill used to prevent the persistent lesions from mutating into cancer. In 2011, we published a paper presenting data on iloprost, which showed preventive characteristics in persistent lesions.1 It wasn’t a large randomized trial with lung cancer as an endpoint. Histology was the endpoint, and the histology got better. Interestingly, it got better in former smokers, which is what you want, simply because there are too many carcinogenic issues in current smokers to sort out the drug’s preventive effect. It’s an exciting lead but will require a phase III randomized trial to show a reduction in lung cancers or a reduced risk.

Initiatives Are there any initiatives underway at the International Association for the Study of Lung Cancer that you’d like to share with readers? continued on page 37


FOR ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML IN CHRONIC PHASE (CP)

Choose TASIGNA first

TASIGNA provides superior MMR* rates vs imatinib at 12 months and <1% progression to AP/BC1† (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], P<0.0001)1 *Major molecular response (MMR)=≥3 logs below baseline (≤0.1% international scale [IS]).1 †

Progression to accelerated phase or blast crisis (AP/BC) includes patients with clonal evolution and CML-related death.2

INDICATION AND BOXED WARNING TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome. WARNING: QT PROLONGATION AND SUDDEN DEATHS ■ TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and follow any dose adjustments ■ Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome ■ Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors ■ Patients should avoid food 2 hours before and 1 hour after taking dose Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on the following pages.


IN THE TREATMENT OF ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML-CP Less than 1% of TASIGNA patients progressed to AP/BC1 Progression to AP/BC at 24 months

2

vs

0.7%

6%

0.7%

17 6%

TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

TASIGNA

Imatinib

(n=282)

(n=283)

TASIGNA significantly improved the rate of MMR compared with imatinib at 12 months—the primary end point of the ENESTnd (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], 300trial mg bid 400 P<0.0001) mg qd1

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for RQ-PCR testing. The primary end point was MMR at 12 months.1,2

IMPORTANT SAFETY INFORMATION ■

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter

Caution is recommended in patients with a history of pancreatitis The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase

TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING) ■ ■

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

©2012 Novartis

The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Grapefruit products should also be avoided The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) TASIGNA must not be taken with food TASIGNA exposure is increased in patients with impaired hepatic function 3/12

AM7-1033710


TASIGNA maintained the difference in MMR rates through 24 months1,2 At 12 months

Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA The exposure of TASIGNA is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do. The safety and effectiveness of TASIGNA in pediatric patients have not been established

Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on adjacent pages.

At 24 months

In newly diagnosed Ph+ CML-chronic phase, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, headache, nausea, fatigue, and myalgia TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2011. 2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-851.


Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS • Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and follow any dose adjustments (5.2, 5.3, 5.6, 5.12). • Sudden deaths have been reported in patients receiving nilotinib (5.3). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2). • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors (5.7). • Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome. 1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information]. 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2) in the full prescribing information]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)]. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)]. 5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)]. 5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information]. 5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information]. 5.10 Tumor Lysis Syndrome Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. 5.11 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information]. 5.12 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption.

5.13 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.14 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. 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 of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)]. Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 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. Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 25 months (range 0.1 – 35.4 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 2.5% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse events regardless of causality was observed in 9% of patients. Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse drug reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed. Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Skin and subcutaneous Rash 37 18 <1 2 tissue disorders Pruritus 20 7 <1 0 Alopecia 11 6 0 0 Periorbital edema <1 15 0 0 Gastrointestinal Nausea 20 39 1 1 disorders Constipation 17 6 0 0 Diarrhea 14 40 <1 2 Vomiting 11 24 0 <1 Abdominal pain upper 15 11 <1 <1 Abdominal pain 14 10 1 0 (continued)


Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Nervous system Headache 30 18 3 <1 disorders General disorders Fatigue 21 16 1 1 and administration Pyrexia 11 12 <1 0 site conditions Asthenia 11 10 <1 0 Edema, peripheral 8 18 0 0 Face edema <1 11 0 <1 Musculoskeletal and Myalgia 14 18 <1 0 connective tissue Arthralgia 17 13 <1 <1 disorders Muscle spasms 11 31 0 <1 Pain in extremity 11 13 <1 <1 Back pain 14 11 <1 1 Respiratory, thoracic Cough 14 9 0 0 and mediastinal disorders Infections and Nasopharyngitis 22 17 0 0 infestations Upper respiratory tract infection 14 10 <1 0 Eye disorders Eyelid edema 1 16 0 <1 aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP CML-AP N=321 N=137 All CTC All CTC Grades Gradesb Grades Gradesb Body System and Preferred Term (%) 3 / 4 (%) (%) 3 / 4 (%) Skin and subcutaneous Rash 36 2 29 0 tissue disorders Pruritus 32 <1 20 0 Night sweat 12 <1 27 0 Alopecia 11 0 12 0 Gastrointestinal Nausea 37 1 22 <1 disorders Constipation 26 <1 19 0 Diarrhea 28 3 24 2 Vomiting 29 <1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 <1 12 <1 Dyspepsia 10 <1 4 0 Nervous system Headache 35 2 20 1 disorders General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17 11

2 <1 <1 2 2 <1

16 15 15 18 15 12

0 0 2 1 <1 1

Respiratory, thoracic and mediastinal disorders

Cough Dyspnea Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

24

<1

15

0

12

0

10

0

Metabolism and nutritional disorders

Anorexia

12

<1

15

<1

Psychiatric disorders

Insomnia

12

1

7

0

Vascular disorders

Hypertension

10

2

11

<1

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0

Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

Imatinib 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

10 12 4

9 21 5

301 312 11

423 424 27

7 6 5 4 4 2 1 <1 1 0 <1

3 0 8 <1 3 1 <1 2 1 0 0

18 12 17 7 4 6 7 2 3 4 2

18 6 15 9 4 4 7 9 2 3 5

0 0

<1 <1

<1 <1

1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (≥1% and <10%), uncommon (≥0.1% and <1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including nasopharyngitis, pharyngitis, rhinitis), pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: oral papilloma. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythaemia, leukocytosis, eosinophilia. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, decreased appetite. Uncommon: dehydration, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia. Psychiatric Disorders: Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, ocular surface disease. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.


Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatotoxicity, hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy. Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including noncardiac chest pain), pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations: Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, lipoprotein increased (including very low density and high density), blood parathyroid hormone increased. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Š Novartis T2011-126 November 2011


ASCOPost.com  |   APRIL 15, 2012

PAGE 37

News

Summary of ASCO Provisional Clinical Opinion on Palliative Care by Ronald Piana

T

he ASCO provisional clinical opinion on palliative care recently published1 was based largely on data from seven published randomized controlled trials, including a phase III lung cancer trial by Temel and colleagues, which was the trigger for the new recommendations.2 The trial’s principal outcome was quality of life, which was measured by the Functional Assessment of Cancer Therapy–Lung Trial Outcome Index (FACT-LTOI). The investigators reported that patients assigned to palliative care intervention had measurably higher quality-of-life scores compared with those who received standard care alone. Although the PCO See Page 93 acknowledged certain weaknesses in the study design, the findings demonstrated a marked increase in quality of life for patients with cancer when

palliative care services were initated upon a diagnosis of metastatic disease.

PDQ Report At ASCO’s request, the NCI’s Physician Data Query (PDQ) Supportive and Palliative Care Editorial Board provided a written assessment of the trial by Temel et al. The ASCO Panel is grateful to PDQ for this assessment. The PDQ board concluded that introducing palliative care at time of diagnosis did not result in “a burdensome number of extra visits,” and that the intervention used multiple strategies to care for a heterogeneous population. The report appraised the six additional studies cited by the PCO and commented that the literature in this field is still “in its infancy,” requiring more research and documentation of solutions in diverse cancer populations. The NCI editorial board concluded that it is premature to issue a PCO meant to apply to a general population

Paul A. Bunn, Jr, MD

Closing Thoughts

continued from page 30

Any last thoughts on the state of lung cancer research? As we know, lung cancer is the leading cause of cancer death in the United States, accounting for an astounding 30% of all cancer deaths in our nation. And yet, consider the research-funding bills recently passed by Congress. Appropriations for the Department of Defense, for example, include $120 million allocated for breast cancer, but only $12 million for lung cancer research. We are primed to make a difference in this deadly disease. In the past, one could argue that there was a dearth of scientific avenues to explore, but that’s certainly not the case today. So the question remains: Why is the nation’s deadliest cancer given the least amount of federal funding?

Lung cancer comes in one of four types, and we need to know the relationships among histology, molecular features, and outcome. About every 10 years, the World Health Organization changes the pathologic classifications. In the past, that’s been based on the appearance of cells under the microscope with no relation to molecular features. To that end, our pathology committee at the International Association for the Study of Lung Cancer is collecting data from thousands of patients worldwide to ascertain the relationship between the molecular features and clinical outcome. Another initiative at the International Association for the Study of Lung Cancer involves staging. Naturally, staging becomes a more accurate clinical guide as we develop better tests. For example, there were no CT scans when the original staging systems were developed. Now we have PET-CT and brain MRI scans, and we can collect data from hundreds of thousand of patients to help create more accurate staging systems that better reflect outcomes.

Disclosure: Dr. Bunn has been a consultant with honorarium for Amgen, Bristol-Myers Squibb, Daiichi Sankyo, Merck, Agennix, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Novartis, OSI, Sanofi-aventis, Pfizer, Eli Lilly, Genentech/Roche, GlobeImmune, Biodesix, Merrimack, and Celgene.

Reference 1. Keith RL, Blatchford PJ, Kittelson J, et al: Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res 4:793-802, 2011.

of patients with cancer. After reviewing the PDQ report, the ASCO panel responded that although literature review has limitations, the PCO is based on a detailed examination of all available current trial data. The panel emphasized that the majority of trial patients accepted palliative care intervention, and quality-of-life outcomes were positive across all seven trials. It may be too early in the palliative care initiative to define all the essential components in the concurrent oncology/palliative care model. However, it is important to note that in the Temel et al study of patients with lung cancer, two key principles of palliative care— open communication and medically appropriate goal-setting—had the most influence on treatment choices and patient survival. Patients who understood their life expectancy and the risk-to-reward estimate of treatments opted for less aggressive end-of-life care but lived

longer with better quality of life. As the data indicate, palliative care interventions do no harm to patients. In fact, most trials showed an increase in quality of life and lower use of resources, the ASCO panel concluded. The provisional clinical opinion is subject to review, as further data become available.

References 1. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol. February 6, 2012 (early release online). 2. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010. See page 3 in this issue of The ASCO Post for an in-depth interview with Thomas J. Smith, MD, one of the lead authors of the ASCO provisional clinical opinion on palliative care.

Not All KRAS Mutations Are Alike in Non–Small Cell Lung Cancer By Matthew Stenger

M

utations in the KRAS oncogene play a critical role in cancer cell growth and resistance to treatment. In colorectal cancer, the presence of any mutant amino acid substitution in the KRas protein predicts a poorer response to targeted therapy. In non–small cell lung cancer (NSCLC), however, there is conflicting evidence on whether KRAS mutations are predictive of poorer outcome. Ihle and colleagues from The University of Texas MD Anderson Cancer Center in Houston recently assessed associations between specific mutant K-Ras proteins and progression-free survival and tumor gene expression in NSCLC tissue from 215 patients involved in a clinical trial of molecular targeted therapy.1 Patients who had tumors with either K-Ras Gly12Cys or Gly12Val substitutions had significantly worse progression-free survival (median, 1.84 months) than did patients with other mutant KRas proteins (median, 3.35 months) or wild-type K-Ras proteins (median, 1.95 months). Evaluation of signaling pathway activation in a panel of 67 NSCLC

cell lines showed that those with the Gly12Cys or Gly12Val mutations had activated Ral signaling and decreased growth factor–dependent Akt activation, whereas those with the Gly12Asp substitution exhibited activated PI3K and MEK (MAPK/ERK kinase). Molecular modeling studies indicated that different conformations resulting from different K-Ras mutants may result in different associations with downstream signaling transducers. As stated by the investigators, “Not all mutant K-Ras proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant K-Ras proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.”

Reference 1. Ihle NT, Byers LA, Kim ES, et al: Effect of KRAS oncogene substitutions on protein behavior: Implications for signaling and clinical outcome. J Natl Cancer Inst 104:228-239, 2012.


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ACCC 37th Annual National Meeting Community Oncology

ACCC Releases Survey on ‘Oncology Medical Home’

T

he Association of Community Cancer Centers (ACCC) released findings from a survey that explores how community-based cancer care programs view the concept of the “oncology medical home”—a

patient-centered model for coordinated care, whereby payers would reimburse physicians for services that keep patients out of the hospital, thereby reducing total health-care costs.

“ACCC is committed to improved patient engagement, enhanced patient access, and access to all disciplines of the care team—core tenets of a medical home and comprehensive care delivery,” said ACCC Presi-

dent Thomas L. Whittaker, MD, FACP. Oncology medical home may include coordination of care with the primary care providers and the oncology team as well as complement accountable care organizations. Accountable care organizations agree to manage all of the health-care needs for a defined population in a specific period; they are required to report on utilization, cost, and quality of care. The ACCC survey of 216 administrators, oncologists, and oncology nurses—63% of whom work in a hospital-based cancer program— showed that a large majority (184 out of 254 responses) believe the oncology home model could work in their practice or hospital cancer service line.

Caveats Emerge

Clarient Insight®Dx Mammostrat® Reduce your patient’s anxiety with test results available in days… not weeks. Clarient’s InsightDx Mammostrat provides important information independent of proliferation and grade to aid physicians in making appropriate and earlier treatment decisions in order to determine which patients are most likely to recur from breast cancer. Results you can trust. Mammostrat has been studied in more than 4,500 women, including cohorts from NSABP B14 and B20 trials. Learn more about Clarient, a GE Healthcare Company and our world-class anatomic and molecular pathology laboratory services. Visit our booth at the American Society of Breast Disease Symposium. Together, we help you find the difference that makes the difference.

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More than 90 respondents said they were concerned about start-up costs and payer negotiations. However, 46 respondents said they believe a medical home could provide better-quality, collaborative care at lower costs, and they would consider applying for recognition from the National Committee for Quality Assurance. Adding the nonclinicians necessary to staff an oncology medical home did not appear to be a handicap, with fewer than 20% of respondents saying that a financial coordinator, nurse navigator, or social worker would be difficult to justify financially. Nevertheless, half of all respondents said they don’t anticipate their practice or hospital joining or becoming part of an accountable care organization or medical home within the next 2 years—perhaps because 46% have not yet seen a shift in their market away from a traditional buy-and-bill model. By 2017, only 25% of respondents believe their facility will keep its current staffing/billing structure. About 32% of respondents envision their practice or hospital being part of both an accountable care organization and medical home, 26% believe their facility will join or become an accountable care organization, and 18% anticipate becoming a medical home.

Dislcosure: Dr. Whittaker reported no potential conflicts of interest.


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Information Technology

Cancer Informatics: A Future Necessity, but Challenges Abound By Margot J. Fromer

T

he National Cancer Policy Forum of the Institute of Medicine (IOM) recently convened a workshop on cancer informatics to examine and discuss needs and challenges facing biomedical researchers, which will in turn affect the way oncology is practiced in the future. “This is a time of huge scientific opportunity, but significant challenges abound in collection, integration, analysis, and exchange of biomedical data. The problem is growing steadily worse as the amount of data increases exponentially,” said Sharon B. Murphy, MD, Scholar-in-Residence,

IOM Board on Health Care Services, and Chair of the workshop. Workshop objectives were to frame the problem and assess the need for a system of cancer informatics, to raise awareness about the challenges, gaps, and opportunities, and to discuss a vision for transforming the enterprise.

Issues Are Many and Complex “Because of the opportunities provided by molecular understanding of disease, we now have transformative potential for cancer treatment and prevention. Leaders in biomedicine want to link research and care into a seam-

Lessons Learned from caBIG

T

he Cancer Biomedical Informatics Grid (caBIG) is an NCI program that was launched in 2004 in reaction to a “health information tsunami,” said Daniel R. Masys, MD, Chair of the caBIG Oversight Committee and Affiliate Professor in the Department of Biomedical Informatics and Medical Education, University of Washington, Seattle. The caBIG program is “predicated on the availability of a nationwide, interoperable, interconnected information technology platform that enables information sharing. It provides free and Daniel R. Masys, MD open access to tools, data, and infrastructure that allow the cancer and greater biomedical research communities to improve their connectivity, collaboration, and interoperability,” said Dr. Masys. After several years of only modest success, a review committee was established. In March 2011, it concluded that support for informatics tools is even more pressing than originally thought; there is strong support for the original caBIG vision and goals, but the successes were offset by several serious problems; and the overall impact was not commensurate with the $300 million investment. “caBIG really works,” said Dr. Masys, especially in its development of standards for data exchange and interoperability, development and dissemination of tools by academic researchers, and dialogue on interoperability of clinical and research software.

Committee Recommendations Nevertheless, the review committee concluded, caBIG put the cart before the horse by using a technology-centric approach to data sharing. Its plans for expansion were unfocused, it was financially unsustainable, and it lacked independent scientific oversight. Therefore, the committee recommended: ■■ An immediate moratorium on all internal and commercial software development ■■ A 1-year moratorium on new projects and contracts ■■ A 1-year extension on current caBIG-supported community-developed software tools ■■ Ongoing oversight of planned initiatives and an audit of caBIG budget and expenditures As a result of these recommendations, funding for caBIG was decreased by about one-third, and future funding remains up in the air. However, said Dr. Masys, “NCI commitment to computational infrastructure for basic, translational, and clinical cancer research remains strong.”

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

Sharon B. Murphy, MD

Marcia A. Kean, MBA

less process by using advances in information technology [IT],” said Marcia A. Kean, MBA, Chairman of Strategic Initiatives, Feinstein Kean Healthcare, Cambridge, Massachusetts. But, she added, practitioners need evidence-based treatments that also require new information systems and reconfiguration of much existing data. These systems must allow for data liquidity—that is, the rapid, seamless, secure exchange of standards-based information among authorized individual and institutional senders and recipients, which will: ■■ Allow clinicians to have access to all the data they need for decisionmaking and identification of patients at risk for poor outcomes ■■ Allow researchers access to data needed to support discovery of molecular signatures that identify populations at risk, are predictive of response to therapy, provide prognosis and risk of recurrence information, and facilitate identification of new targets by drug developers that can be used for nonresponders Lawrence N. Shulman, MD, Chief Medical Officer, Dana-Farber Cancer Institute, said that the old days are over. “We are at a point in cancer research where we have the opportunity for a truly transformative approach that will accelerate not only our understanding of the biology of cancer, but also development of new, more effective therapies.”

Critical Challenges There are technical obstacles as well, said Ms. Kean. First, the sheer quantity of data is overwhelming. Second, data are not uniform. There are no standard vocabularies, which makes it difficult to translate from one discipline to another. Third, software vendors have no incentive to build interconnected systems that would undermine their profit potential, and IT systems developed in academia are site-specific and can’t serve

Lawrence N. Shulman, MD

a larger enterprise. Fourth, the growing complexity in oncology research hinges on deciphering intricate networks of molecular pathways that predict responses to treatment. This creates an increasing need to integrate genetics, genomics, proteomics, and other fields into new drug development, which in turn creates a need for new computational tools and algorithms. George Poste, DVM, PhD, Del E. Webb Chair in Health Innovation, Arizona State University, noted that in biomedical research, raw data is increasingly cheap, but if it is ill defined, not standardized, and statistically underpowered, it is of little value. He described the critical challenges: ■■ Negative findings are often highly instructive but rarely reported. ■■ Discovery phase knowledge is accelerating, but there is little successful translation to clinical practice. ■■ Products with uncertain and/or limited efficacy are a continuing problem. ■■ Powerful research tools do not compensate for poor sampling and weak analytical and statistical rigor.

Health IT and Electronic Health Records Electronic health records are generally looked on with favor. Their advantages are the amount and type of data that can be stored and the ready amenability to analysis. But the many gaps in privacy protection need to be addressed. Deven McGraw, JD, LLM, MPH, Director of the Health Privacy Project, Center for Democracy and Technology, Washington, DC, said that if privacy and security are built into electronic health records from the outset, consumers and professionals will be more likely to adopt them. She said that the Health Insurance Portability and Accountability Act (HIPAA) in its current form will continued on page 40


The ASCO Post  |   APRIL 15, 2012

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Information Technology

Cancer Informatics continued from page 39

not be sufficient. It is a foundation on which to base new privacy protections, but it was designed to regulate only the sharing of information among healthcare providers. New privacy policies need to be wider and deeper. Policy-

makers should focus on consistency of regulations across governing jurisdictions, strengthening federal law to go beyond storage and transmission, consumer participation in and control of B:8.375” what is contained in electronic health T:7.875” records, and control of marketing and S:7” commercial use.

Last year, the Centers for Medicare & Medicaid Services (CMS) began reimbursement for adoption of provider systems that support electronic health records. The agency’s criteria center on reporting requirements and quality measures, but systems are not required to communicate with one another. The

absence of such provisions, said Ms. Kean, disincentivizes the health informatics and IT developer communities from solving the challenges of robust information exchange. Because so many data are required to make clinical decisions, Dr. Shulman said, electronic health records “can facilitate practice, but they are not yet practical because of the current state of technology. Many elements are missing, and those that exist are often not in a structured format.” He said that Dana-Farber shares electronic health records with seven institutions and listed essential data, all of which must be encoded and collated: demographics, tumor type and staging, genomic and molecular data, treatment plan, tumor response, toxicity, patient-reported outcomes, diseasefree progression, and survival. He added that patients will more accurately report adverse events if they can do it on their home computers as they experience symptoms, and this can happen only with a patient portal as part of the electronic health record system.

Experience in the Real World

B:11.125”

S:10”

T:10.5”

Is there more to

William S. Dalton, MD, PhD, President and CEO, Moffitt Cancer Center, asked one of the ultimate questions: “How do we develop an integrated system that can deal with an overwhelming amount of information to support personalized medicine—and that is usable by clinicians?”

angiogenesis than VEGF-A? VEGF-A DOES NOT ACT ALONE As tumors grow, other angiogenic factors such as VEGF-B and placental growth factor (PlGF) can also contribute to angiogenesis.1-3 Inhibiting additional angiogenic factors beyond VEGF-A has become an important area of oncology research. For additional information about the role of VEGF-A, VEGF-B, and PlGF in angiogenesis, go to www.VEGFandBeyond.com. Sanofi and Regeneron are investigating the potential impact of broad blockade of angiogenic growth factors, including VEGF-A, VEGF-B, and PlGF.

References: 1. Zhang F, Tang Z, Hou X, et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. PNAS. 2009;106:6152-6157. 2. Taylor AP, Rodriguez M, Adams K, et al. Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence. Int J Cancer. 2003;105:158-164. 3. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131:463-475. US.AFL.12.03.002 4/12 Printed in U.S.A. © 2012 sano-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

William S. Dalton, MD, PhD

A requisite network will involve providers, patients, and researchers, all of whom contribute and share information toward a clinically annotated repository for tumor and normal specimens to form the basis for evidence-based care. Moffitt is now collaborating with Oracle Corporation and 18 other hospitals to build a secure data analysis platform, called Total Cancer Care. It aggregates and analyzes data related to diagnosis, treatment, follow-up, and biospecimens for thousands of people. The system also supports analysis of


ASCOPost.com  |   APRIL 15, 2012

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Information Technology

DNA sequencing with other sources of patient information in the hope that it will result in information about outcomes in patients with common biomarkers. But there are gaps in the system. “At a time of huge scientific opportunity, it is challenging to work with so much data, and the problem is worsening,” said Brad Pollock, MPH, PhD, Henry B. Dielman Distinguished University Chair, and Chairman of the Department of Epidemiology, University of Texas Health Science Center, San Antonio. He said that a paradigm shift is occurring with the ever-increasing availability of data. We are “moving a traditional research framework of ‘hypotheses in search of data’ to ‘data in search of hypotheses.’ Historically, most novel clinical oncology discoveries have been made using a hypothesisdriven research framework employing study designs that use data efficiently.” Electronic health records often suffer from identity crises. That is, different databases in use within the same NCI-designated cancer center and do not routinely interoperate. “We need to bring clinical data up to the same standards as high-quality research data, and we need better data mining and filtering approaches for sorting through massive datasets,” said Dr. Pollock.

Envisioning the Future Leroy Hood, MD, PhD, President, Institute for Systems Biology, Seattle, who was one of the early pioneers in technology development for the Human Genome Project, said that within a decade, every human being will be surrounded by a virtual cloud of billions of data points that will make possible what he calls “P4 medicine”: Predictive—based on health history, DNA sequencing, and regular multiparameter blood measurements, which will provide the knowledge to predict one or more diseases Preventive—design of therapeutic and preventive drugs and vaccines tailored to individuals’ predictive characteristics Personalized—using unique individual genetic variations to mandate particular treatments Participatory—patient-driven social networks surrounding disease and wellness “P4 medicine will have enormous societal import and will transform every part of health care. It will shift the focus from illness to wellness and

involve a new set of technologies and ways of looking at health,” he said. He added that “Genomic identification will be standard in medical records, and when combined with phenotypic data, will provide the means to make inferences about an individual’s health and treatment of disease.” For instance: ■■ Nanotechnology approaches to protein measurement will result in tests that can evaluate 50 specific proteins from 50 organs as a way of evaluating health rather than just disease. ■■ Detailed analyses via digitization from a single cell—even a single molecule (transcriptomes, RNAomes, proteomes, metabolomes)—will reveal normal as well as disease mechanisms. This means that eventually the cost of care will

resources, software, and data over a network—will increase T-Gen’s computer sequencing and analysis capacity by 1,200%. Spyro Mousses, PhD, Director and Professor, TGen Center for Biointelligence, said that more and more health-care providers see the advantage of moving data to the cloud. Cloud computing eliminates many single silos in health information management, at the same time offering significant efficiency and cost savings. “Storage represents about 20% of the costs of health IT, so the cloud allows organizations to use only the space they need immediately,” he said McKesson Specialty Health, launched after the acquisition of US Oncology, continues to drive clinical decision support and workflow effi-

We need to bring clinical data up to the same standards as high-quality research data, and we need better data mining and filtering approaches for sorting through massive datasets. — Brad Pollock, MPH, PhD

drop to a point where it can be exported to the developing world. ■■ Computational and mathematical tools will deal with staggering amounts of data. For example, the amount of information that can be obtained from millions of people with billions of data points can provide deep fundamental insights into predictive medicine, if all of it can be stored.

Collaborations Can Work August Calhoun, PhD, Vice President, Dell Healthcare and Life Sciences Services, said that Dell is the first company of its kind to commit millions of dollars in technology and manpower to address childhood cancer through personalized medicine. It has joined with the Translational Genomics Research Institute (TGen), Phoenix, to improve treatment of pediatric neuroblastoma. “Our role is to support research to identify and share personalized treatments and to expand the first FDA-approved personalized medicine trial for pediatric cancer.” Dell’s cloud computing technology—which enables the sharing of

ciencies in iKnowMed, an affordable electronic health record for community-based practices, said Asif Ahmad, Senior Vice President, Information and Technology Services, McKesson Specialty Health. iKnowMed is now available to 1,200 physicians and more than 10,000 users, comprising almost a million patient records. It provides immediate 24/7 access to patient charts, cancer diagnosis and staging for all patients, an extensive regimen library to facilitate evidencebased treatment decisions, safety alerts when medication conflicts or high toxicity levels occur, and identification of appropriate clinical trials. The system also streamlines billing, reimbursement, and scheduling. “When our technological expertise is combined with clinical data, delivery of patient care is transformed,” said Mr. Ahmad. “The business end of a practice can be revolutionized to enhance clinical outcomes, financial results, and operational efficiency.”

Meeting the Challenges Dr. Poste suggested that because data are often trapped in hierarchical

organizational structures, more time should be devoted to rapid, real-time data access and personnel training in these skills. Moreover, new organizational structures, alliances, and business models will have to be devised. Ms. Kean proposed a coalition of stakeholders. “Disparate sectors of the research and clinical communities have a common need for data exchange that affects the overall health enterprise. We envision a nonprofit membership organization consisting of commercial, academic, and consumer stakeholders. It would encompass information-based biomedicine in which all data about clinical care are used to develop new treatments. It would nurture a community dedicated to an open framework, as well as support a flourishing system of biomedical organizations.” For example: ■■ Any organization with a data exchange need could bring a project to the coalition and trigger some or all of its activities. ■■ All data would be recorded in standards-based formats and curated through appropriate structures. ■■ Open frameworks would define standards by which technology components can interoperate. ■■ The coalition would begin with well defined projects supported by a user with a specific need. Solutions could be built in small increments, and users would provide feedback for the next cycle of development. ■■ It could serve as a broker in the biomedical system, linking those who need digital frameworks with those who provide them. ■■ Patient advocacy groups could share information about the molecular underpinnings of disease by linking biospecimen repositories. ■■ Pharmaceutical researchers could interpret and share data that lead to identification and validation of significant biomarkers. They also could gain a national clinical trials infrastructure. Pharmaceutical marketers could collaborate on reports of adverse reactions.

Disclosure: Dr. Poste is a member of the Board of Directors for Caris Life Sciences. Ms. Kean disclosed that Feinstein Kean Healthcare is a contractor to various government entities, including the National Cancer Institute, as well as to numerous life science innovator companies. Dr. Dalton is CEO of Moffitt Cancer Center and subsidiary company M2Gen. Drs. Murphy, Pollock, Shulman, Calhoun, Ms. McGraw, and Mr. Ahmad reported no potential conflicts of interest.


SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E AR S UR V IVAL R ATE I S 17 % F O R PATIENTS W ITH M E TAS TATIC S OF T TIS S UE SA RC OMA , YE T S I G N I F ICANT THER APEUTIC A D VAN CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1003549-0001


ASCOPost.com  |   APRIL 15, 2012

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Direct from ASCO

2012 Breast Cancer Symposium to Expand Tumor Board Session, Add ‘Meet the Professors’ Session Also enhanced: Poster walks, Q&A sessions

Lori J. Pierce, MD

T

he days of attending the Breast Cancer Symposium, just quietly listening to useful lectures, and then going home are over. In recent years, the meeting’s sponsors and planners have worked to make the 3-day gathering far more interactive and as intimate as a meeting with 1,500 attendees can be. “We’ve worked hard to create a much more interactive meeting. We’ve tried to make sure ours has more intimacy compared to other breast cancer meetings,” said Lori J. Pierce, MD, a radiation oncologist at the University of Michigan Comprehensive Cancer Center, a past cochair of the Breast Cancer Symposium, and current member of the symposium’s steering committee.

Bring Your Cases to the Tumor Board At this year’s meeting, in addition to showcasing the latest controversies and debates in the field and offering forward-thinking, collaborative discussions on optimizing treatment and patient care, for the first time ever, the symposium’s popular tumor board session—during which a panel of breast cancer experts discuss particularly con-

founding cases—will be extended and opened up to audience participation. “This year, audience members can bring up their difficult cases for the panel to discuss—that’s brand new,” Dr. Pierce noted. Also this year, the poster walks will be opened up to anyone who would like to join. Previously, poster walks were limited to fellows, who would follow a leading breast cancer specialist on a narrated stroll from one fascinating study to the next. Now anyone interested in enhancing their awareness of new research can join, said Dr. Pierce. This is a chance to “rub elbows” with some of the leaders in breast cancer.

ncourage your patients to review ASCO’s newly updated Managing the Cost of Cancer Care booklet, which can help them make informed treatment decisions. This resource explains the various costs associated with cancer treatment,

Along with ASCO, sponsors of the symposium include the American Society of Breast Disease, the American Society of Breast Surgeons, the American Society for Radiation Oncology, the National Consortium of Breast Centers, Inc, and the Society of Surgical Oncology. Also at the symposium, this year’s Gianni Bonadonna Breast Cancer Award recipient will be announced. The Gianni Bonadonna Breast Cancer Research Fellowship funds an early-career investigator

Volume 29, Issue 15

Meet the Professors Attendees can also participate in this year’s new Meet the Professors sessions, talking one-on-one with breast cancer experts about case management or any topic that’s weighing on them, Dr. Pierce said. In addition, the question-and-answer portion of the symposium sessions will go on longer than ever before, an enhancement made because of popular demand. “No matter how much time you allow for Q&A, there’s always desire for more,” Dr. Pierce commented. “So this time we’ve lengthened it in each session, giving attendees a chance to interact with some of the leading clinicians and practitioners in breast cancer.” Beyond the multidisciplinary educational sessions, the symposium will offer multiple opportunities to network with colleagues—interactions that can be just as valuable.

Help Your Patients Understand Cost of Care

E

Sponsors from all Disciplines

key provisions in the 2010 healthcare reform law that are now being implemented, and the financial resources available to help offset expenses related to care. The booklet is available for download at www. cancer.net/managingcostofcare, and print copies are available through the ASCO University Bookstore (www. cancer.net/estore).

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

committed to conducting breast cancer research at the awardee’s institution and under the mentorship and supervision of the awardee. It consists of a 1-year grant in the amount of $50,000.  To register for this year’s Breast Cancer Symposium, go to www. breastcasym.org, and select “Register for the Symposium.” The abstract submission deadline is May 15, 2012.

© 2012. American Society of Clinical Oncology. All rights reserved.

5 most-accessed Top 10Top most-accessed articles recently published articles published in 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO

JCO.org Testing for Discordance at Metastatic Relapse: Does It Matter?

Tumor Genetic Testing for Patient Selection in Phase I Clinical Trials: The Case of PI3K Inhibitors

ROS1 Rearrangements in Lung Cancer: A New Genomic Subset of Lung Adenocarcinoma

Selecting Individualized Treatment for Patients With Ductal Carcinoma in Situ of the Breast: The Search Continues

Molecular States Underlying Androgen Receptor Activation: A Framework for Therapeutics Targeting Androgen Signaling in Prostate Cancer


The ASCO Post  |   APRIL 15, 2012

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Direct from ASCO

ASCO Advocates for Solutions to Oncology Drug Shortage Crisis

A

SCO continues to call for three specific actions by Congress to help avert shortages of essential treat-

ments for children and adults living with cancer. ASCO President Michael P. Link, MD, outlined the priorities in

February at an FDA news briefing on the recent methotrexate and liposomal doxorubicin (Doxil) shortages.

AMG 386: Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-1: A Phase 3, Randomized, Double-Blind Trial of Weekly Paclitaxel Plus AMG 386 or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of AMG 386 With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Primary Endpoint: • Progression-free ee survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Key Secondary Endpoint: • Overall survival (OS)

Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

AMG 386 IV QW + Paclitaxel IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + Paclitaxel IV QW (3 on/1 off)

OS

R A N D O M I Z A T I O N

AMG 386 IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

AMG 386 IV QW Monotherapy

Primary

PFS

2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

Placebo IV QW Monotherapy

Key Secondary

OS

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

AMG 386 is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

For Additional Information:: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com Trials.com (20090508) T • www.ClinicalTrials.gov Trials.gov (NCT01204749) T

© 2012 Amgen Inc. All rights reserved.

AMG 386 is an investigatio i tigational agent that at has not been approved ed by the FDA for the use se underr investigatio tigation forr this ttrrial.

For Additional Informat Information on: • Amgen Call Center: (866) 57-AMGEN • www w.Amgen .AmgenT Trials.com T rials.com (20101129) • www.ClinicalTrials.gov Trials.gov T rials.gov (NCT01493505)

In his remarks, Dr. Link called for Congress to appoint a joint U.S. House and Senate bipartisan working group to develop permanent legislative solutions within 60 days. He then outlined three priorities that ASCO believes are essential to address shortages: ■■ Require advance notification of potential shortages—FDA should receive confidential notification from manufacturers of market withdrawals or manufacturing interruptions 6 months in advance, or as soon as such problems become known. This information is essential to FDA’s ability to help address manufacturing issues or to identify alternative drug sources before shortages occur. ■■ Provide economic incentives to ensure continued availability— Congress should provide incentives for companies to develop contingency plans, for example, involving alternate suppliers of raw materials and redundancies in manufacturing. Additional incentives should be considered to encourage manufacturers to enter and remain in the market for essential medications that are susceptible to shortage. ■■ Establish FDA user fees for generic drugs—Expand FDA’s authority to collect user fees from generic drug manufacturers as part of the regulatory approval process, similar to fees paid by branded drug makers. These fees should be used to ensure that FDA has the resources to quickly review applications for generic drugs either in or at risk of shortage, and speed the availability of these medicines to patients. The fees would also provide flexibility for FDA to incentivize production of key drugs, for example, by charging reduced fees for companies that demonstrate adequate contingency plans for manufacturing disruptions. ASCO will continue to call on Congress to pass legislation with these solutions. Please continue to visit ASCO in Action (ascoaction. asco.org) for the latest information on the Society’s efforts in resolving the oncology drug shortage crisis.

© 2012. American Society of Clinical Oncology. All rights reserved.


ASCOPost.com  |   APRIL 15, 2012

PAGE 45

Direct from ASCO

Research of Two 2012 Foundation Merit Award Recipients Highlighted

S

tudies led by Nathan Sheets, MD, and Mark Jesus Magbanua, PhD, were recently featured in the Genitourinary Cancers Symposium press program. Both researchers are 2012 Conquer Cancer Foundation of ASCO Merit Award recipients, and each has made noteworthy discoveries in prostate cancer.

of ASCO Merit Awards are designed to promote clinical research by young oncology scientists. Awardees are selected based on the scientific merit of their abstracts, and recipients of the

GU Merit Awards have the opporB:8.375” tunity to present their research and T:7.63” interact with other clinical investigaS:6.875” tors at the GU Symposium. Learn more about the Merit

Awards at www.conquercancerfoundation.org.

© 2012. American Society of Clinical Oncology. All rights reserved.

Radiotherapies Compared Dr. Sheets, a third-year radiation oncology resident at the University of North Carolina at Chapel Hill, and his team of researchers compared two types of radiation therapy that are designed to aim beams of radiation directly at a tumor. The researchers discovered that intensity-modulated radiation therapy is better than conventional conformal radiation therapy at reducing side effects and the recurrence of prostate cancer after treatment. In addition, intensity-modulated radiotherapy is less expensive than either conformal radiotherapy or proton-beam radiotherapy, another type of radiation therapy, which uses protons instead of x-rays to treat cancer.

Exercise–Prostate Cancer Link Dr. Magbanua, Associate Specialist in the Department of Medicine at the University of California, San Francisco, and his team found that men with early-stage prostate cancer who exercise vigorously at least 3 hours a week have genes that are expressed differently in the prostate than those who do not exercise as intensely. In two previous studies, the researchers involved in this study found links between exercise—especially vigorous activity—and a lowered risk of death from prostate cancer or worsening of the disease. The goal of this study was to try to understand why exercise showed these benefits; the results showed that vigorous exercise may help some genes work better at controlling cancer growth. The Conquer Cancer Foundation

The truth hurts. the healthcare system is broken. let’s put it back together. At Cardinal Health Specialty Solutions, we understand the financial complexities oncologists face. That’s why we’re working together with practices like yours to Specialty that Pharmaceutical Distribution develop solutions will enable you to offer the best treatment possible for GPO –Contracts Services reimbursement and reducing paperwork. your patients all while &optimizing By combining people with innovative technology, together we can Third intelligent Party Logistics Services Specialty Pharmaceutical Distribution help heal the system. Clinical Pathways GPO Contracts & Services RX Specialty Pharmacy Specialty Pharmaceutical Distribution Third Party Logistics Services

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The ASCO Post  |   APRIL 15, 2012

PAGE 46

Direct from ASCO

2012 Annual Meeting to Highlight NCI’s ‘Provocative Questions’ and Offer First-ever Pre–Annual Meeting Seminars

A

s this year’s ASCO Annual Meeting was being planned, the NCI was developing and releasing its “Provocative Questions” project— an effort to stimulate the cancer community to ask itself 24 key questions in order to advance the treatment of cancer and provide better care. It quickly became clear to ASCO’s Cancer Education Committee that the 2012 Annual Meeting’s content should delve deeply into many of the 24 questions, essentially helping the NCI spur the research community to use laboratory, clinical, and population sciences

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

in more effective and imaginative ways. “The Cancer Education Committee thought it would be helpful for clinicians, investigators, and other cancer professionals to get some perspective on what these questions are, how to think about them, and hopefully contribute to that dialogue,” said Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute and Chair of ASCO’s Cancer Education Committee.

Compelling Inquiries Among the questions are: How do public health challenges like obesity

Top 5 articles Top 10 most-accessed recently published articles published in 2011 in in Journal of Oncology Practice Journal of Clinical Oncology

What’s Hot in

JOP

jop.ascopubs.org Perspective Palliative Care: A Lifeline to Quality of Life

Health Policy Understanding Patients’ Attitudes Toward Communication About the Cost of Cancer Care

 usiness of Oncology B Productivity Assessment of Physician Assistants and Nurse Practitioners in Oncology in an Academic Medical Center

Health Care Delivery Factors Associated With Pain Among Ambulatory Patients With Cancer With Advanced Disease at a Comprehensive Cancer Center

Perspective Update on Direct-to-Consumer Marketing in Oncology

and the environment play into the risk of developing cancer? How can biologic and genomic methods help us to better understand and better treat cancer? How can we come up with drug therapies for target molecules that have historically been considered ‘undruggable’? What is the nature of resistance? “These are issues that oncologists deal with every day,” said Dr. Burstein. “The questions get to the whys and wherefores of cancer as it stands right now, and that’s what makes them so compelling.” Thus, many of the educational sessions at the 2012 Annual Meeting—to be held June 1–5 at McCormick Place in Chicago with the theme “Collaborating to Conquer Cancer”—will highlight selected provocative questions. To learn more about the sessions related to the NCI’s 24 provocative questions, visit chicago2012.asco.org.

Harold J. Burstein, MD, PhD

in Oncology for the Advanced Practice Provider seminar, cosponsored with the Association of Physician Assistants in Oncology and the Oncology Nursing Society, also provides an opportunity for advanced practice providers who usually attend separate educational events to jointly learn about the latest trends in oncology and symptom and side-effect management.

New: Q&A after Plenary Session and Core Sessions

Many attendees of the Annual New Seminars before the Meeting will be pleased to find a quesAnnual Meeting tion-and-answer session following the Also new this year is the Pre–Anplenary this year, where a to-be-deternual Meeting mined speaker will Seminar series, to discuss and answer The questions be held the afterquestions about noon of Thursday, one of the session’s get to the whys and May 31, continupractice-changing wherefores of cancer ing through noon abstracts. on Friday, June 1, Also new this as it stands right now, the first day of the year: The track and that’s what makes Annual Meeting. formerly known as them so compelling. Three seminars “General Oncolare being offered: ogy” has been re—Harold J. Burstein, MD, PhD ■■ Clinical Care named “Core Sesin Oncology sions.” Designed to for the Adhelp busy oncolovanced Practice Provider gists streamline their Annual Meeting ■■ Designs for Contemporary Earlyexperience, the Core Session track Phase Clinical Trials includes topics such as controversies ■■ New Drugs in Oncology in particular disease areas, personalThese intimate, discussion-based ized care, and new developments in the seminars will offer education on exfield. These sessions are scheduled with panded topics of interest to oncolominimal overlap. The sessions can be gists and other advanced practice found in the ePlanner under the Core providers. The seminars’ seat availSessions track listing. ability will be kept small, to encourTo learn more, and to register for age interactive sessions. the Annual Meeting and Pre–AnThe seminars are designed for the nual Meeting Seminars, visit chicaprovider who either can’t stay for the go2012.asco.org. Annual Meeting or who wants to add © 2012. American Society of Clinical more educational sessions to his or her Oncology. All rights reserved. meeting experience. The Clinical Care


CML treatment has come a long way. But not far enough. Resistance and intolerance do still occur. In fact, a post-imatinib study found 65% of patients discontinued dasatinib as a second-line therapy after 5 years.1 In another post-imatinib study, 70% of patients discontinued nilotinib after 4 years. 2 For many of these patients, unmet medical need still exists.

Visit CMLResponseProject.com to learn more. References: 1. Shah NP, Cortes JE, Schiffer CA, et al. Five-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2011; Chicago, IL. 2. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. Š2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5344512


The ASCO Post  |   APRIL 15, 2012

PAGE 48

AACR News American Association for Cancer Research

AACR Inducts Frank McCormick, PhD, FRS, DSc (hon) as President; Elects Charles L. Sawyers, MD, as President-elect, 2012-2013

L

eadership of the American Association for Cancer Research (AACR) inducted Frank McCormick, PhD, FRS, DSc (hon), as President of the society during the AACR Annual Meeting held earlier this month

Hughes Medical Institute investigator. Additionally, he is a Professor in the Cell and Developmental Biology Program and the Department

of Medicine at the Joan & Sanford Weill Graduate School of Medical Sciences of Cornell University, New York.

Advertisement

LITTLE THINGS MAY SEEM INSURMOUNTABLE FOR PATIENTS WITH CHEMOTHERAPY-INDUCED ANEMIA Frank McCormick, PhD, FRS, DSc (hon)

Dr. McCormick is the Director of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center. He holds the E. Dixon Heise distinguished professorship in oncology and the David A. Wood distinguished professorship of tumor biology and cancer research at UCSF. Additionally, he is the Associate Dean of the UCSF School of Medicine and a distinguished professor in residence in the department of microbiology and immunology as well as in the department of biochemistry and biophysics. Dr. McCormick succeeds Judy E. Garber, MD, MPH, Director of the Center for Cancer Genetics and Prevention at the Dana-Farber Cancer Institute, Associate Professor of medicine at Harvard Medical School and Associate Physician of medicine and Attending Physician of medical service at Brigham and Women’s Hospital in Boston. Dr. Garber served with distinction as AACR president for the 2011 to 2012 term and will assume the role of Past-President (2012-2013).

Charles L. Sawyers, MD, Named President-elect The members of the AACR have elected Charles L. Sawyers, MD, as their President-elect for 20122013. Dr. Sawyers is Chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center and a Howard

Renewed Commitment to Research Funding “I am deeply honored to serve as President-elect of the AACR,” said Dr.


ASCOPost.com  |   APRIL 15, 2012

PAGE 49

AACR News

Sawyers. “We are in the midst of a transformative decade in cancer research, with many new therapies emerging from our work that are improving the lives of cancer patients around the world. Yet we are at risk of failing to realize this full vision due to the economic challenges faced by our nation. Now is not the time

to cut our investment in cancer research. I will work with the outstanding staff of the AACR to get this important message to the leadership in Washington.”

AACR Members Elected to Board of Directors In addition, the members of AACR

have elected five distinguished scientists to serve on the AACR Board of Directors for the 2012 to 2015 term: Kenneth C. Anderson, MD, PhD (hon.); Lewis C. Cantley, PhD; Michelle M. Le Beau, PhD; Benjamin G. Neel, MD, PhD; and Karen H. Vousden, PhD. Charles L. Sawyers, MD

Advertisement

ACTIVE MANAGEMENT OF CANCER-RELATED ANEMIA MAY HELP REDUCE ITS OVERALL IMPACT ANEMIA IS COMMON IN CANCER PATIENTS RECEIVING CHEMOTHERAPY In patients

receiving chemotherapy, anemia (Hb < 11 g/dL) was present in over 50% of those with ovarian, breast, and non-small cell lung cancer and approximately 40% of those with colorectal and head and neck cancer.* Anemia also was observed in approximately half of patients receiving platinum-, anthracycline-, taxane-, or gemcitabine-based chemotherapy regimens.*1

SYMPTOMS OF ANEMIA ARE OFTEN DUE TO THE HYPOXIA-RELATED EFFECTS ON ORGAN FUNCTION Signs and symptoms include

pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.2,3

HEMOGLOBIN LEVELS AND PERFORMANCE SCORES ARE CORRELATED The European

Cancer Anaemia Survey, a prospective observational survey that enrolled patients regardless of disease status or cancer treatment, showed a significant correlation between Hb level and performance status at enrollment (n = 14,912 evaluable).† Though poor performance status was observed in all Hb level groups (< 8 g/dL to ≥ 12 g/dL), the lower the Hb level, the more likely patients would be ambulatory but unable to work, would stay in bed or chair more than 50% of the day, or would be totally confined to bed or chair.4,5

Hb levels significantly correlate with performance status†4,5

% OF PATIENTS

WHO score at enrollment:

n = ‡

90 80 70 60 50 40 30 20 10 0

0–1 2 (eg, ambulatory but unable to work) 3 (eg, in bed/chair > 50% of the day) 4 (eg, bed/chair bound)

84.0

75.2 60.0 49.2

8750

Mean (SD) 0.8 (0.8) WHO score

10.1

5.0 0.5

2.3 0.2 ≥ 12.0

27.7

19.3

13.5

10.0 – 11.9

8.0 – 9.9

26.7 16.0 2.2

HEMOGLOBIN LEVELS (g/dL)

< 8.0

4214

1242

187

1.0 (0.8)

1.4 (1.0)

1.7 (1.1)

8.0

PATIENTS CAN BECOME ANEMIC WITHIN THE FIRST 2 CYCLES OF CHEMOTHERAPY

When data from 1,821 patients with cancer who began receiving chemotherapy at Hb ≥ 12 g/dL were analyzed to determine relative risk for anemia, 62% of patients experienced a Hb decline of 1.5 g/dL within a median of 6.1 to 7.2 weeks and 51% had a Hb decline of 2 g/dL within a median of 7.3 to 8.9 weeks.6 Low Hb levels have been associated with an increased likelihood of chemotherapy dose delays and dose reductions.7 How might clinicians reduce the overall impact of anemia?

PATIENT EDUCATION IS AN IMPORTANT ASPECT OF ACTIVE ANEMIA MANAGEMENT

NCCN recommends that Hb levels ≤ 11 g/dL or ≥ 2 g/dL below baseline prompt an evaluation of anemia in order to characterize the anemia and correct any underlying comorbidities. At this point, a detailed history, physical, and further laboratory tests are suggested, which include a CBC with indices, onset of symptoms (eg, syncope, dyspnea, headache, fatigue), comorbidities, and exposure to antineoplastic drugs and radiation.8 ASCO/ASH recommends that clinicians also discuss the benefits and harms of therapeutic options with patients undergoing myelotoxic chemotherapy who become anemic.9

For more information about chemotherapy-induced anemia, please visit anemia.com/professional/cia. *N (anemia patients evaluated) = 42,923. Data from January 1, 2000, through December 31, 2007, from a retrospective, observational, cohort study of 47,159 adult patients with cancer were obtained through electronic medical records at community and hospital-affiliated clinical oncology practices throughout the United States. The mean baseline Hb prior to initiating chemotherapy was 12.4 g/dL across all tumor types. †Observational, prospective, multisite survey of patients with solid or hematological tumors. Survey enrollment was conducted from January to July 2001, with data collected for up to 6 data points or 6 months of scheduled clinic visits. ‡Missing data for n = 519. References: 1. Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L. Clin Ther. 2009;31:2416-2432. 2. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Available at: http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed March 30, 2011. 3. Ludwig H, Strasser K. Semin Oncol. 2001;28:7‐14. 4. Ludwig H, Van Belle S, Barrett-Lee P, et al. Eur J Cancer. 2004;40:2293-2306. 5. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. 1979. Available at: http://whqlibdoc.who.int/offset/WHO_OFFSET_48. pdf. Accessed February 17, 2011. 6. Barrett-Lee J, Ludwig H, Birgegård G. Oncology. 2006;70:34-48. 7. Repetto L. Crit Rev Oncol Hematol. 2009;72:170-179. 8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia. v2.2012. Available at: http://www.nccn.org. Accessed September 28, 2011. 9. Rizzo DJ, Brouwers M, Hurley P, et al. J Clin Oncol. 2010;28:4996-5010.

©2011 Amgen. All rights reserved. 62288-R1-V2

Kenneth C. Anderson, MD, PhD (hon), is the Kraft Family Professor of Medicine, Vice Chair of the Joint Program in Transfusion Medicine and Research Associate of the Center for Blood Research at Harvard Medical School. Dr. Anderson is also the Director of the Lebow Institute for Myeloma Therapeutics, Director of the Jerome Lipper Multiple Myeloma Center, Medical Director of the Blood Component Laboratory, Attending Physician of the Bone Marrow Transplantation Service, Associate Professor of Medicine at Dana-Farber Cancer Institute, Associate Medical Director at Brigham and Women’s Hospital Blood Bank and Associate Physician at Brigham and Women’s Hospital, Boston. Lewis C. Cantley, PhD, is Director of the Beth Israel Deaconess Cancer Center in Boston, Professor of Systems Biology at Harvard Medical School and Chief of the Division of Signal Transduction at Beth Israel Deaconess Medical Center. Michelle M. Le Beau, PhD, is the Arthur and Marian Edelstein Professor in the department of medicine, section of hematology/oncology, Director of the University of Chicago Comprehensive Cancer Center and Director of the Cancer Cytogenetics Laboratory at the University of Chicago. Benjamin G. Neel, MD, PhD, is Director of the Ontario Cancer Institute at University Health Network, which includes The Campbell Family Cancer Research Institute at Princess Margaret Hospital. He is also Professor in the department of medical biophysics at the University of Toronto and holds a Tier 1 Canada Research Chair in signal transduction and disease. Karen H. Vousden, PhD, is Director of the Beatson Institute for Cancer Research in Glasgow, Scotland.


The ASCO Post  |   APRIL 15, 2012

PAGE 50

JCO Spotlight Prostate Cancer

New Biomarker Predicts Survival in Advanced Prostate Cancer By Alice Goodman

R

esearchers at Memorial SloanKettering Cancer Center have developed the Bone Scan Index (BSI), which is the first quantitative imaging response biomarker that can assess response to treatment and prognosticates for survival in men with metastatic castration-resistant prostate cancer.

Based on Bone Scintigraphy “We have shown for the first time that it is possible to develop a quantitative imaging response biomarker for assessing treatment effects in bone. The BSI, which is based on bone scintigraphy, can express as See Page 93 a single number the amount of disease progression or regression as a result of treatment for patients with metastatic

castration-resistant prostate cancer,” said Michael J. Morris, MD, of Memorial Sloan-Kettering Cancer Center, New York. Dr. Morris is senior author of this study, which was recently published in the Journal of Clinical Oncology.1 Prior to development of the Bone Scan Index, there was no reproducible or quantifiable way to describe responses using bone scans. As Dr. Morris explained, bone scintigraphy is an imperfect tool that images the bone, not the cancer itself, and for which there are few standard descriptors of post-treatment changes. “The bone scan shows the derivative effect on the bone surrounding the metastasis,” he said. “And we do not have a standard quantitative expression that tells us whether a patient is responding to treatment. The BSI is such an expression. It is a single quan-

EXPERT POINT OF VIEW

“T

he Bone Scan Index (BSI) is a very important new quantitative imaging biomarker to help us better assess patients with metastatic prostate cancer in a robust and reproducible way, particularly those with bone-dominant disease,” said Lawrence Schwartz, MD, Chair of the Department of Radiology at Columbia University School of Medicine, New York. The BSI is prognostic for survival, and also indicates which patients are experiencing disease proLawrence Schwartz, MD gression on therapy in a reproducible and quantitative manner, he continued. “Potentially, the marker would affect the course of therapy. It would enable you to tell earlier whether a patient is progressing and whether changes in therapy are needed, and also this tool can tell you whether a different therapy is working,” Dr. Schwartz explained. Once the Bone Scan Index is validated in further study with other therapeutics, and it is automated, Dr. Schwartz believes that it will become widely adapted. “In general, [the trend is for] imaging to become more quantitative, and this is another good step in that direction,” he said.

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

Bone Scan Index to Assess Treatment Response in Prostate Cancer ■■ The Bone Scan Index (BSI) is a quantitative biomarker based on tumor

burden in the bone that can assess response to treatment and is prognostic for survival in metastatic castration-resistant prostate cancer.

■■ BSI is the first imaging response biomarker with this ability. ■■ BSI was superior to PSA, the method traditionally used to assess response. ■■ Once BSI is automated, it can be used on a widespread basis. titative output that describes all the lesions in a patient’s body, rising or falling depending on how a patient is responding to treatment. These posttreatment fluctuations prognosticate for survival.” The Bone Scan Index is a method of expressing the tumor burden in bone as a percentage of the total skeletal mass based on “reference man” skeletal masses. (Created in 1974 by the International Commission on Radiological Protection, reference man provides a standard set of biologic characteristics modeled on a hypothetical young Caucasian male.) The study describes an association between BSI and survival. Bone scans of 88 men with metastatic castration-resistant prostate cancer who were enrolled in four clinical trials were analyzed to calculate BSI at baseline and 3 and 6 months on treatment. The percent change in BSI from baseline to 3 and 6 months was prognostic for survival. A doubling in BSI was associated with almost a twofold increase in risk of death.

Compared with PSA When Bone Scan Index was compared with prostate-specific antigen (PSA)—the traditional method of determining response to treatment—change in PSA was not prognostic for survival. “We compared PSA head-to-head with BSI, and found that BSI was a more accurate indicator of treatment

benefit,” Dr. Morris stated. “Even older imaging modalities like bone scintigraphy can be analyzed correctly and

Michael J. Morris, MD

developed as quantitative imaging biomarkers that capture important survival information, and appear to be superior to traditional methods like PSA.” Dr. Morris and colleagues are now working on automating the Bone Scan Index so that it is computer-generated instead of being computed manually. “When that automation is ready for prime time, every clinician out there will be able to use BSI as a response biomarker,” he stated.

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

Reference 1. Dennis ER, Jia X, Stephenson RD, et al: Bone scan index: A quantitative treatment response biomarker for castrationresistant metastatic prostate cancer. J Clin Oncol. January 9, 2012 (early release online).

Don’t Miss These Important Reports Inside this Issue of The ASCO Post Genitourinary Oncology see pages 20, 22, and 24

Lung Cancer

see pages 29, 30, and 37

Breast Cancer

see pages 15, 52, and 63


Now Enrolling

The Medical Division at Lilly Oncology is currently enrolling patients in a phase 3 trial of the VEGF receptor-2 antagonist ramucirumab (IMC-1121B)

REACH*: A Second-line Hepatocellular Carcinoma (HCC) Trial

Randomization

• H CC after progression on or intolerance to first-line sorafenib • C hild-Pugh score of <9 (Child-Pugh A or B [B7 or B8]) • A t least 1 measurable or evaluable viable lesion not previously treated with locoregional therapy

N=~544

Best supportive care + blinded ramucirumab 8 mg/kg IV infusion every 2 weeks

Best supportive care + blinded placebo 8 mg/kg IV infusion every 2 weeks

Treat until progressive disease, intolerable toxicity, noncompliance, withdrawal of consent, or investigator decision

Study Objectives Primary endpoint:

Secondary endpoints:

• Overall survival (OS)

• Progression-free survival (PFS)

• Safety profile of ramucirumab

• Best objective response rate (ORR)

• Ramucirumab serum concentrations

• Time to radiographic progression

• Pharmacodynamics of ramucirumab

• P atient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life

• Immunogenicity of ramucirumab

For further information, please contact ImClone Systems by e-mail at ClinicalTrials@imclone.com or visit www.clinicaltrials.gov (identifier number NCT01140347). Note that, for an investigator to participate, the study must be approved by the investigator’s country competent health authority. Ramucirumab (IMC-1121B) is an investigational new drug. The safety and efficacy of ramucirumab have not been established for the use under investigation. There is no guarantee that ramucirumab will receive regulatory approval and become commercially available for the use under investigation.

* REACH: A Multicenter, Randomized, Double-blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) versus Placebo and BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma Following First-line Therapy With Sorafenib

March 2012 All rights reserved. MAP 7166-46730


The ASCO Post  |   APRIL 15, 2012

PAGE 52

Expert’s Corner

Advances in Axillary Surgery for Patients with Breast Cancer A Conversation with Barbara L. Smith, MD, PhD By Caroline Helwick main. In an interview with The ASCO Post, Barbara L. Smith, MD, PhD, a surgical oncologist and Director of the Breast Program at Massachusetts General Hospital, Boston, offered her perspective on some of the key issues and remaining questions regarding sentinel node biopsy and axillary surgery in 2012.

comes from such studies have confirmed that sentinel node mapping accurately identifies node-positive patients and is therefore an effective staging tool. What is the rate of axillary failure after a negative sentinel node biopsy? Long-term follow-up of some of these same studies showed that axillary recurrence rates are extremely low in patients with a negative sentinel node biopsy, and are no higher after sentinel node biopsy alone than after axillary lymph node dissection. Axillary recurrence rates were 0.4% with dissection and 0.7% with sentinel node biopsy in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial,2 and 0% and 0.8%, respectively, in the Veronesi study.4 Overall survival was also similar, at 90% to 93%, respectively.

Accuracy of Sentinel Node Mapping Barbara L. Smith, MD, PhD

R

esults from the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, which found no benefit for completion axillary nodal dissection in patients with breast cancer involving one to two positive sentinel nodes,1 have led to changes in breast cancer management, though points of discussion re-

How confident can clinicians be today that sentinel node mapping is effective? Success rates with sentinel node– mapping range from 95% to 99%, with false-negative rates generally less than 10%. In three studies that provided data from sentinel node biopsy and axillary lymph node dissection, the percentage of nodepositive patients was essentially the same with either approach.2-4 Out-

Why would the axillary recurrence rates be so low, if the false-negative rate with sentinel node biopsy is about 10%? We know that not all positive axillary nodes will progress and become clinically significant. Also, sentinel node–positive patients often receive tangent radiation to cover the axilla, which sterilizes tumor deposits, and patients almost always receive systemic therapy, which we know contributes to local control.

Role of Local Therapy What happens if these additional components of treatment are eliminated? This is an important question, because it applies to patients with negative sentinel nodes who have mastectomy without radiation, or, increasingly, have accelerated partial breast irradiation rather than whole-breast irradiation. continued on page 54

International Study Confirms ACOSOG Z0011

P

reliminary findings of the International Breast Cancer Study Group (IBCSG) 23-01 trial1 show no benefit for axillary lymph node dissection in patients with only minimally involved sentinel nodes, thereby supporting the results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial.2 IBCSG 23-01 results were reported at the 2011 San Antonio Breast Cancer Symposium by Viviana Galimberti, MD, of the European Institute of Oncology in Milan, Italy. “It seems likely that IBCSG 2301 and ACOSOG Z0011 will change clinical practice, allowing no axillary lymph node dissection in early breast cancer, especially when the sentinel node is minimally involved,” Dr. Galimberti said. “This will reduce complications from axillary dissection without an adverse effect on survival.”

tioned at 50- to 100-μm intervals, and all sections were examined. Patients were randomly assigned to have axillary lymph node dissection or sentinel node biopsy only. The intent-to-treat population consisted of 931 patients, and after a median follow-up of 57 months there were 98 events. Approximately two-thirds had tumors <  2  cm, more than 80% were estrogen receptor–positive, 90% underwent breast-conserving surgery

was observed in one patient (0.2%) and five patients (1.1%), respectively. The 5-year overall survival rate was 98% in each arm.

Study Implications “There was no difference in the primary endpoint, disease-free survival, which fulfilled the protocol-specified criterion for noninferiority,” Dr. Galimberti reported. She added that disease-free survival was higher (88%)

Our results are preliminary and we must wait for the full analysis. Nevertheless, we have robust data suggesting that from now on, we may not need to do axillary dissection in patients with minimally involved sentinel nodes. —Viviana Galimberti, MD

Design and Data IBCSG 23-01 was designed to determine whether axillary lymph node dissection is necessary in patients with tumor ≤ 5 cm and minimal sentinel node involvement, defined as one or more micrometatastic sentinel nodes (≤  2 mm). On permanent or frozen samples, each node was entirely sec-

and radiotherapy, and two-thirds had hormonal therapy without chemotherapy. The 5-year disease-free survival rate was 87.3% in patients undergoing axillary lymph node dissection and 88.4% for those with sentinel node biopsy alone (P  = .48). Regional recurrence

than anticipated (70%), and there was an unexpectedly low rate of reappearance of tumor in the undissected axilla (1.1%). “This is an important trial, but our results are preliminary and we must wait for the full analysis,” she said. “Nevertheless, we have robust data

Viviana Galimberti, MD

suggesting that from now on, we may not need to do axillary dissection in patients with minimally involved sentinel nodes.”

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

References 1. Galimberti V, Cole BJ, Zurrida S, et al: Update of International Breast Cancer Study Group trial 23-01 to compare axillary dissection versus no axillary dissection in patients with clinically node negative breast cancer and micrometastases in the sentinel node. 2011 San Antonio Breast Cancer Symposium. Abstract S3-1. Presented December 8, 2011. 2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis. JAMA 305:569-575, 2011.


Don’t miss the latest program

FOLOTYN® (pralatrexate injection): An Antifolate for Patients With Relapsed or Refractory PTCL Indication FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The indication for FOLOTYN is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated.

Francine Foss, MD Professor of Medical Oncology Co-Director, Lymphoma, Leukemia & Myeloma Program Yale Cancer Center New Haven, Connecticut

Listen to Dr. Foss discuss these topics and more: Design and results of the PROPEL study: the first large, prospective, single-arm, open-label, international trial ever conducted for relapsed or refractory PTCL

Safety and efficacy profile of an antifolate in the treatment of relapsed or refractory PTCL

Overall response rate, median time to first response, and duration of response to treatment of relapsed or refractory PTCL

Important Safety Information for FOLOTYN® (pralatrexate injection) Warnings and Precautions • FOLOTYN may suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Monitor blood counts and omit or modify dose for hematologic toxicities. • Mucositis may occur. If ≥Grade 2 mucositis is observed, omit or modify dose. Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis. • Fatal dermatologic reactions may occur. Dermatologic reactions may be progressive and increase in severity with further treatment. Patients with dermatologic reactions should be monitored closely, and if severe, FOLOTYN should be withheld or discontinued. • Tumor lysis syndrome may occur. Monitor patients and treat if needed. • FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN and pregnant women should be informed of the potential harm to the fetus. • Use caution and monitor patients when administering FOLOTYN to patients with moderate to severe renal function impairment.

• Elevated liver function test abnormalities may occur and require monitoring. If liver function test abnormalities are ≥Grade 3, omit or modify dose. Adverse Reactions • The most common adverse reactions were mucositis (70%), thrombocytopenia (41%), nausea (40%), and fatigue (36%). The most common serious adverse events were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. Use in Specific Patient Population • Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother. Drug Interactions • Co-administration of drugs subject to renal clearance (e.g., probenecid, NSAIDs, and trimethoprim/sulfamethoxazole) may result in delayed renal clearance. Please see accompanying brief summary of Prescribing Information.

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The ASCO Post  |   APRIL 15, 2012

PAGE 54

Expert’s Corner

Barbara L. Smith, MD, PhD

nel nodes (n = 325) or isolated tumor cells only (n = 40), and none received radiation. Systemic therapy was given to all patients with invasive cancers and to 35% who underwent mastectomy for ductal carcinoma in situ. At 70 months follow-up, recurrences were observed in only two patients with

continued from page 52

We looked at this at our institution in 487 clinically node-negative patients who underwent sentinel node biopsy, with a median of two nodes removed, then underwent mastectomy.5 There were 365 patients with negative senti-

Brief summary of Full Prescribing Information for FOLOTYN® (pralatrexate injection)—Please consult Full Prescribing Information. INDICATIONS AND USAGE FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progressionfree survival or overall survival has not been demonstrated. WARNINGS AND PRECAUTIONS Bone Marrow Suppression FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose. Mucositis Treatment with FOLOTYN may cause mucositis. If ≥Grade 2 mucositis is observed, omit dose and follow guidelines in Table 1. Dermatologic Reactions FOLOTYN has been associated with severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients [2.1%]) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). These reactions may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Patients with dermatologic reactions should be monitored closely, and if severe, FOLOTYN should be withheld or discontinued. Tumor Lysis Syndrome Tumor lysis syndrome has been reported in patients with lymphoma receiving FOLOTYN. Patients receiving FOLOTYN should be monitored closely and treated for complications. Folic Acid and Vitamin B12 Supplementation Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis. Pregnancy Category D FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. 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. Decreased Renal Function Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure. No data are available to safely guide the use of FOLOTYN in patients with end stage renal diease undergoing dialysis and therefore its use in these patients is not recommended. Elevated Liver Enzymes Liver function test abnormalities have been observed after FOLOTYN administration. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function. ADVERSE REACTIONS The most common adverse reactions observed in patients with peripheral t-cell lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia, nausea, and fatigue. 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 reflect the rates observed in practice. The safety of FOLOTYN was evaluated in 111 PTCL patients in a single-arm clinical study in which patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range 1-540 days). Most Frequent Adverse Reactions Table 4 summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0). Table 4 Adverse Reactions Occurring in PTCL Patients (Incidence ≥10% of patients) N=111 Total Preferred Term Any Adverse Event

Grade 3

Grade 4

N

%

N

%

N

%

111

100

48

43

34

31

Mucositisa

78

70

19

17

4

4

Thrombocytopeniab

45

41

15

14

21

19b

Nausea

44

40

4

4

0

0

Fatigue

40

36

5

5

2

2

Anemia

38

34

17

15

2

2

Constipation

37

33

0

0

0

0

Pyrexia

36

32

1

1

1

1

Edema

33

30

1

1

0

0

Cough

31

28

1

1

0

0

Epistaxis

29

26

0

0

0

0

Vomiting

28

25

2

2

0

0

Neutropenia

27

24

14

13

8

7

Diarrhea

23

21

2

2

0

0

Dyspnea

21

19

8

7

0

0

Anorexia

17

15

3

3

0

0

Preferred Term

N

%

N

%

N

%

Hypokalemia

17

15

4

4

1

1

N=111 Total

Grade 3

Grade 4

Rash

17

15

0

0

0

0

Pruritus

16

14

2

2

0

0

Pharyngolaryngeal pain

15

14

1

1

0

0

Liver function test abnormalc

14

13

6

5

0

0

Abdominal pain

13

12

4

4

0

0

Pain in extremity

13

12

0

0

0

0

Back pain

12

11

3

3

0

0

Leukopenia

12

11

3

3

4

4

Night sweats

12

11

0

0

0

0

Asthenia

11

10

1

1

0

0

Tachycardia

11

10

0

0

0

0

Upper respiratory tract infection

11

10

1

1

0

0

Stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts b Five patients with platelets <10,000/µL c Alanine aminotransferase, aspartate aminotransferase, and transaminases increased a

Serious Adverse Events Forty-four percent of patients (n=49) experienced a serious adverse event while on study or within 30 days after their last dose of FOLOTYN. The most common serious adverse events (>3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all FOLOTYN trials at doses ranging from 30 to 325 mg/m2. Discontinuations Twenty-three percent of patients (n=25) discontinued treatment with FOLOTYN due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n=7) and thrombocytopenia (5%, n=5). Dose Modifications The target dose of FOLOTYN was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n=77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered. Post Marketing Experience Toxic epidermal necrolysis has been identified during post approval use of FOLOTYN. 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 (see Warnings and Precautions). DRUG INTERACTIONS No formal clinical assessments of pharmacokinetic drug-drug interactions between FOLOTYN and other drugs have been conducted. The effect of coadministration of the uricosuric drug probenecid (an inhibitor of multiple transporter systems including the multidrug resistance-associated protein 2 (MRP2) efflux transporter) on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in delayed clearance of pralatrexate and a commensurate increase in exposure. When administering FOLOTYN to patients receiving probenecid or other drugs that may affect relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due to increased drug exposure. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D (see Warnings and Precautions). FOLOTYN can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/ day (0.36 mg/m2/day or about 1.2% of the clinical dose on a mg/m2 basis) given on gestation days 7 through 20. Treatment with pralatrexate caused a dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. There was also a dose-dependent increase in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/m2/ day) or greater given on gestation days 8 through 21 also caused abortion and fetal lethality. This toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses. 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. Nursing Mothers It is not known whether pralatrexate 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 this drug, a decision should be made whether to discontinue nursing or to discontinue FOLOTYN, taking into account the importance of FOLOTYN to the mother. Pediatric Use Pediatric patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established. Geriatric Use In the PTCL efficacy study, 36% of patients (n=40) were 65 years of age and over. No overall differences in efficacy and safety were observed in patients based on age (<65 years compared with ≥65 years). No dosage adjustment is required in elderly patients with normal renal function. Hepatic Impairment Formal studies have not been performed with FOLOTYN in patients with hepatic impairment. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical trials: total bilirubin >1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT)

negative sentinel nodes (0.6%) and in none of the patients with isolated tumor cells, even though these patients did not receive radiation. Both relapses were in patients with extensive highgrade ductal carcinoma in situ who did not receive systemic therapy. These data and data from mastecto-

>2.5 × upper limit of normal (ULN); and AST or ALT >5 × ULN if documented hepatic involvement with lymphoma. Renal Impairment See Warnings and Precautions. OVERDOSAGE No specific information is available on the treatment of overdosage of FOLOTYN. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on FOLOTYN’S mechanism of action the prompt administration of leucovorin should be considered. PATIENT COUNSELING INFORMATION See FDA-approved Patient Package Insert. Patients should be instructed to read the Patient Package Insert carefully. DOSAGE AND ADMINISTRATION FOLOTYN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Peripheral T-cell Lymphoma The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous (IV) push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. Vitamin Supplementation Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of FOLOTYN, and dosing should continue during the full course of therapy and for 30 days after the last dose of FOLOTYN. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with FOLOTYN (see Warnings and Precautions). Monitoring and Dose Modifications Management of severe or intolerable adverse reactions may require dose omission, reduction, or interruption of FOLOTYN therapy. Monitoring Complete blood cell counts and severity of mucositis should be monitored weekly. Serum chemistry tests, including renal and hepatic function, should be performed prior to the start of the first and fourth dose of a given cycle. Dose Modification Recommendations Prior to administering any dose of FOLOTYN: • Mucositis should be ≤Grade 1. • Platelet count should be ≥100,000/µL for first dose and ≥50,000/µL for all subsequent doses. • Absolute neutrophil count (ANC) should be ≥1,000/µL. Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in Tables 1, 2, and 3. Table 1 FOLOTYN Dose Modifications for Mucositis

a

Mucositis Gradea on Day of Treatment

Action

Dose upon Recovery to ≤Grade 1

Grade 2

Omit dose

Continue prior dose

Grade 2 recurrence

Omit dose

20 mg/m2

Grade 3

Omit dose

20 mg/m2

Grade 4

Stop therapy

Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities Blood Count on Day of Treatment Platelet <50,000/µL

Duration of Toxicity 1 week

Action Omit dose

Dose upon Restart Continue prior dose

2 weeks

Omit dose

20 mg/m2

3 weeks

Stop therapy

ANC 500-1,000/µL 1 week and no fever

Omit dose

Continue prior dose

Omit dose, give G-CSF or GM-CSF support Omit dose, give G-CSF or GM-CSF support

Continue prior dose with G-CSF or GM-CSF support 20 mg/m2 with G-CSF or GM-CSF support

1 week ANC 500-1,000/µL with fever 2 weeks or or recurrence ANC <500/µL 3 weeks or Stop therapy 2nd recurrence

Table 3 FOLOTYN Dose Modifications for All Other Treatment-related Toxicities

a

Toxicity Gradea on Day of Treatment

Action

Dose upon Recovery to ≤Grade 2

Grade 3

Omit dose

20 mg/m2

Grade 4

Stop therapy

Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0)

Manufactured for: Allos Therapeutics, Inc. Westminster, CO 80020 1-888-ALLOS88 (1-888-255-6788) FOLOTYN, ALLOS, and the mobius triangle symbol are all registered trademarks of Allos Therapeutics, Inc. U.S. Patent: 6,028,071 and 7,622,470 Rev.6: February 2012 © 2012 Allos Therapeutics, Inc. All rights reserved.

my patients suggest that negative sentinel nodes really do not need additional local therapy. But, importantly, most patients in these studies received systemic therapy, which is likely a major contributor to local control in sentinel node biopsy patients. So, to sum up, what can be concluded about negative sentinel nodes? Large randomized trials solidly confirm that a negative sentinel node biopsy provides staging and prognostic information equivalent to a negative axillary lymph node dissection. Survival after a negative sentinel node biopsy is equivalent to survival after a negative axillary dissection. For clinically nodenegative patients, sentinel node biopsy is the standard of care for staging.

Occult Metastasis How concerned should clinicians be about nodes containing isolated tumor cells, which can’t be classified as “positive” or “negative”? A key part of sentinel node biopsy is enhanced pathologic assessment, usually with serial sections and immunohistochemistry. These techniques can identify very small tumor deposits that traditional H&E staining can miss. But how frequently is the sentinel node found to be immunohistochemistrypositive after it’s been shown to be H&E-negative? In other words, what is the frequency of occult sentinel node metastasis? In ACOSOG Z0010, the rate was 10%,6 and in NSABP B-32, it was about 16%.7 ACOSOG Z0010 assessed the impact of these occult metastases and found that survival at 5 years was significantly lower in patients with H&Epositive sentinel nodes (93%) than in those with H&E-negative nodes (96%; P = .0002). However, when stratifying the H&E-negative nodes by immunohistochemistry status, no difference in overall survival was shown (95% vs 96%; P = .53).6 The investigators concluded that tumor deposits identified only on immunohistochemistry had no impact on prognosis in patients as they are currently treated. And in B-32,7 a significant reduction in overall, disease-free, and distant disease-free survival was shown, but the absolute magnitude of the differences was extremely small. The 5-year overall survival difference was just 1.2%. The authors concluded that occult metastases were an independent prognostic factor, but that there was no clinical benefit to routine immunohistochemistry in H&E-negative sentinel


ASCOPost.com  |   APRIL 15, 2012

PAGE 55

Expert’s Corner

Table 1: Patients Requiring Axillary Dissection Axillary node dissection is recommended for the following situations:

■■ Clinically node-positive disease ■■ Inflammatory breast cancer that is locally advanced ■■ Three or more positive nodes

biopsy arm, but after sentinel node biopsy alone, only 0.9% had axillary relapse. All patients received whole-breast irradiation, and at least 96% per arm received systemic treatment. This is important to keep in mind.

■■ Residual palpable nodes after sentinel node biopsy

Change in Practice

■■ Gross extranodal tumor extension

So, which patients still need an axillary dissection, and for whom can it be safely eliminated? Sentinel node biopsy can now replace dissection for lumpectomy patients with negative nodes undergoing either lumpectomy or mastectomy. Sentinel node biopsy can also replace dissection for lumpectomy patients with one to two positive sentinel nodes where data on the precise number of additional positive axillary nodes is not needed for treatment decisions. At present, we still recommend axillary lymph node dissection for patients with palpable axillary nodes, three or more positive sentinel

■■ Patients who are sentinel node biopsy–positive and undergoing mastectomy

■■ Patients receiving neither radiotherapy nor systemic therapy ■■ When information from dissection could change therapy ■■ When no sentinel node is identified nodes. Nodal staging should be based on the size of the metastatic deposit, not the means of detection.

Who Requires Axillary Dissection? For patients with a positive sentinel node, when is axillary dissection necessary? It used to be standard for a patient with a positive sentinel node to have complete axillary lymph node dissection, but ACOSOG Z0011 showed otherwise. Patients in the Z0011 trial had clinical N0, T1-2 tumors, H&Edetected sentinel node metastases, lumpectomy with whole-breast irradiation, and adjuvant systemic therapy. For patients meeting the eligibility criteria, the local recurrence risk was remarkably low after sentinel node biopsy only. At a median follow-up of 6.3 years, the local (in-breast) recurrence rate was 3.6% after axillary lymph node dissection and 1.8% after sentinel node biopsy. Regional node recurrence rates were 0.5% and 0.9%, respectively, and total locoregional recurrence rates were 4.1% and 2.8%, respectively (P = .11). Overall and disease-free survival rates were also not significantly different. At the 2011 San Antonio Breast Cancer Symposium, we heard confir-

mation of these findings in an update of the International Breast Cancer Study Group Trial 23-01 (see sidebar).8 The study compared axillary lymph node dissection and sentinel node biopsy alone and found no difference in 5-year disease-free survival (88% per arm). The axillary relapse

Many of us in practice embrace the Z0011 results and thus reserve axillary dissection for patients not meeting Z0011 criteria and those with gross disease upon palpation. This change in practice is a real quality-of-life advance for our patients. —Barbara L. Smith, MD, PhD

rate was only about 1% after sentinel node biopsy. ACOSOG Z0011 concluded that for clinically node-negative patients who have one or two positive sentinel nodes and undergo radiotherapy and systemic therapy, the routine use of axillary node dissection is no longer justified, but adjunctive therapies clearly played a role in disease control in that trial. In the axillary lymph node dissection arm, 27% of patients were found to have additional positive nodes, and we can assume the same would be true in the sentinel node

nodes, gross extranodal tumor and positive sentinel nodes after neoadjuvant therapy, or when patients undergoing mastectomy have positive nodes (Table 1). We are likely to see trials comparing radiation to dissection in such patients. Many of us in practice embrace the Z0011 results and thus reserve axillary dissection for patients not meeting Z0011 criteria and those with gross disease upon palpation. This change in practice is a real quality-of-life advance for our patients.

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

References 1. Guiliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis. JAMA. 305:569-575, 2011. 2. Krag DN, Anderson SJ, Julian TB, et al: Technical outcomes of sentinel-lymphnode resection and conventional axillarylymph-node dissection in patients with clinically node-negative breast cancer: Results from the NSABP B-32 randomized phase III trial. Lancet Oncol 8:881-888, 2007. 3. Mansel RE, Fallowfield L, Kissin M, et al: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC trial. J Natl Cancer Inst 98:599-609, 2006. 4. Veronesi U, Paganelli G, Viale G, et al: A randomized comparison of sentinel node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349:546-553, 2003. 5. Fiedler AG, Covarrubias FD, Kim E, et al: Risk of axillary recurrence after a negative sentinel node biopsy without radiation: Implications for partial breast irradiation. 2010 Breast Cancer Symposium. Abstract 22. Presented October 2, 2012. 6. Cote R, Giuliano AE, Hawes D, et al: ACOSOG Z0010: A multicenter prognostic study of sentinel node and bone marrow micrometastases in women with clinical T1/T2 N0M0 breast cancer. J Clin Oncol 28(18S):Abstract CRA504, 2010. 7. Weaver DL, Ashikaga T, Krag DN, et al: Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med 364:412-421, 2011. 8. Galimberti V, Cole BF, Zurrida S, et al: Update of International Breast Cancer Study Group Trial 23-01 to compare axillary dissection versus no axillary dissection in patients with clinically node negative breast cancer and micrometastases in the sentinel node. 2011 San Antonio Breast Cancer Symposium. Abstract S3-1. Presented December 8, 2011.

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The ASCO Post  |   APRIL 15, 2012

PAGE 56

Opinion Hematology

Treating Acute Promyelocytic Leukemia without Chemotherapy By Farhad Ravandi, MD

T

hroughout the course of medical history, we have witnessed innovations that have initially been met with skepticism but have later revolutionized our management of patients with specific disorders. The recent history of oncology drug development is full of instances where a drug that was effectively used as salvage therapy was clearly demonstrated to be better than the established “standard” in the initial treatment of the same disease. Examples of this include tyrosine kinase inhibitors in Philadelphia chromosome– positive acute lymphoblastic leukemia, second-generation tyrosine kinase inhibitors in chronic myeloid leukemia, fludarabine in chronic lymphocytic leukemia, cladribine in hairy cell leukemia, and thalidomide (Thalomid) in multiple myeloma. For obvious ethical reasons, the natural course of drug development in oncology follows the path from salvage to front-line therapy. An agent that is able to effectively salvage patients for whom the “standard” initial therapy has failed is likely to be more potent and associated with a higher likelihood of achieving a response in the front-line setting, particularly if used in combination with other established effective drugs.

All-trans Retinoic Acid and Arsenic Trioxide The introduction of all-trans retinoic acid (ATRA) clearly revolutionized the treatment of acute promyelocytic leukemia (APL), improving response rates and disease-free and overall survival, particularly when ATRA was also used for maintenance.1 Single-agent ATRA is, however, associated with rapid development of resistance and relapse, and initial randomized trials clearly demonstrated that the combination of ATRA with chemotherapy was superior. However, despite the significant advantage of regimens combining chemotherapy and ATRA, relapses do occur in a proportion of patients, necessitating second-line therapy, namely arsenic trioxide (Trisenox).2 A brief look at recent trials involving the use of arsenic trioxide in the treatment of APL clearly demonstrates that the drug has followed the typical path from salvage

to front-line therapy. Early studies in the salvage setting demonstrated arsenic trioxide to be very potent against this disease. In the U.S. multicenter phase II study that led to its approval, 85% of patients with relapsed APL treated with single-agent arsenic trioxide, achieved a complete response, with the majority achieving a complete molecular response.2 This compares favorably with the complete response rates achieved using single-agent anthracyclines (hitherto the most effective agents against APL cells) in earlier clinical trials, establishing arsenic trioxide as the most potent single agent against APL. A number of studies have examined the potential role of arsenic trioxide in the initial treatment of patients with APL. In studies conducted by Indian

therapy. We conducted a phase  II trial of arsenic trioxide plus ATRA with or without gemtuzumab ozogamicin (Mylotarg) in patients with high-risk disease, and have demonstrated the feasibility and efficacy of this strategy.4 Among the 82 patients first reported, 75 patients achieved complete remission and one patient achieved complete remission with incomplete recovery of platelets, for an overall response rate of 92%. These were durable responses with an estimated 3-year survival of 85%. A group from China also conducted a study of ATRA plus arsenic trioxide for induction, but they used combination chemotherapy for consolidation in all patients. Another strategy, currently being explored by the European APL group in an ongoing study, is to combine arsenic trioxide with chemo-

With the withdrawal of gemtuzumab ozogamicin by the FDA, it is not clear whether a truly chemotherapyfree regimen will be feasible in all patients. —Farhad Ravandi, MD

and Iranian groups, the drug has proven to be highly effective in producing very durable remissions, particularly in patients with low-risk disease. Repeated treatment for consolidation has been shown to be beneficial. However, lack of universal success and modest long-term leukemia-free and overall survival rates have suggested a potential need to combine arsenic trioxide with other drugs.

Alternative Strategies In the United States, one strategy has been to introduce arsenic trioxide in the consolidation setting. A large, randomized intergroup study showed better disease-free and overall survival for patients who received arsenic trioxide during consolidation compared to those who received chemotherapy alone (although not statistically significant for overall survival).3 Others, including our group at The University of Texas MD Anderson Cancer Center, have examined the possibility of eliminating or minimizing the role of chemo-

therapy and ATRA to maximize their potential antileukemic effects, with the main concern for such a combination being toxicity.

Bleeding and Thrombosis Despite significant advances in treating APL, the initial therapy of this disease remains fraught with danger, with a significant proportion of patients developing life-threatening complications of bleeding and thrombosis. Early diagnosis and initiation of therapy with ATRA is very important to reduce the risk of these complications. The bleeding tendency is known to be exacerbated by the use of chemotherapy, which results in the breakdown of leukemic cells and release of procoagulant material into the circulation, and leads to the worsening of disseminated intravascular coagulation and consumptive coagulopathy—the hallmark of the disease. Therefore, a strategy that circumvents the use of chemotherapy may be desirable. Furthermore, many patients, particularly the elderly and those

Farhad Ravandi, MD

with cardiac dysfunction, may not be able or willing to tolerate the effects of combination chemotherapy. Although the potential long-term risks of chemotherapeutic agents (such as the development of secondary cancers) are limited, this can be cited as another potential advantage of a chemotherapy-free regimen. With the withdrawal of gemtuzumab ozogamicin by the FDA, it is not clear whether a truly chemotherapy-free regimen will be feasible in all patients. We have substituted a dose of idarubicin for gemtuzumab in our regimen, so far with comparable results. However, ATRA plus arsenic trioxide is clearly an effective treatment, particularly for patients with low-risk disease and those unable to receive traditional cytotoxic chemotherapy.

Disclosure: Dr. Ravandi has been a member of advisory boards and has received honoraria from Cephalon.

References 1. Tallman MS, Andersen JW, Schiffer CA, et al: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021-1028, 1997. 2. Soignet SL, Frankel SR, Douer D, et al: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:38523860, 2001. 3. Powell BL, Moser B, Stock W, et al: Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751-3757, 2010. 4. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504-510, 2009. Dr. Ravandi is Associate Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.


FOCUSED ON YOUR

PATIENTS

© 2012 Novartis

February 2012

ZOM-1036266


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Hematology for the Oncologist

Update on Novel Anticoagulants: Dabigatran Etexilate By Rajiv K. Pruthi, MBBS

E

fficacy and safety of traditional anticoagulants (eg, vitamin K antagonists) are well recognized, given their long-standing use in clinical practice. However, the novel anticoagulants have several potential advantages over the vitamin K antagonists. Even so, in light of their recent introduction into clinical practice, lack of widespread understanding of their pharmacologic characteristics, and lack of long-term safety data, their use should be undertaken with caution. Dabigatran etexilate mesylate (Pradaxa), the first novel anticoagulant to be approved by the FDA, is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and high risk of stroke. The FDAapproved dose is 150 mg orally twice daily in patients with normal renal function and 75 mg orally twice daily for those with a creatinine clearance rate of 15 to 50  mL/min. Currently, there are no dosing guidelines for patients with creatinine clearance <  15 mL/min or patients who are dialysisdependent.

RE-LY Trial The FDA approval was based on the RE-LY trial (Randomized Evaluation of Long-term Anticoagulant Therapy), a noninferiority trial of over 18,000 patients in which patients were randomized to either dabigatran etexilate (110 or 150 mg orally twice daily) or to adjusted-dose warfarin (international normalized See Page 93 ratio [INR] target 2–3). Overall, dabigatran was noninferior to warfarin in prevention of stroke and in reducing risk of hemorrhage.1 In anticoagulation trials, the primary aim is to reduce the risk of thromboembolism; this risk reduction is generally accompanied by an increased risk of hemorrhage. Thus, it is important to know which subsets of patients benefitted from being on dabigatran compared to warfarin. Dr. Pruthi is Associate Professor, Mayo Clinic College of Medicine, Mayo Comprehensive Hemophilia Center Department of Internal Medicine/Hematology Special Coagulation Laboratory, Department of Laboratory Medicine and Hematopathology, Mayo Clinic, Rochester, Minnesota.

In this trial, quality of anticoagulation control with warfarin was defined as percentage of time the patients’ INRs were within target range, and these values were stratified into quartiles (<  57.1%, 57.1% to 65.5%, 65.5% to 72.6%, and >  72.6%), with the latter two quartiles representing good and excellent control.2 Superiority of dabigatran (150  mg twice daily) in reducing the risk of nonhemorrhagic stroke was demonstrable predominantly in moderately or poorly controlled patients (INR within target range <  65% of the time). In the group of

Warnings and Precautions Dabigatran etexilate’s optimal absorption requires gastric acidity; however, dose modification is not required for patients on proton pump inhibitors. Hepatic activation to its active form, dabigatran, results in peak plasma concentrations at approximately 1 to 2 hours after oral administration and a mean terminal half-life of between 9 and 13 hours, with approximately 80% of the drug cleared renally. Unlike with warfarin, drug interactions do not occur with agents metabolized by the cytochrome P450 enzyme complex. However, p-glycoprotein transporter

For major and high-bleeding-risk surgery, discontinuation of dabigatran at least 48 hours preoperatively in patients with normal creatinine clearance, is recommended. —Rajiv K. Pruthi, MBBS

patients with well controlled INRs, dabigatran was not superior for nonhemorrhagic stroke. Nonhemorrhagic toxicity included dyspepsia, which occurred in approximately 10% of patients on dabigatran compared to approximately 5% of patients on warfarin and was the most common reason for discontinuation of dabigatran (21% discontinued dabagatrin vs 17% who discontinued warfarin). Myocardial infarction occurred slightly more often in patients on dabigatran (~0.7%) than in those on warfarin (0.53%). The overall rates of major hemorrhage were not significantly different—approximately 3% for either anticoagulant—with patients on antiplatelet agents having a higher risk of bleeding. Subset analysis demonstrated that patient’s on dabigatran had significantly lower rates of intracranial hemorrhage (0.1%) compared with warfarin (0.38%), irrespective of patient age, but higher rates of gastrointestinal hemorrhage. It is critical to note that patients >  75 years of age had higher rates of major and extracranial hemorrhage on dabigatran compared to warfarin. Thus, in this trial, the net clinical benefit (balancing the risks of thrombosis and hemorrhage) of dabigatran was greatest mainly in patients under age 75 years and in those with poor INR control.

inhibitors (eg, amiodarone, verapamil, or quinidine) increase dabigatran levels, and p-glycoprotein inducers (eg, rifampin) reduce dabigatran levels. Currently, there are no dosage adjustment guidelines available for patients who need one of the aforementioned drugs and dabigatran. For major and high-bleeding-risk surgery, discontinuation of dabigatran at least 48 hours preoperatively in patients with normal creatinine clearance, is recommended. For those with impaired renal function, longer preoperative discontinuation periods (eg, 5 days) are appropriate. Routine preoperative coagulation testing provides no useful information, given the variable and inconsistent effect on the prothrombin time and activated partial thromboplastin time. If available, a prolonged thrombin time may indicate residual drug effect. None of the routinely available assays is predictive of risk for surgical hemorrhage.

Management of Bleeding The approach to management of hemorrhage varies with timing of ingested dose, location, and severity of hemorrhage. Minor bleeding (eg, recurrent epistaxis) may be managed on an outpatient basis. The decision on withholding additional doses is based on the balance of risks vs benefits and

Rajiv K. Pruthi, MBBS

requires an assessment of drug compliance (eg, to ensure that extra doses were not consumed), evaluation of possible changes in renal function (estimation of creatinine clearance), and a search for anatomic abnormalities that may explain the hemorrhage. Major bleeding generally requires inpatient management, institution of general and specific measures, and potentially mobilization of a multidisciplinary health-care team including, for example, specialists in nephrology, gastroenterology, surgery, and interventional radiology. General measures for hemorrhage include holding dabigatran, attention to and management of hemodynamic stability, and a search for anatomic defects that may explain hemorrhage (such as gastrointestinal ulcers that may be amenable to endoscopic control). Aside from packed red blood cell transfusions as indicated, empiric fresh frozen plasma transfusion is not advised—the prolonged clotting times are a reflection of factor inhibition and not deficiency. Activated charcoal is effective in cases of recent dabigatran ingestion. In addition, hemodialysis effectively removes 60% of dabigatran over a 2to 3-hour dialysis session. However, given its extensive volume of distribution (50–70  L), a “rebound” increase in dabigatran plasma levels may occur after hemodialysis. There is currently no antidote to dabigatran, and procoagulant hemostatic agents such as recombinant factor VIIa or activated prothrombin complex concentrates have no effect on in vitro clotting times. Moreover, there is no published evidence of clinical benefit when such agents are infused in the bleeding patient on dabigatran.

Recommendations Although clinical trials of primary and secondary prevention and treatment of venous thromboembolism


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Hematology for the Oncologist

have been published,4 dabigatran is currently not FDA-approved for these indications. Pending availability of long-term safety data (eg, slightly increased risk of myocardial infarction), off-label uses (eg, secondary prophylaxis of venous thromboembolism in patients with and without malignancies, and use in mechanical heart valves) should be undertaken with caution. At the present time, dabigatran should not routinely replace warfarin or low molecular weight heparin in prophylaxis of venous thromboembolism in patients with cancer. So, in this environment of directto-consumer advertising, how does one apply the current state of knowledge about dabigatran to management of the atrial fibrillation patient already on warfarin and those who are warfarin-naive? For the former patient, it depends on the quality of INR control. As recently outlined by the American College of Cardiology Foundation/American Heart Association, patients on warfarin with excellent INR control would have little to gain by switching to dabigatran.3 For patients with moderate to poor INR control who are young (< 75 years of age), a balanced and detailed discussion on the risks, benefits, and options for management of hemorrhage should be undertaken in a shared decision-making process.

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

Hematology for the Oncologist

H

ematology for the Oncologist is guest edited by Ayalew Tefferi, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. The series is intended to provide guidance in managing hematologic issues that may present in your patients with cancer.

Ayalew Tefferi, MD

References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139-1151, 2009. 2. Wallentin L, Yusuf S, Ezekowitz MD, et al: Efficacy and safety of dabigatran compared with warfarin at different

levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376:975-983, 2010. 3. Wann LS, Curtis AB, Ellenbogen KA, et al: 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): A report of the Ameri-

can College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 57:1330-1337, 2011. 4. Bauer KA: Recent progress in anticoagulant therapy: Oral direct inhibitors of thrombin and factor Xa. J Thromb Haemost 9(suppl 1):12-19, 2011.


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FDA Update

ODAC Offers Recommendations on Two Sarcoma Drugs

T

he FDA’s Oncologic Drugs Advisory Committee (ODAC) recently recommended approval of one drug for sarcoma but rejected another. The panel voted 11 to 2 that clinical studies support a favorable benefit-risk assessment for use of pazopanib (Votrient) in treating patients with advanced soft-tissue sarcoma who have received prior chemotherapy. On the same day, ODAC voted 13 to 1 against the use of the investigational agent ridaforolimus (Taltorvic) as maintenance therapy for patients with metastatic soft-tissue sarcoma or bone sarcoma whose disease has not progressed after at least four cycles of chemotherapy. The ODAC provides FDA with independent expert advice and recommendations. However, the final decision regarding approval is made by FDA. 

Pazopanib Pazopanib is a kinase inhibitor that is already approved in the United States for the treatment of patients with advanced renal cell carcinoma. For the current indication being considered, ODAC reviewed findings from one phase III clinical study and one phase II study. The panel noted that patients with gastrointestinal stromal tumours (GIST) and adipocytic sarcomas were not included in the phase III trial of pazopanib. “Treatment options for patients with advanced soft-tissue sarcoma are limited; we are therefore pleased that the committee took a favorable view of the clinical data for Votrient.” said Rafael Amado, MD, Senior Vice President, GlaxoSmithKline Oncology. “We look forward to continuing the regulatory process.” 

Ridaforolimus Ridaforolimus is an investigational small-molecule inhibitor of mammalian target of rapamycin (mTOR), a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT, and PTEN, known to be important to malignancy. Merck and ARIAD Pharmaceuticals previously announced that the FDA has accepted for filing and review the New

Drug Application (NDA) for ridaforolimus. As part of an exclusive license agreement with ARIAD, Merck is responsible for the development and worldwide commercialization of ridaforolimus in oncology. ARIAD intends to copromote

ridaforolimus in the United States. “Merck remains confident in the potential of the investigational agent ridaforolimus for an indication where patients have limited options,” said Eric Rubin, MD, Vice President, Clinical

Research Oncology, Merck. “We remain committed to bringing forward this promising therapy for patients with metastatic sarcoma, and look forward to further discussions with the FDA regarding this application.”

TREANDA® is her chemo.

This is her therapy.


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FDA Update

FDA Commissioner Statement: Surgeon General’s Report on Youth Smoking

T

he recent report on “Preventing Tobacco Use Among Youth and Young Adults” by the Surgeon General not only documents the devastating consequences of tobacco use for our nation’s youth, but also represents a clarion call

for bold action at every level of government to implement proven strategies to keep kids off tobacco. (See page 29 in this issue of The ASCO Post for more on the new report on youth smoking) After years of steady progress, de-

clines in the use of tobacco by youth and young adults have slowed for cigarette smoking and stalled for smokeless tobacco use. This report makes it abundantly clear, young people are highly susceptible to tobacco advertising and

Single-agent treanDa tripled median PFS in patients with cLL*

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

• TREANDA was generally well tolerated in the pivotal phase 3 trial

6 months median PFS

P<.0001

• The most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150)

HR†=0.27 (95% CI‡: 0.17, 0.43)

0

5

10

15

20

25

30

35

40

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatmentnaïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles

45

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. ‡ CI=confidence interval.

Single-agent treanDa produced a 74% orr§ in patients with indolent B-cell nHL that had progressed ORR§: INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA (NHL) THAT HAS PROGRESSED

57%

PR (n=57)

0

74%

Total ORR

(95% CI: 64.3, 82.3)

17%

CR/CRu (n=17)

20

40

60

• TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles • TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176)

80

100

Patients responding (%) Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.

§

• The most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)

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’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Selected Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA l

Discover the elements of efficacy and safety Learn more at treanDa.com Please see accompanying brief summary of full Prescribing Information.

Oncology

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2214 January 2012

marketing activities leading many youth to a lifetime of addiction coupled with serious health consequences. This is the first Surgeon General’s Report on youth since President continued on page 62


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FDA Update

Surgeon General’s Report on Youth Smoking continued from page 61

Obama signed the bipartisan Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) into law in 2009. That law gave FDA, for the first time, explicit and broad

authority to regulate tobacco products to reduce the tremendous toll caused by their use in our country. The importance of a principal focus of that law – protecting our kids – is dramatically underscored by the findings in this Surgeon General’s Report. In just over 2 years, the Tobacco Con-

trol Act has allowed FDA to implement a wide array of new restrictions to reduce the access and attractiveness of tobacco products to young people. FDA is implementing the law’s ban of cigarettes with fruit, candy, and certain other flavors. And for cigarettes and smokeless tobacco, FDA is enforcing the age of 18 as the

Brief Summary of Prescribing Information INDICATIONS AND USAGE: 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 for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. 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 closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have 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]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. 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. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing 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 maintaining adequate volume status, 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. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. 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. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. 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. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. 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. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled 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. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. 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. In the randomized CLL clinical study, non-hematologic 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 randomized CLL clinical study and 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 TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

national minimum age of purchase for these products, the ban on vending machine sales, the ban on sales of single cigarettes and give-away of free samples of cigarettes, the ban on use of brand name sponsorship of concerts and sporting events, the requirements for new smokeless tobacco warnings to communicate

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 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

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 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 significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm 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 8 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. 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) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53) 13 (7)

0

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0


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PAGE 63

FDA Update

health risks, and the prohibition on misleading advertising claims that imply products are safer. In addition, FDA protects the nation’s youth by conducting inspections to ensure that tobacco retailers comply with these requirements; to date, more than 40,000 retail inspections have been completed.

FDA welcomes the authoritative and comprehensive scientific findings in the Surgeon General’s Report and will use these facts as we propose tobacco product regulations to protect our nation’s health and to conduct sciencebased education campaigns to inform the public—particularly young peo-

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) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *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%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

ple—about the harmful ingredients in tobacco products with the goal to prevent initiation. By applying the science contained in this and other Surgeon General’s reports we can help make tobacco-related death and disease a part of America’s past, not its future. —Margaret A. Hamburg, MD

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] 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. 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] 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. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer 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 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then 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. Admixture Stability. TREANDA 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 refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: 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. 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. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

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 post-marketing 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] 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. PostMarketing Experience. The following adverse reactions have been identified during post-approval 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 pruritus, irritation, pain, and swelling. 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] OVERDOSAGE: The intravenous LD 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.

FDA Approves New Silicone Gel–filled Breast Implant

T

he FDA recently approved a silicone gel-filled breast implant manufactured by Sientra Inc for breast augmentation in women at least 22 years old and breast reconstruction in women of any age. As a condition of approval, Sientra is required to conduct postapproval studies that will assess long-term safety and effectiveness outcomes as well as the risks of rare disease outcomes. With this approval, there are now three FDA-approved silicone gel–filled breast implants in the United States, manufactured by Allergan, Mentor, and Sientra. “Data on these and other approved silicone gel-filled breast implants continue to demonstrate a reasonable assurance of safety and effectiveness,” said William Maisel, MD, MPH, Deputy Director for Science in the FDA’s Center for Devices and Radiological Health.

‘Not Lifetime Devices’ “It’s important to remember that breast implants are not lifetime devices. Women should fully understand risks associated with breast implants before considering augmentation or reconstruction surgery, and recognize that long-term monitoring is essential.” said Dr. Maisel. The FDA based its Sientra approval on 3 years of clinical data from 1,788 participants. Complications and outcomes reflected those found in previous studies of other breast implants and included tightening of the area around the implant (capsular contracture), reoperation, implant removal, an uneven appearance (asymmetry), and infection.

The ASCO Post

50

DOSAGE AND ADMINISTRATION: 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:

Manufactured by: Pharmachemie B.V. The Netherlands

Manufactured for: Cephalon, Inc. Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates. TRE-2263 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

March 2011 All rights reserved.

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The ASCO Post  |   APRIL 15, 2012

PAGE 64

In the Clinic

Erwinia chrysanthemi Asparaginase for Acute Lymphoblastic Leukemia in Patients with Hypersensitivity to E coli–derived Asparaginase 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.

Indication

E

rwinia chrysanthemi asparaginase (Erwinaze) was recently approved as a component of a multiagent chemotherapeutic regimen for patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to Escherichia coli–derived asparaginase (Elspar, and a pegylated form, Oncaspar).1-3 Approval was based on a single-arm, open-label study of Erwinia asparaginase treatment in 58 ALL patients who were unable to continue receving pegaspargase or asparaginase derived from E coli due to allergic reactions. The major efficacy outcome was achievement of sustained serum asparaginase activity levels of at least 0.1 IU/mL, a threshold that is known to result in depletion of asparagine to levels that predict efficacy. Threshold asparaginase activity levels were reached in all 48 patients with available measurements.

How It Works Erwinia asparaginase reduces circulating levels of the amino acid asparagine by catalyzing the deamidation of

Erwinia Asparaginase for Acute Lymphoblastic Leukemia ■■ Erwinia chrysanthemi

asparaginase (Erwinaze) has been approved as part of chemotherapy for patients with acute lymphoblastic leukemia and hypersensitivity to E coli–derived asparaginase (Elspar, Oncaspar).

■■ As a substitute for a planned

dose of pegaspargase, the recommended dose of Erwinia asparaginase is 25,000 IU/ m2 IM three times a week for six doses. As a substitute for a scheduled dose of native E coli asparaginase, Erwinia asparaginase should be given at 25,000 IU/m2 IM.

asparagine to aspartic acid and ammonia. Leukemic cells are unable to synthesize asparagine, which is required for

protein metabolism and survival, due to lack of asparagine synthetase activity. Reduction of circulating asparagine

levels results in cytotoxicity specific for leukemic cells by depriving them of an exogenous source of the amino acid.


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In the Clinic

OF NOTE Erwinia asparaginase carries warnings/precautions for serious hypersensitivity reactions, including anaphylaxis, pancreatitis, glucose intolerance, thrombosis, and hemorrhage.

How It Is Given To substitute for a dose of pegaspargase, the recommended dose of Erwinia asparaginase is 25,000 IU/m2 IM three times a week (Monday/Wednesday/Friday) for six doses (for each planned dose of pegaspargase). To substitute for a dose of native E coli asparaginase, Erwinia asparagi-

nase should be given at 25,000 IU/m2 IM (in place of each scheduled dose of native E coli asparaginase within a treatment).

Safety Profile The safety of Erwinia asparaginase has been evaluated in the 58 patients treated in the clinical study supporting

approval and in 574 patients treated in an expanded access program (Erwinaze Master Treatment Protocol). Common adverse events were similar in severity and incidence to those attrib-

OF NOTE Erwinia asparaginase reduces circulating levels of asparagine, which deprives leukemic cells of exogenous amino acid, resulting in targeted cytotoxicity. utable to E coli–derived asparaginase. The most common adverse events included systemic allergic reactions (17%), pancreatitis (4%), abnormal transaminases (3%), coagulopathies (3%), hemorrhage (1%), nausea (2%), vomiting (2%), and hyperglycemia (2%). Grade 3 or 4 adverse events included allergic reactions, pancreatitis, hyperglycemia, thrombosis, hemorrhage, and elevated transaminases. Serious hypersensitivity reactions, including anaphylaxis, occurred in 5% of patients. Erwinia asparaginase carries warnings/precautions for serious hypersensitivity reactions, including anaphylaxis, pancreatitis, glucose intolerance, thrombosis, and hemorrhage.

References 1. U.S. Food and Drug Administration: Asparaginase Erwinia chrysanthemi. Available at http://www.fda.gov/AboutFDA/ CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm280543.htm. Accessed February 29, 2012. 2. ERWINAZE (asparaginase Erwinia chrysanthemi) for injection, intramuscular use, prescribing information. EUSA Pharma (USA), Inc, November 2011. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125359lbl.pdf. Accessed February 29, 2012. 3. Vrooman LM, Supko JG, Neuberg DS, et al: Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 54(2):199-205, 2010.

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 (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


The ASCO Post  |   APRIL 15, 2012

PAGE 66

Journal Spotlight Hematology

New Data Guide Treatment for Rare Form of Hodgkin Lymphoma By Matthew Stenger

N

odular lymphocyte predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of Hodgkin lymphoma cases. It is distinguished from classic Hodgkin lymphoma by a variety of clinical and pathologic features, including expression of B-cell associated antigens such as CD20. Given that the overall prognosis in limited-stage NLPHL is extremely good, the goals of therapy should be to maintain high cure rates and avoid future secondary complications, similar to the treatment goals in limited-stage classic Hodgkin lymphoma. Classic Hodgkin lymphoma is typically treated with a combined-modality approach consisting of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD-like chemotherapy and radiation therapy. Optimal treatment for limited-stage NLPHL has not yet been defined. Two studies of treatment of limited-stage NLPHL were recently published in the journal See Page 93 Blood. A retrospective analysis by Savage and colleagues1 indicated that ABVD or ABVD-like chemotherapy as part of primary treatment is associated with improved time to progression and progression-free survival compared with radiotherapy alone. A phase  II trial reported by Eichenauer and colleagues2 in the German Hodgkin Study Group indicated that although first-line treatment with the anti-CD20 antibody rituximab (Rituxan) appears to be inferior to radiotherapy alone and combinedmodality treatment, investigation of combination approaches including anti-CD20 antibody treatment in NLPHL is warranted.

Retrospective Analysis of ‘RT Era’ vs ‘ABVD Era’ Savage and colleagues analyzed outcomes in patients in the British Columbia Cancer Agency Lymphoid Cancer Database with limited-stage NLPHL (stage IA/IB or IIA, nonbulky disease <  10 cm) who were treated prior to 1993 with radiotherapy alone (RT era, n  = 32) and another group treated after 1993, generally with two cycles of ABVD-like therapy followed by radiotherapy (ABVD era, n  = 56).1 Of 56 ABVD era patients, 14 did not receive

radiotherapy and 6 received only radiotherapy. Four ABVD era patients received MOPP (mechlorethamine, vincristine, procarbazine, prednisone) plus ABV. One RT era patient received MOPP. Most patients were male (75% in each group), most were aged 40 years or younger (62.5% of RT era patients and 61% of ABVD era patients), most had stage  I disease (66% and 59%, respectively), and mass size was 5 cm or smaller (72% and 66%, respectively) in most patients with measurements. In the total patient group, there were no significant differences between patients with stage I disease and those with stage II disease with regard to 10-year time to progression (88% vs 88%) or progression-free survival (74% vs 88%). Univariate analysis showed no impact on progression-free survival for male sex, age greater than 49 years, or mass greater than 5 cm.

ABVD Bests Radiotherapy Alone Patients treated in the ABVD era had markedly better long-term outcomes than those in the RT era, including a markedly reduced incidence of relapse and transformation to aggressive lymphoma. Median follow-up for living patients was 6.4 years (range, 1.2–40.5 years). For patients treated in the ABVD era, 10-year time to progression was increased from 76% to 98% (P = .0074), progression-free survival from 65% to 91% (P  = .0024), and overall survival from 84% to 93% (P = .07) compared with those treated in the RT era. The only lymphoma relapse observed in ABVD era patients was in a patient who received RT alone. In contrast, with a median time to progression of 5.3 years, there were 12 relapses in RT era patients, including 5 cases of transformation to aggressive lymphoma. An “as treated” analysis comparing outcomes in patients who received chemotherapy in either era as part of primary treatment (n  = 51, median follow-up of living patients, 5.7 years) vs those receiving radiotherapy alone in either era (n = 35, median follow-up of living patients, 18.6 years) showed a significantly greater 10-year progression-free survival rate among patients receiving chemotherapy (100% vs 77.5%, P  = .0029). No relapses occurred in the chemotherapy patients, compared with 10 among those re-

Update on Nodular Lymphocyte-predominant Hodgkin Lymphoma ■■ Two studies published in Blood addressed treatment of limited-stage nodular lymphocyte-predominant Hodgkin lymphoma.

■■ A retrospective analysis indicated that ABVD or ABVD-like chemotherapy as part of primary treatment is associated with improved time to progression and progression-free survival compared with radiotherapy alone.

■■ A phase II trial reported by the German Hodgkin Study Group indicated that first-line rituximab proved inferior to radiotherapy alone and combined-modality treatment.

ceiving RT alone. Most relapses in the radiotherapy-alone patients occurred within 5 years of diagnosis.

Rituximab in Newly Diagnosed Stage IA NLPHL In a single-arm phase  II trial conducted by Eichenauer and colleagues,2 28 evaluable patients with newly diagnosed stage IA NLPHL received four weekly infusions of rituximab at 375 mg/m2. Patients had a median age of 40 years, 71% were male, and 72% had supradiaphragmatic disease. After diagnostic lymph node biopsy, 39% of patients were in complete remission and 61% had residual disease. At a median follow-up of 43 months, the overall response rate was 100%, with complete remission in 86% and partial remission in 14%. Progression-free survival estimates at 12, 24, 36, and 48 months were 96%, 85%, 81%, and 77%, respectively. Relapse occurred in seven patients (25%), and two developed secondary solid tumors. All relapses occurred in patients with residual disease after diagnostic lymph node resection. No grade 3 or 4 adverse events were observed. As noted by the investigators, although the response rate with rituximab in first-line treatment was excellent—as are response rates with rituximab in relapsed or more advanced disease—the 25% relapse rate after a median 43-month follow-up does not compare well with outcomes reported for radiotherapy alone or combined-modality treatment.

Earlier Investigations In a German Hodgkin Study Group retrospective analysis of 131 patients with early-stage disease receiving radiotherapy alone or combinedmodality therapy, the freedom from

treatment failure rate at 43 months was 95%.3 A single center analysis of 113 patients with stage I or II disease receiving radiotherapy alone showed a 5-year progression-free survival of 95% with a median follow-up of 136 months for living patients. However, secondary malignancy was the main cause of death in this group.4 The authors noted that “anti-CD20 antibodies have a favorable toxicity profile and may be offered to young patients who are at particular risk for long-term side effects, such as secondary malignancies. In addition, the combination of anti-CD20 antibodies and chemotherapy may also improve efficacy and decrease toxicity of NLPHL treatment in early unfavorable, advanced, or relapsed disease.”2

References 1. Savage KJ, Skinnider B, Al-Mansour M, et al: Treating limited-stage nodular lymphocyte-predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood 118:4585-4590, 2011. 2. Eichenauer DA, Fuchs M, Pluetschow A, et al: Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte-predominant Hodgkin lymphoma: A report from the German Hodgkin Study Group. Blood 118:4363-4365, 2011. 3. Nogova L, Reineke T, Eich HT, et al: Extended field radiotherapy, combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte–predominant Hodgkin’s lymphoma: A retrospective analysis from the German Hodgkin Study Group (GHSG). Ann Oncol 16:1683-1687, 2005. 4. Chen RC, Chin MS, Ng AK, et al: Early-stage lymphocyte-predominant Hodgkin’s lymphoma: Patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28:136-141, 2010.


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PAGE 67

FDA Update

Liposomal Vincristine Receives Positive Vote from ODAC

T

alon Therapeutics, Inc, announced the Oncologic Drugs Advisory Committee voted 7 yes, 4 no, and 2 abstain that evidence from clinical studies supports a favorable benefitrisk assessment for use of vincristine sulfate liposomes injection (Marqibo). The manufacturer is seeking an indication for the treatment of adult Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph– ALL) in second or greater relapse or that has progressed following two or more lines of antileukemia therapy. The FDA decision (PDUFA) date for the drug is May 13, 2012. “We are very pleased the majority of the ODAC members agree that Marqibo offers a meaningful benefit/ risk ratio for a very rare patient population that has a grave prognosis and no current standard of treatment,” stated Steven R. Deitcher, MD, President, Chief Executive Officer and Board Member of Talon Therapeutics. “Based on prior FDA discussions, we have received Special Protocol Assessment (SPA) agreement for a large, randomized phase III trial in front-line adult elderly ALL with sites currently open for enrollment. We look forward to working closely with the FDA in the

coming weeks to address any remaining questions they may have.” The new product is a novel, targeted formulation of the FDA-approved anticancer drug vincristine. Talon has been de-

veloping the drug for the treatment of adult, Ph– ALL and adult aggressive non-Hodgkin lymphoma. Vincristine, a microtubule inhibitor, is FDA-approved for ALL. Talon’s encapsulation

formulation is designed to provide prolonged circulation of the drug in the blood and accumulation at the tumor site. These characteristics are intended to increase the dose of vincristine delivered in a safe and effective manner.

FDA Drug Approvals, January–April 2012 ■■ Imatinib mesylate tablets

(Gleevec) approved for the adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive gastrointestinal stromal tumors (GIST).

■■ Vismodegib capsules

(Erivedge) approved for the treatment of metastatic basal cell carcinoma or locally advanced basal cell carcinoma.

■■ Axitinib tablets (Inlyta) for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.

■■ Glucarpidase injection

(Voraxaze) for the treatment of toxic plasma methotrexate concentrations (> 1 μmol/L) in patients with delayed methotrexate clearance due to impaired See Page 93 renal function.

Unified in our uncompromising commitment to improving patient care in renal cell carcinoma For more information visit www.aveopharma.com or www.astellas.com.

For more information, visit fda.gov. ©2011 AVEO Pharmaceuticals, Inc. and Astellas Pharma US, Inc.

011L-073-4740

12/11

Printed in the USA


The ASCO Post  |   APRIL 15, 2012

PAGE 68

Patient’s Corner Gastrointestinal Oncology

Cancer Does Not Have to Be a Death Sentence

What made my treatment for colon cancer so bearable was that I believed I could be cured. By Marsha Axler, as told to Jo Cavallo

W

hen I found a large amount of blood on my toilet tissue just before Thanksgiving in 2010, I wasn’t too concerned. At just 45 years old, I was in excellent health, and other than the bloody stool I had no other symptoms signaling that something was seriously wrong. My primary care physician thought that I probably had internal hemorrhoids, a problem common in women who have had multiple pregnancies, he said, and recommended seeing a gastroenterologist if the bleeding continued longer than a week. Because of my age, having cancer was the last thought on anyone’s mind.

Urgency Overcomes Modesty Although the bleeding had subsided during the month of December, by January it was back and I immediately saw a gastroenterologist. Although he never mentioned the possibility of cancer, because I had been adopted as an infant and didn’t know my biologic parents’ medical history, he recommended doing a colonoscopy. The prospect of undergoing the procedure and exposing that part of my body made me uncomfortable. I’m a modest person and I didn’t want anyone examining my colon, but the urgency in his voice when he said, “I’d rather do this sooner than later,” made me realize that I had to put aside my

apprehension and have the test. When the procedure was over, the doctor said he had found a 4-cm tumor that he was certain was malignant. The news was shocking because all along I kept thinking my problem was just hemorrhoids. A biopsy confirmed his diagnosis. Fortunately, subsequent blood tests and a CT scan showed that the tumor had not spread to my liver or lungs. There was more positive news following my surgery to remove the tumor. Because the cancer had not

a foot of my colon was removed— thankfully, I didn’t need to have a colostomy bag. And even though I had to face 12 cycles of the chemotherapy regimen FOLFOX (leucovorin, fluorouracil, oxaliplatin), the thought that I would come out the other side of having cancer likely cured kept me focused on getting well, despite encountering severe physical and emotional side effects that made me want to quit by round eight of my chemotherapy.

Having an oncologist who spent as much time with me as necessary to go over every detail of my progress and who encouraged me to get to the finish line of my treatment made me feel like I was his most important patient. That attitude kept me positive and driven to succeed. —Marsha Axler

spread beyond two nearby lymph nodes, it was staged as IIIA disease and my oncologist was optimistic that my colon cancer was curable.

Staying Positive Although the surgery to remove the tumor was extensive—nearly

Having an oncologist who spent as much time with me as necessary to go over every detail of my progress and who encouraged me to get to the finish line of my treatment made me feel like I was his most important patient. That attitude kept me positive and driven to succeed.

Marsha Axler

Facing the Future Throughout the past year, my goal was to handle my cancer diagnosis with dignity and grace because I thought if I do die, I want to leave my two teenage sons with a legacy of courage and determination. It was also important for me to educate my friends on the necessity of getting regular colonoscopy screenings—usually a conversation stopper—because the test had saved my life and I wanted them to know that it could save theirs, too. A few months ago, I was told that I’m cancer-free. The news was both exciting and liberating. Everything I’ve been through since being diagnosed has been worth it because surviving colon cancer is enabling me to have many more years with my family. And I’m grateful for every day of my life.

Marsha Axler teaches computer technology in Voorhees, New Jersey.

Don’t Miss These Important Reports Inside this Issue of The ASCO Post Richard J. Boxer, MD, on Our Patients, Our Teachers, page 1

Patricia Ganz, MD, on Impaired Cognitive Function Following Chemotherapy, page 15

Farhad Ravandi, MD, on Treating Acute Promyelocytic Leukemia without Chemotherapy, page 56

Paul A. Bunn, Jr, MD, on the Future of Lung Cancer Treatment, page 30

Barbara L. Smith, MD, PhD, on Advances in Axillary Surgery for Patients with Breast Cancer, page 52

Rajiv K. Pruthi, MBBS, on Novel Anticoagulants: Dabigatran Etexilate, page 58

Visit The ASCO Post online at ASCOPost.com


In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?


Introducing Jakafi™ (JAK-ah-fye) First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

Jakafi is a trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved. RUX-1008D 02/12

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)


Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b ≥35% reduction in spleen volume1,2,a

≥50% improvement in Total Symptom Score1,2,a,b

50

41.9

P < 0.0001

30 20 10 0

45.9 P < 0.0001

40

Patients (%)

Patients (%)

40

50

30 20 10

0.7 Jakafi (n = 155)

0

Placebo (n = 154)

5.3 Jakafi (n = 148) Placebo (n = 152) Baseline mean TSS = 18.0 Baseline mean TSS = 16.5

Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive and JAK2 V617F-negative patients, relative to placebo2 Most patients not treated with Jakafi experienced increased splenomegaly and worsening of symptoms1

Visit www.jakafi.com/JAKtarget for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

TSS = Total Symptom Score. a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b

Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF, including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. November 2011. 2. Data on file. Incyte Corporation.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference


The ASCO Post  |   APRIL 15, 2012

PAGE 72

News

ASCO’s Blueprint Sets Goals for Accelerating Cancer Progress Calls for innovative cancer trial design to spur targeted drug development By Jo Cavallo

A

SCO recently issued a report, Accelerating Progress Against Cancer: 07 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1 ASCO’s Blueprint for Transforming Clini-

cal and Translational Cancer Research, which outlines the Society’s 10-year plan for improving cancer outcomes. Central

to achieving that goal are three steps, including (1) therapy development based on the detailed molecular characteriza-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

tions of each patient and his tumor; (2) designing smarter, faster clinical trials that provide evidence for effective treatments targeted to patients most likely to benefit; and (3) harnessing health information technology that integrates clinical research and all relevant patient information, such as tumor characteristics, site, and prior treatments. To succeed, the authors noted, collaboration is required from all stakeholders in the cancer research community, including public and private research sponsors, professional societies, the NCI and NCI-funded Clinical Trials Cooperative Groups, policymakers, patient advocacy organizations, and government regulatory agencies.

Neal J. Meropol, MD

Biggest Challenge “The biggest challenge to success is getting the key constituencies to overcome inertia and to adopt and invest their energy in the possible. It’s very easy to continue on a path that we’ve been on for the past 20 years, and the challenge is for everyone to rethink together how we might do better on behalf of our patients,” said Neal J. Meropol, MD, Co-Executive Editor of ASCO’s Blueprint, and Division Chief, Hematology and Oncology, Department of Medicine, University Hospitals Case Medical Center, Seidman Cancer Center and Case Western Reserve University School of Medicine, Cleveland. Over the next 3 years, ASCO plans to convene workshops with experts from all key groups to solidify plans for implementation of the Blueprint’s recommendations. ASCO’s Cancer Research Committee is organizing the first meeting to develop consensus on priorities for prevention and therapeutic strategies and biomarker development. ASCO is also working with the FDA on a series of meetings to discuss how minimal residual disease endpoints can be used to develop drugs for three types of leukemia—acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leu-


ASCOPost.com  |   APRIL 15, 2012

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News

Michael P. Link, MD

kemia—as a predictive surrogate for how patients will fare long-term. “In chronic myeloid leukemia, for example, we can actually measure, with a fair degree of sensitivity in patients in remission, the depth of their remission. We know that minimal residual disease is a very, very highly predictive surrogate for how the patient is ultimately going to do. ASCO is helping to sponsor a meeting with the FDA to discuss how we can validate this information as a surrogate endpoint for the efficacy of new [leukemia] drugs,” said ASCO President Michael P. Link, MD, Lydia J. Lee Professor in Pediatric Oncology at Stanford University School of Medicine.

Smarter, Faster, More Effective Clinical Trials Central to achieving extended patient survival rates and reducing cancer deaths is the design of targeted See Page 93 clinical trials based on the specific molecular characteristics of a patient’s cancer and the development of a multidrug-cocktail approach that targets the multiple molecular triggers for each cancer subtype. “I think the whole clinical trial paradigm is going to change because we will have a combination of targeted agents that are almost custom-designed for

each patient and we will see [quickly] whether the drug or drug combination is a success or failure. We hope to have a series of definitive trials in which we won’t have to wait 3  years to have an answer about a drug’s effectiveness. We should have the answer within months of accruing patients,” said Dr. Link. Critical to the success of the new clinical trial paradigm is overcoming the challenges posed by the competitive and intellectual property concerns of pharmaceutical companies with regard to testing of drugs in combinations. In addition, the approval process for combination therapies will need to be worked out with the FDA. That said, there have been precedents for pharmaceutical companies collaborating in clinical trials of multiple drugs, including a phase I study of Merck’s AKT inhibitor MK-2206 and AstraZeneca’s mitogens-activated protein kinase 1 inhibitor AZD6244 in the treatment of solid tumors. “Pharmaceutical companies are [increasingly] open to the idea of testing drugs in combination with a competitor’s product. The key element is that it has to ultimately make financial sense for their stockholders. One way ASCO can help is to work with the FDA to ensure that there is clarity regarding how joint development can occur in such a way that it is beneficial to multiple sponsors and at the same time minimizes their risk,” said Dr. Meropol.

Partnering with Patient Advocates The ASCO report also calls on the FDA and pharmaceutical companies to recognize patients’ quality-of-life concerns in addition to treatment effectiveness as considerations for new drug approval and to include that information on drug labels. To develop a consensus

Marking 40 Years of Cancer Progress

I

t’s been 40 years since President Richard Nixon declared, “The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease,” and later signed into law the National See Page 93 Cancer Act of 1971. Passage of the law enabled the allocation of increased federal funding for research, which has resulted in extended survival rates and breakthroughs in treatments aimed at specific molecular pathways of cancer cells. Some of the milestones reached in the prevention, diagnosis, and treatment of cancer over the past 4 decades include the following achievements: ■■ Cancer survivorship has increased from 3 million to 12 million. ■■ Early detection through routine screenings has helped to increase 5-year survival rates for breast cancer to over 90%. ■■ Better therapies have increased survival rates for some childhood cancers to over 90%. ■■ Advances in genetics have led to the development of over 30 molecularly targeted drugs that attack cancerous tumors while sparing healthy cells For more information, visit ASCO’s CancerProgress.Net, an interactive website that chronicles advances in cancer care through an easy-to-read decade-by-decade timeline. The site is updated regularly to include the latest progress in cancer research as well as links to government agencies overseeing federal cancer research and drug approval.

on what constitutes “meaningful patient outcomes,” ASCO will work with patient advocates to bring together a group of experts from industry, biomedical research, NCI, FDA, and health insurers. Looking ahead over the next decade, the report cites advances in health information technology as crucial to improving patient care and speeding research in molecularly targeted therapies. To accomplish those goals, ASCO is developing a rapid learning system for cancer care, which will house a secure central database of real-time patient-reported information, such as side effects from treatment, data from tumor biospecimens to allow physicians to assess the best treatment for each patient, and a

system for alerting patients to appropriate clinical trials. “We’re convinced that this Blueprint is the way forward to accelerating progress in cancer care and we will do everything possible to ensure its success,” said Dr. Link.

Disclosure: Drs. Meropol and Link reported no potential conflicts of interest.

Reference 1. Kris MG, Meropol NJ, Winer EP (eds): Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research. Alexandria, Virginia; American Society of Clinical Oncology; 2011. Available at asco.org/blueprint. Accessed March 1, 2012.

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James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

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The ASCO Post  |   APRIL 15, 2012

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News American Society of Clinical Oncology

Oncology Professionals and Leaders to be Honored at ASCO Annual Meeting

E

ach year through its Special Awards Program, ASCO recognizes researchers, patient advocates, and leaders of the global oncology community who, through their work, have made significant contributions to enhancing cancer care. These re-

cipients of ASCO’s highest, most prestigious awards collectively represent significant strides in cancer treatment and leadership in the oncology community. “All of the oncology professionals and leaders who will be receiving

this year’s Special Awards have made a great impact on cancer prevention, care and treatment around the globe,” said George Sledge, MD, ASCO Immediate Past President and Chair of the Special Awards Selection Committee. “We are honored to commend

their contributions and accomplishments in the field of oncology with ASCO’s most prestigious awards.

Among the 2012 ASCO Special Awards Honorees are: David A. Karnofsky Memorial Award and Lecture

Now Enrolling A Randomized Phase 3 Trial

Kanti R. Rai, MB, BS

KEY INCLUSION CRITERIA:

Kanti R. Rai, MB, BS, is the recipient of the 2012 David A. Karnofsky Memorial Award and Lecture for his outstanding achievements in cancer research and for his influence on the treatment of patients with cancer. Dr. Rai is chief of the Chronic Lymphocytic Leukemia Research and Treatment Program at North Shore-Long Island Jewish (LIJ) Health System and the Joel Finkelstein Cancer Foundation Professor of Medicine at Hofstra North Shore-LIJ School of Medicine, where he also holds the title of professor of molecular medicine. As an investigator with The Feinstein Institute for Medical Research, Dr. Rai is known for establishing the Rai clinical staging system for chronic lymphocytic leukemia (CLL), which is based on an analysis of how the body is affected by the abnormal lymphocytes. Dr. Rai has continued to remain at the forefront of research in the studies of natural history of CLL, improving prognostic markers and in developing newer and hypothesis-driven strategies of therapy for this disease.

• Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas (AJCC Stage IV)

Science of Oncology Award and Lecture

R A N D O M I Z E D

Placebo Q2W + Gemcitabine Ganitumab 12 mg/kg Q2W + Gemcitabine Ganitumab 20 mg/kg Q2W + Gemcitabine

OS Primary endpoint

Ganitumab (AMG 479) is an investigational IGF1R inhibitor that has not been approved by the FDA.

Rakesh K. Jain, PhD, A.W. Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School

• Previously untreated with chemotherapy or radiation • ECOG Performance Status 0 or 1 For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20060540) • www.ClinicalTrials.gov (NCT01231347)

Oncology

Rakesh K. Jain, PhD ASCO 2011 Journal Ad_AMG479_090611.indd 1

9/6/2011 5:08:17 PM


ASCOPost.com  |   APRIL 15, 2012

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News

Visit

and Director of E.L. Steele Laboratory of Tumor Biology at the Massachusetts General Hospital Cancer Center, is the recipient of the 2012 Science of Oncology Award and Lecture. By combining his extensive expertise and experience in engineering, mathematics, tumor biology, and physiology, Dr. Jain has created a novel approach to imaging technologies in cancer research that has provided unprecedented molecular, cellular, anatomical, and functional insights into tumor barriers and how to overcome them. His discoveries have fundamentally changed the thinking of scientists and clinicians about how antiangiogenic agents work in people with cancer. Dr. Jain’s research also represents a premier example of benchto-bedside translation in oncology.

ASCO-American Cancer Society Award and Lecture

The ASCO Post at the

Matti S. Aapro, MD

nedy Award and Lecture for Scientific Excellence in Geriatric Oncology. An active researcher and frequent international lecturer, Dr. Aapro’s clinical interests include new drug development, breast cancer, cancer in the elderly, and supportive care. He was chair of the scientific and organizing committees of the International Union Against Cancer’s World Cancer Congress in 2008 in Geneva, Switzerland, and continued to serve UICC in 2010, in Shenzhen, China. Dr. Aapro has also authored or coauthored numerous articles and book chapters on various aspects of cancer treatment.

American Society of Clinical Oncology Annual Meeting BOOTH 6068

Pediatric Oncology Award and Lecture Rowan T. Chlebowski, MD, PhD

Rowan T. Chlebowski, MD, PhD, is the recipient of the 2012 ASCOAmerican Cancer Society Award and Lecture for his pioneering work in the prevention and management of cancer. As the chief of medical oncology and hematology at the Harbor-UCLA Medical Center and researcher at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Dr. Chlebowski has been involved in full-scale clinical trials addressing issues related to breast cancer prevention and therapy and women’s health. As a Women’s Health Initiative (WHI) investigator, he led reports on estrogen alone and estrogen plus progestin influence on cancer endpoints where findings have substantially changed clinical use of menopausal hormone therapy worldwide with associated reduction in breast cancer incidence.

B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology Matti S. Aapro, MD, dean of the Multidisciplinary Oncology Institute in Genolier, Switzerland, and executive director of the International Society of Geriatric Oncology (SIOG), is the recipient of the 2012 B.J. Ken-

Ching-Hon Pui, MD

Ching-Hon Pui, MD, is the recipient of the 2012 Pediatric Oncology Award and Lecture for his outstanding scientific achievements in the field of pediatric oncology. Dr. Pui currently serves as chair of the department of oncology at St. Jude Children’s Research Hospital; co-leader of the hospital’s Hematological Malignancies Program; medical director of the St. Jude International Outreach China Program; and holder of the Fahad Nassar AlRashid Chair of Leukemia Research. For nearly 20 years, Dr. Pui has been a leader in the molecular definitions of childhood leukemia and of developing clinical protocols based on those findings. The current emphasis of his research is placed on genome-wide studies to understand leukemogenesis, and to identify “driver” molecular lesions and new drugs for target therapy. Watch future issues of The ASCO Post for news on other notable awardees to be honored at the upcoming Annual Meeting in June.

Photo by © ASCO/Todd Buchanan 2011

Visit the publisher of

The ASCO Post, Harborside Press, at BOOTH 6069


The ASCO Post  |   APRIL 15, 2012

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Calendar

2012 Oncology Meetings APRIL

MAY

3rd European Lung Cancer Conference April 18-21 • Geneva, Switzerland For more information: www.esmo.org

4th IMPAKT Breast Cancer Conference May 3-5 • Brussels, Belgium For more information: www.esmo.org

Diagnosis and Treatment of Advanced Forms of Prostate Cancer, Bladder Cancer and Kidney Cancer April 20-21 • Kiev, Ukraine For more information: http://nbscience.com Organisation for Oncology and Translational Research 8th Annual Conference April 20-21 • Kyoto, Japan For more information: www.ootr-institute.org/ 2nd Annual Stomach Cancer Education Symposium April 21 • Hollywood, Florida For more information: www.cantstomachcancer.org 3rd International Video Workshop on Radical Surgery in Gynaecological Oncology April 26-28 • Prague, Czech Republic For more information: www.ivw2012.cz 8th European Oncology Nursing Society Spring Convention April 26-27 • Geneva, Switzerland For more information: www.ecco-org.eu American Radium Society Annual Meeting April 28-May 2 • Las Vegas, Nevada For more information: www.americanradiumsociety.org American Roentgen Ray Society Annual Meeting April 29-May 4 • Vancouver, Canada For more information: www.arrs.org 2nd Annual Antibodies for Cancer Therapy April 30-May 4 • Boston Massachusetts For more information: www.pegsummit.com/cancer-antibodies

ONS 37th Annual Congress May 3-6 • New Orleans, Louisiana For more information: www.ons.org State of the Art Techniques in IMRT, IGRT, SBRT, Proton and Brachytherapy May 4-6 • Las Vegas, Nevada For more information: www.astro.org Current Strategies in the Treatment of Multiple Myeloma, Lymphoma and Leukemia May 12 • Dallas, Texas For more information: www.cancernetus.com Accelerating Anticancer Agent Development and Validation Workshop May 16-18 • Bethesda, Maryland For more information: www.acceleratingworkshop.org AUA Annual Meeting May 19-23 • Atlanta, Georgia For more information: www.aua2012.org

ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org Apoptosis and Cancer June 14-15 • Cambridge, United Kingdom For more information: www.abcam.com Melanocytes and Melanoma: From Basic Science to Clinical Applications June 18-20 • Malmö, Sweden For more information: www.melanoma2012.org 4th Molecular Diagnostics for Cancer Drug Development June 25-28 • Boston, Massachusetts For more information: http://moleculardiagnostics-cancer.com Cancer Vaccines & Active Immunotherapeutics: 3rd Annual Summit June 26-28 • Boston, Massachusetts For more information: http://cancervaccines-meeting.com MASCC/ISOO International Symposium on Supportive Care in Cancer June 28–30 • New York, New York For more information: www.kenes.com/mascc

13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

AUGUST Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org 10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com UICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec, Canada For more information: www.worldcancercongress.org

Keystone Symposia: The Role of Inflammation during Carcinogenesis May 20-25 • Dublin, Ireland For more information: www.keystonesymposia.org

SEPTEMBER JUNE ASCO Annual Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org Cambridge Healthtech Institute’s 10th Annual Meeting: Next-Gen Kinase Inhibitors June 4-6 • Cambridge, Massachusetts For more information: www.healthtech.com

JULY Best of ASCO® Chicago July 12-13 • Chicago, Illinois For more information: http://boa2012.asco.org

Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org

Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma

continued on page 82


new indication

for the First-Line Treatment of Recurrent Locoregional or Metastatic SCCHN in Combination With Platinum-Based Therapy With 5-FU

erbitux: now approved

In 5 IndIcatIons across 2 tumor types ERBITUX Indications Head and Neck Cancer

new

n ERBITUX速 (cetuximab) is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck n ERBITUX, in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck n ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed

Metastatic Colorectal Cancer n ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens n ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma n Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS n Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions n Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated Scan QR code for in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with more information. By squamous cell carcinoma of the head and neck treated in a clinical trial with European scanning the QR code, Union (EU)-approved cetuximab in combination with platinum-based therapy you are confirming you with 5-fluorouracil (5-FU). Closely monitor serum electrolytes, including serum are a US Healthcare Professional. magnesium, potassium, and calcium, during and after ERBITUX administration SCCHN=squamous cell carcinoma of the head and neck.

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.


Important Safety Information Including Boxed WARNINGS Infusion Reactions n Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical

trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions n Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest n Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of

the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In three patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity n Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD

Dermatologic Toxicities n In clinical studies of ERBITUX, dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial

inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 4 and 5. Severe acneiform rash occurred in 1-17% of patients — Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin n The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established

— Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

Electrolyte Depletion n Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 4 and two other clinical trials in colorectal

cancer and head and neck cancer, respectively and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3-4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidence of hypomagnesemia was similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3-4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy. — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary


Late Radiation Toxicities n The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX (cetuximab) in combination

with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing n In women of childbearing potential, appropriate contraceptive measures must be used during treatment with

ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus

n It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in

human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events n The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions,

cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus

n The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

n The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX

in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneiform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) vs radiation alone included: radiation dermatitis (23%/18%), acneiform rash (17%/1%), and weight loss (11%/7%)

n The most frequent adverse events for EU-approved cetuximab in combination with platinum-based therapy with

5-FU (CT) (n=219) vs CT alone (n=215) (incidence ≥40%) were acneiform rash (70%/2%), nausea (54%/47%), and infection (44%/27%). The most common grade 3/4 adverse events for cetuximab in combination with CT (≥10%) vs CT alone included: infection (11%/8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

n The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%)

n The most frequent adverse events seen in patients with metastatic colorectal cancer (n=354) treated with ERBITUX plus irinotecan in clinical trials (incidence ≥50%) were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common grade 3/4 adverse events (≥ 10%) included: diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2011 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US12AB01813

11/11


ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4), in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] Colorectal Cancer: Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.] Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information.] Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Pharmacology (12.1), Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 4, and 5 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 5, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 4, and 5. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 4 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

Erbitux1111PBSwip3.indd 1

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions with Erbitux (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1,3,4, and 5, Erbitux was discontinued in 3–10% of patients because of 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 data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 4) or Phase 2 (Studies 3 and 5) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck: Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 15 3 2 0 Infusion Reactionb Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages d 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse events in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).

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Table 2:

Incidence of Selected Adverse Events (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU Alone 5-FU (n=215) (n=219) Table 2: Incidence of Selected Adverse Events (≥10%) in Patients with Recurrent Locoregional Disease or System Organ Class Grades Grades Grades Metastatic SCCHN Grades Preferred Term 1–4 3 and 4 Cetuximab1–4 3 and 4 EU-Approved % of Patients Platinum-based plus Platinum-based Therapy with Therapy with Eye Disorders 5-FU Alone 5-FU Conjunctivitis 10 0(n=219) 0 0 (n=215) Gastrointestinal Disorders System Organ Class Grades Grades Grades Grades Nausea 54 4 Preferred Term 1–4 4 3 and 4 47 1–4 3 and 4 Diarrhea 26 5 16 1 % of Patients General Disorders and AdministrationEye SiteDisorders Conditions Conjunctivitis 10 0 0 13 0 0 Pyrexia 22 1 Disorders a 10 2 <1 0 Infusion ReactionGastrointestinal Nausea 54 4 47 4 Infections and Infestations Diarrhea 26 5 16 1 44 11 27 8 Infectionb General Disorders and Metabolism and Nutrition Disorders Administration Site Conditions Anorexia 25 1 Pyrexia 22 5 0 14 13 1 Hypocalcemia Infusion Reactiona 12 5 1 10 4 2 <1 0 Hypokalemia Infections and Infestations 12 7 7 5 b 44 5 11 5 27 8 HypomagnesemiaInfection 11 1 Metabolism and Nutrition Skin and Subcutaneous Tissue DisordersDisorders c Anorexia 25 9 5 14 1 70 2 0 Acneiform Rash Hypocalcemia 12 5 4 5 1 Rash 28 2 0 Hypokalemia 12 2 7 7 5 Acne 22 0 0 Hypomagnesemia 11 2 5 5 1 Dermatitis Acneiform 15 0 0 Skin and Subcutaneous Tissue Disorders Dry Skin 14 0 <1 0 70 9 2 0 Acneiform Rashc Alopecia 12 7 0 Rash 28 0 5 2 0 a Infusion reactionAcne defined as any event of “anaphylactic reaction”, “hypersensitivity”, “dyspnea”,0 22 2“fever and/or chills”, 0 b sepsis-related or “pyrexia” on Dermatitis the first day of dosing. Infection – this term excludes Acneiform 15 2 events which 0 are presented0 separately. c Acneiform as “acne”, “dermatitis acneiform”, Dry Skin rash defined as any event described 14 0 <1 “dry skin”,0 “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash =0 Alopecia 12 papular”, or “rash 0 pustular”. Chemotherapy 7 cisplatin + 5-fluorouracil or carboplatin a Infusion reaction defined +as5-fluorouracil any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first dosing. inInfection this term excludes sepsis-related events which are For cardiac disorders, approximately 9%dayof ofsubjects both the– EU-approved cetuximab plus chemotherapy andpresented c Acneiform rash defined as any event event. described “acne”,of“dermatitis acneiform”, chemotherapy-onlyseparately. treatment arms in Study 2 experienced a cardiac Theasmajority these events occurred “dry in skin”, “exfoliative rash”, “rash”, erythematous”, “rash “rashand papular”, pustular”. Chemotherapy = patients who received cisplatin/5-FU, with“rash or without cetuximab as macular”, follows: 11% 12% or in “rash patients who received + 5-fluorouracil or carboplatin + 5-fluorouracil cisplatin/5-FU withcisplatin or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with For cardiac disorders, of subjects in both the EU-approved cetuximab and or without cetuximab, respectively. In approximately both arms, the9%incidence of cardiovascular events was higher inplus thechemotherapy cisplatin chemotherapy-only treatment armstoincardiovascular Study 2 experienced event. Thewas majority of these events occurred in with 5-FU containing subgroup. Death attributed eventaorcardiac sudden death reported in 3% of the patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with with 5-FU alone arm. or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin Colorectal Cancer: Monotherapy —Death Tableattributed 3 contains selected adverse in 562 patients receiving with Erbitux 5-FU containing subgroup. to cardiovascular eventevents or sudden death was reported in 3% of the best supportive patients care (BSC) or with (cetuximab) monotherapy forand metastatic cancer in in thealone cetuximab plusErbitux platinum-based therapy with 5-FU arm 2% in thecolorectal platinum-based chemotherapy alone arm. at the recommended dose and schedule (400 mg/m2 initial dose, followed by Study 4. Erbitux with was5-FU administered 250 mg/m2 weekly). Colorectal Cancer: Erbitux Monotherapy — Table 3 contains selected adverse events in 562 patients receiving b

best supportive care (BSC) aloneEvents or withOccurring Erbitux (cetuximab) for Advanced metastatic colorectal Incidence of Selected Adverse in ≥10% ofmonotherapy Patients with Colorectalcancer in Study 4. Erbitux waswith administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by a Carcinoma Treated Erbitux Monotherapy 250 mg/m2 weekly). Erbitux plus BSC BSC alone Table 3: Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal (n=288) (n=274) Carcinomaa Treated with Erbitux Monotherapy Grades Any Grades Body System Any BSC alone 3Erbitux and 4plus BSC Grades 3 and 4 Preferred Term Gradesb (n=288) (n=274) % of Patients Grades Any Grades Body System Any Dermatology Preferred Term 3 and 4 Grades 3 and 4 Gradesb Rash/Desquamation 89 12 <1 % 16 of Patients Dry Skin 49 0 11 0 Dermatology Pruritus 40 8 0 Rash/Desquamation 89 2 12 16 <1 Other-Dermatology 27 6 1 Dry Skin 49 1 0 11 0 Nail Changes Pruritus 21 4 0 40 0 2 8 0 Body as a WholeOther-Dermatology 27 1 6 1 Nail Changes 21 33 0 4 0 Fatigue 89 76 26 Body as a Whole Fever 30 1 18 <1 c 89 5 33 76 26 20 Infusion ReactionsFatigue 30 <1 1 18 <1 Rigors, Chills Fever 13 4 0 c 20 5 Infusion Reactions Pain 13 14 <1 4 0 Abdominal Pain Rigors, Chills 59 52 16 Pain Pain-Other 51 16 34 7 Abdominal Pain 59 14 52 16 Headache 33 11 0 Pain-Other 51 4 16 34 7 Bone Pain 15 3 7 2 Headache 33 4 11 0 Pulmonary Bone Pain 15 3 7 2 Dyspnea 48 16 43 12 Pulmonary Cough 29 2 19 1 Dyspnea 48 16 43 12 GastrointestinalCough 29 2 19 1 Constipation Gastrointestinal 46 4 38 5 Constipation 46 4 38 5 Diarrhea 39 2 20 2 Diarrhea 39 6 2 20 2 Vomiting 37 29 6 Vomiting 37 1 6 29 6 Stomatitis 25 10 <1 Stomatitis 25 10 1 10 <1 Other-Gastrointestinal 23 18 8 23 0 10 18 8 Mouth Dryness Other-Gastrointestinal 11 4 0 Mouth Dryness 11 0 4 0 Infection Infection Infection without Infection neutropenia 35 13 17 6 without neutropenia 35 13 17 6 Neurology Neurology Insomnia 30 15 1 Insomnia 30 1 1 15 1 Confusion 15 9 2 Confusion 15 6 6 9 2 Anxiety 14 8 1 Anxiety 14 2 2 8 1 Depression 13 6 <1 Depression 13 1 1 6 <1 a a Adverse reactions frequently in Erbitux-treated patientswith compared with bcontrols. Adverse events Adverse reactions occurring moreoccurring frequentlymore in Erbitux-treated patients compared controls. Adverse bevents c CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, were using the NCI were graded using thegraded NCI CTC, V 2.0. Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, bronchospasm, chest tightness,chest swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, visual disturbances, or other)by recorded by the investigator as pain, pruritus, sweating, tremors, shaking, cough, visual cough, disturbances, or other) recorded the investigator as BSC = best infusion-related. infusion-related. BSC = best supportive caresupportive care

Table 3:

Erbitux in Combination with Irinotecan — The most frequently reported adverse events in 354 patients treated Erbitux in Combination with The most reported adverseasthenia/malaise events in 354 (73%), patients treated with Erbitux plusIrinotecan irinotecan in—clinical trials frequently were acneiform rash (88%), diarrhea (72%), and with Erbitux plus nausea irinotecan in clinical trials were Grades acneiform (88%), asthenia/malaise (73%), diarrhea (72%), andasthenia/ (55%). The most common 3–4rash adverse events included diarrhea (22%), leukopenia (17%), nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/ malaise (16%), and acneiform rash (14%). malaise (16%), and acneiform rash (14%).

Erbitux1111PBSwip3.indd 2

Erbitux1111PBSwip3.indd 2

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux (cetuximab) has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody neutralizing positivityforin immunogenicity. an assay may be influenced responses by several Immunogenicity: As with (including all therapeutic proteins,antibody) there is potential Immunogenic factors toincluding assay timing radiometric of sample assay collection, medications, and cetuximab weremethodology, assessed usingsample either ahandling, double antigen or an concomitant ELISA assay. Due to limitations underlying disease. For theseandreasons, comparison the incidence of antibodies to Erbitux with receiving the incidence in assay performance sampling timing, theofincidence of antibody development in patients Erbituxof antibodies to other has products mayadequately be misleading. (cetuximab) not been determined. Non-neutralizing anti-cetuximab antibodies were detected in 5%

(49 of 1001) of evaluableThe patients without apparent effect has on the safety or antitumor activity of Erbitux. use of Erbitux. Postmarketing Experience: following adverse reaction been identified during post-approval BecauseThe thisincidence reactionofwas reported from is a population of uncertain size, it was always possible to reliably estimate antibody formation highly dependent on the sensitivity andnot specificity of the assay. Additionally, the observed incidence aofcausal antibody (including to neutralizing antibody) positivity in an assay may be influenced by several its frequency or establish relationship drug exposure. factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and

• Aseptic meningitis underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS

The following has been identified during post-approval use of Erbitux. A drug Postmarketing interaction studyExperience: was performed in whichadverse Erbituxreaction was administered in combination with irinotecan. There was Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. its frequency or establish a causal relationship to drug exposure.

USE IN • SPECIFIC POPULATIONS Aseptic meningitis Pregnancy: Category C — There are no adequate and well-controlled studies of Erbitux in pregnant DRUGPregnancy INTERACTIONS women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be A drug interaction study was performed in which was administered in combination withHuman irinotecan. wasto essential for normal organogenesis, proliferation, and Erbitux differentiation in the developing embryo. IgG isThere known no placental evidence ofbarrier; any pharmacokinetic interactions Erbitux cross the therefore, Erbitux may be between transmitted fromand theirinotecan. mother to the developing fetus, and has the potentialUSE to IN cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if SPECIFIC POPULATIONS the potential benefitPregnancy justifies theCategory potentialC risk to the are fetus. Pregnancy: — There no adequate and well-controlled studies of Erbitux in pregnant

women. Based on animal were models, EGFRweekly has been in the the control of prenatal human development andcetuximab may be Pregnant cynomolgus monkeys treated withimplicated 0.4 to 4 times recommended dose of for normal organogenesis, proliferation, and differentiation in theday developing embryo. Human IgGwas is known to (based essential on body surface area) during the period of organogenesis (gestation [GD] 20–48). Cetuximab detected cross the placental may from be transmitted from the thefetal developing fetus, and or hasother the in the amniotic fluid andbarrier; in the therefore, serum ofErbitux embryos treated dams at mother GD 49.toNo malformations potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred ifat potential benefit justifies the potential risk to the fetus. doses oftheapproximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab

Nursing(based Mothers: It issurface not known whether is organogenesis secreted in human milk.day IgG[GD] antibodies, such as Erbitux, can be on body area) during theErbitux period of (gestation 20–48). Cetuximab was detected excretedin inthehuman milk. many drugs excreted humandams milkatand of the potential fororserious amniotic fluidBecause and in the serum of are embryos fromintreated GDbecause 49. No fetal malformations other adverseteratogenic reactions effects in nursing infants from Erbitux, a decision should be made whether to discontinue occurred in offspring. However, significant increases in embryolethality and abortionsnursing occurredoratto discontinue drug, taking into account of the drugdose to the mother. If(based nursing interrupted, based on dosesthe of approximately 1.6 to 4 timesthe theimportance recommended human of cetuximab on istotal body surface area). the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be be resumed earlier than 60milk. days following thedrugs last dose of Erbitux. excreted in human Because many are excreted in human milk and because of the potential for serious adverse in nursing infants from Erbitux, a decision should bepatients made whether to discontinue nursing orThe to Pediatric Use:reactions The safety and effectiveness of Erbitux in pediatric have not been established. discontinue the drug, taking into account the importance of the drug evaluated to the mother. If nursing patients is interrupted, based on pharmacokinetics of cetuximab, in combination with irinotecan, were in pediatric with refractory the mean of cetuximab [see Clinical Pharmacology (12.3) inwas Full administered Prescribing Information], nursing shouldupnotto solid tumors in anhalf-life open-label, single-arm, dose-finding study. Erbitux once weekly, at doses 2 be resumed than 60 daysfrom following the years last dose Erbitux. 250 mg/m , to 27 earlier patients ranging 1 to 12 old;ofand in 19 patients ranging from 13 to 18 years old. No new safety signalsUse: were in pediatric patients. The pharmacokinetic profileshave of cetuximab theThe two Pediatric Theidentified safety and effectiveness of Erbitux in pediatric patients not been between established. pharmacokinetics combination with irinotecan, were patients appeared with refractory age groups were similarofatcetuximab, the 75 andin 150 mg/m2 single dose levels. Theevaluated volume inofpediatric the distribution to be 2 to solid tumors an open-label, single-arm, dose-finding administered once weekly, at doses independent of dosein and approximated the vascular spacestudy. of 2–3Erbitux L/m2.was Following a single dose of 250 mg/mup , the , to 0-inf 27 patients ranging from 1 tomg•h/mL 12 years old; andin inthe 19 younger patients ranging from(1–12 13 to 18 yearsn=9) old. and No 250 mean mg/m2AUC geometric (CV%) value was 17.7 (34%) age group years, new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours 2 single dose levels.55The volume of the appeared to be agetogroups were similar the 75 age and group, 150 mg/m (range 69 188 hours) for the at younger and 82 hours (range to 117 hours) fordistribution the adolescent age group. independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the Geriatric Use: Ofmean the 1062 who received with(34%) irinotecan Erbituxage monotherapy five n=9) studies geometric AUC0-infpatients (CV%) value was 17.7 Erbitux mg•h/mL in the or younger group (1–12 inyears, and of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 for the agepatients. group, and 82 hours (range 55 to 117 hours) for the adolescent age group. observed between thesehours) patients andyounger younger Use: Of theconducted 1062 patients who received withneck irinotecan or did Erbitux in five number studies ofof ClinicalGeriatric studies of Erbitux in patients with Erbitux head and cancer notmonotherapy include sufficient 363 patients werethey 65 years of age or older. No overall differences in safety or efficacy were subjectsadvanced aged 65colorectal and overcancer, to determine whether respond differently from younger subjects. observed between these patients and younger patients.

OVERDOSAGE

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of

2 subjects single aged 65dose and of over to determine whetheristhey respond from younger subjects.events were reported The maximum Erbitux administered 1000 mg/mdifferently in one patient. No adverse for this OVERDOSAGE patient.

NONCLINICAL TOXICOLOGY The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the NONCLINICAL TOXICOLOGY Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test in female cynomolgus monkeys weekly doses of 0.4 to 4 timespotential the human dose of cetuximab (based cetuximab for carcinogenic receiving potential, and no mutagenic or clastogenic of cetuximab was observed in theon total body surface area). Cetuximab-treated incidences of irregular or absent cycles, Salmonella-Escherichia coli (Ames) assayanimals or in theexhibited in vivo ratincreased micronucleus test. Menstrual cyclicity was impaired as compared to control animals. These effectsweekly were initially week 25 dose of cetuximab treatment in female cynomolgus monkeys receiving doses ofnoted 0.4 tobeginning 4 times the human of cetuximab (based and on continued the 6-week period. Inanimals this same study, increased there wereincidences no effectsof ofirregular cetuximab treatment on totalthrough body surface area). recovery Cetuximab-treated exhibited or absent cycles, measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and as compared to control monkeys. It is not known if cetuximab canthere impair fertility in humans. continued throughmale the 6-week recovery period. In this same study, were no effects of cetuximab treatment on male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) Animalmeasured Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic Pharmacology cynomolgus monkeys, cetuximab, when administered at dosesdose of findings,Animal including inflammationand/or at theToxicology: injection siteInand desquamation of the external integument. At the highest approximately 0.4 to 4 of times weekly humanesophagus, exposure (based on total body area), resulted in dermatologic level, the epithelial mucosa the the nasal passage, and tongue were surface similarly affected, and degenerative findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at level,dose the epithelial mucosaafter of theapproximately nasal passage,13esophagus, and tongue were similarly affected, and degenerative the highest level beginning weeks of treatment. changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at theCOUNSELING highest dose level beginning after approximately 13 weeks of treatment. PATIENT INFORMATION PATIENT COUNSELING INFORMATION Advise patients: Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both and females during and for 6 months following the last dose of Erbitux therapy. • Omales f the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC aLLC wholly-owned subsidiary of Eli LillyLilly andandCompany, USA Manufactured by ImClone a wholly-owned subsidiary of Eli Company,Branchburg, Branchburg, NJ NJ 08876 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJNJ08543 Distributed and marketed by Bristol-Myers Squibb Company, Princeton, 08543USA USA Co-marketed by Eli Lilly Indianapolis, IN 46285 USAUSA Co-marketed by Eliand LillyCompany, and Company, Indianapolis, IN 46285

Copyright © 2004–2011 ImClone a wholly-owned subsidiary Lillyand andCompany, Company,and and Copyright © 2004–2011 ImClone LLC aLLC wholly-owned subsidiary of of EliEli Lilly Bristol-Myers Company. All rights reserved. Bristol-Myers SquibbSquibb Company. All rights reserved. 1236886A9 1236886A9

Rev November 2011 Rev November 2011 693US11PBS17802

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The ASCO Post  |   APRIL 15, 2012

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Calendar 2012 Oncology Meetings continued from page 76 17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/conference/17th_ICCN

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer

24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu

9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

Markers in Cancer 2012 October 11-13 • Hollywood, Florida For more information: markersincancer.org

Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation​ symposium.org

2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

OCTOBER ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org 14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information:  www.lynnsagebreastcancer 44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org 32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com 12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, United Kingdom For more information: www.siog.org

RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp ASCO’s Quality Care Symposium November 30-December 1 • San Diego, California For more information:quality2012.asco.org

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com

DECEMBER

AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org

35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com

2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

Pan Pacific

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ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

NOVEMBER 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

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CALL FOR ABSTRACTS: April 16, 2012

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ASCOPost.com  |   APRIL 15, 2012

PAGE 83

News

Thomas J. Smith, MD, Appointed Director of Palliative Care, Johns Hopkins Medicine and Sidney Kimmel Comprehensive Cancer Center

T

homas J. Smith, MD, has joined Johns Hopkins as the Director of Palliative Care for Johns Hopkins Medicine and the Hopkins’ Sidney Kimmel Comprehensive Cancer Center.

Thomas J. Smith, MD

Before joining Johns Hopkins, Dr. Smith served as the Medical Director of the Thomas Palliative Care Program and the Co-director of the Massey Cancer Center Cancer Control and Prevention Program at the Virginia Commonwealth University. Board-certified in oncology palliative and hospice medicine, he focuses on neuropathic pain, care at the

Sandra M. Swain, MD, Joins Washington Hospital Center

S

end of life, and cost issues in his research. “Dr. Smith is one of the foremost leaders in the field of palliative care,” said Edward Miller, MD, Dean and

CEO of Johns Hopkins Medicine. “His broad range of expertise in issues related to patients across the medical spectrum needing palliative care and

his outstanding research and clinical care in the oncology setting will set apart our institution’s palliative care program.”

A Network of Knowledge on Every Page Inside every issue: • NCCN Clinical Practice Guidelines in Oncology™ • Comprehensive reviews • CME articles • NCCN Guidelines updates • Provocative editorials and opinions

andra M. Swain, MD, has been appointed Medical Director of Washington Cancer Institute at MedStar Washington Hospital Center, Washington, DC.

Sandra M. Swain, MD

Dr. Swain comes to the Hospital Center from the NCI, where she was the Deputy Director of the Medicine Branch, Chief of the Cancer Therapeutics Branch, and most recently led the intramural breast cancer clinical research effort at the Center for Cancer Research. She is a leader in the design of national clinical trials in early breast cancer. Her cutting-edge research in the causes and treatment of advanced inflammatory breast cancer has made her a leading authority in her field.

Read JNCCN Cover to Cover Visit www.JNCCN.org for more details


The ASCO Post  |   APRIL 15, 2012

PAGE 84

Lab Notes

Ongoing Molecular Research in the Science of Oncology GENE PROFILING Targeted Massively Parallel Sequencing Identifies Clinically Relevant Alterations in Cancer Genes Systematic methods for profiling tumor genomic alterations remain underdeveloped, with current clinical profiling usually being confined to identification of limited numbers of oncogene point mutations. At present, there is no systematic technique for interrogating tumor samples in situ for a comprehensive panel of “actionable” cancer gene alterations—ie, alterations that might affect treatment decisions. Wagle and colleagues from the Dana-Farber Cancer Institute, Boston, recently reported use of a targeted,

massively parallel sequencing approach to detect genomic alterations in formalin-fixed, paraffin-embedded (FFPE) tumor samples. The technique used by these investigators is an adaptation of exon capture (a hybrid selection method that enriches for coding sequences prior to sequencing) and massively parallel sequencing methods that allowed multiple barcoded tumor DNA samples to be pooled into a single sequencing reaction while preserving deep sequencing of the targeted regions. This approach simultaneously identifies mutations and chromosomal copy-number alterations in tumor material.

Impact on Personalized Medicine In this proof-of-concept study, 137 potentially actionable genes (encoding approximately 400,000 cod-

PHOTOGRAPHER’S CORNER

Welcome Spring 2012

ing bases) known to undergo somatic alterations in cancer were sequenced from 10 pooled FFPE tumor DNA samples. A nearly 400-fold mean sequence coverage was achieved, and single-nucleotide variants as well as small insertions/deletions and chromosomal copy-number alterations were simultaneously detected with high accuracy compared with other methods currently in clinical use (eg, OncoMap, a mass-spectrometric genotyping technology that interrogates more than 400 known mutations in 33 cancer genes). Biologically or clinically meaningful alterations were detected in all 10 FFPE samples, including 2 samples that contained only 10% to 20% tumor cells. As the authors stated, “[T]argeted, massively parallel sequencing offers a promising method to detect genetic alterations across a large panel of cancer genes…. This approach may ultimately impact clinical practice by offering a categorical means to identify genetic changes affecting genes and pathways targeted by existing and emerging drugs, thereby speeding the advent of personalized cancer medicine.” Wagle N, et al: Cancer Discovery 2:8293, 2012.

COMBINATION THERAPY Targeted Mutations in ATR Pathway and Implications for Combination Strategies

Special thanks to Nora Janjan, MD, MPSA, MBA, for sharing her photos of bluebonnets, the official state flower of Texas, welcoming spring 2012 in Dr. Janjan’s hometown of Navasota, Texas. “As fragrant as lilacs,” said Dr. Janjan. Share your high-resolution photos of for publication in The ASCO Post. Send your photos to editor@ASCOPost.com.

Many chemotherapy agents work by causing DNA strand breaks or accumulation of DNA replication intermediates. ATR (ataxia-telangiectasia mutated and Rad 3-related protein) is a potential target for combination drug strategies, because signaling of this protein in response to such altered DNA structures results in activation of cellular survival mechanisms. In a recent study, Wilsker and colleagues from the Johns Hopkins University School of Medicine, Baltimore, used a panel of genetically modified human cancer cells to identify the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. It was found that activation of the upstream kinase S-phase–specific cyclin-dependent kinase (Cdk) 2

was required for robust activation of ATR in response to numerous and diverse chemotherapeutic agents, and that Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs. In contrast, downstream signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses for a smaller subset of the drugs tested.

Enhanced Therapeutic Effects These findings indicate that specific inhibition of the Cdk2/ATR/ Chk1 pathway with distinct regulating agents could differentially sensitize cancer cells to a wide range of therapeutic agents. As the investigators stated, “ATR is known to be activated by a broad range of agents that directly or indirectly inhibit DNA replication. Our study of a large panel of approved anticancer agents shows just how broad this range can be and how seemingly disconnected pathways can affect DNA metabolism.” In this regard, they noted that dactinomycin and bortezomib (Velcade), for example, induced a similar dependence on ATR pathways for cell growth after treatment, despite having highly dissimilar mechanisms of action—a finding suggesting that “there may be many avenues by which ATR inhibitors might provide enhanced therapeutic effects.” A number of ATR inhibitors currently are in preclinical evaluation. The investigators suggested that, on the basis of findings in their study, “If these inhibitors prove to be sufficiently specific, they may facilitate many potential combinatorial strategies that may be broadly applicable to many types of cancer.”

Wilsker D, et al: Mol Cancer Ther 11:98107, 2012.

TREATMENT RESISTANCE Androgen Deprivation Therapy May Lead to Castration Resistance in Prostate Cancer Although androgen-deprivation therapy is effective in inducing regression of androgen-dependent prostate cancer, relapse often occurs in an androgen-independent manner and is associated with poor prognosis. The


ASCOPost.com  |   APRIL 15, 2012

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Lab Notes

mechanisms underlying castration resistance are not fully understood. Sung and colleagues from See Page 93 Shanghai Jiao Tong University, China, and Genentech, San Francisco, recently studied the potential contribution of androgen deprivation to epithelial–mesenchymal transition, a key developmental process that is also implicated in poor outcomes in a number of cancers, including prostate cancer. The investigators found that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants exhibit epithelial–mesenchymal transition as well as increased stem cell–like features following androgen deprivation. Further, they found a significant increase in mesenchymal markers (eg, VIMENTIN, ZEB1, CADHERIN11, FIBRONECTIN1) in prostate tumors from patients who had received androgen-deprivation therapy compared with patients who had not and despite variation in age and tumor grade among those who had received such treatment. Additional findings suggested that epithelial–mesenchymal transition was mediated by a bidirectional feedback loop involving the androgen receptor and the Zeb1 transcription factor, with each acting to inhibit the other.

Alternative Approach According to Sung and colleagues, their study shows that “whereas andro-

The ASCO Post

gen deprivation can effectively control prostate tumor size initially, it simultaneously promotes [epithelial–mesenchymal transition], an unintended consequence that may ultimately lead to castration resistance. Hence, a rational alternative approach [to treatment] may be to inhibit [epithelial–mesen-

chymal transition] in combination with [androgen-deprivation therapy] to prevent disease progression.” In this regard, an antagonist to Ncadherin, a protein involved in epithelial–mesenchymal transition, has been shown to delay establishment of castration resistance. As the investiga-

tors noted, blocking epithelial–mesenchymal transition at a stage when castration resistance is already present may also be feasible since inhibition of Zeb1 may act to reverse epithelial– mesenchymal transition.

Sun Y, et al: Cancer Res 72:527-536, 2012.

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

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Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

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*This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010. Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

Now available for patients with ductal carcinoma in situ (DCIS)


The ASCO Post  |   APRIL 15, 2012

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Sorafenib plus Capecitabine for HER2-negative Advanced Breast Cancer The addition of sorafenib (Nexavar) to capecitabine (Xeloda) improved progression-free survival among women with locally advanced or metastatic HER2-negative breast cancer in a randomized, double-blind, placebocontrolled phase IIB trial. “There was no significant improvement for overall survival,” the investigators reported in the Journal of Clinical Oncology. Median survival was 22.2 months for patients receiving sorafenib vs 20.9 months for those receiving placebo.

SOLTI-0701 Study A total of 229 patients were randomly assigned to first-line or secondline capecitabine at 1,000 mg/m2 orally twice a day for days 1 to 14 of every 21-day cycle, with sorafenib at 400 mg orally twice a day or placebo. Sorafenib is an oral multikinase inhibitor that has both antiproliferative and antiangiogenic activity. “Prior chemotherapy, including taxane and/or anthracycline treatment, was allowed but was limited to one regimen for advanced disease. Prior hormone therapy and radiation were allowed,” the researchers noted. Patients receiving sorafenib had a significant improvement in progression-free survival, See Page 93 with a median of 6.4 months vs 4.1 months for those receiving placebo. “This translated into a 42% reduction in the relative risk of disease progression or death,” the authors stated. The study, SOLTI-0701, was conducted by the SOLTI Spanish Breast Cancer Research Group and supported in part by Onyx Pharmaceuticals and Bayer HealthCare Pharmaceuticals, which also provided sorafenib free of charge and editorial support. “The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients,” the investigators concluded. “A phase  III confirmatory trial has been initiated with a reduced sorafenib dose.” The most common toxicity was hand-foot skin reaction/ hand-foot syndrome, which occurred more frequently in patients receiving

sorafenib (90% vs 66% in the control group) and earlier (median time to first incidence 14 vs 64 days). Hand-foot skin reaction/syndrome and diarrhea, which occurred in 58% of patients receiving sorafenib vs 30% of those receiving placebo, were the most common adverse effects leading to discontinuation in both groups of patients.

RESILIENCE Study The phase III trial, known as RESILIENCE, began recruiting patients in November 2010 and is similar in design to SOLTI-0701, but “uses a different dosing schema and requires a more aggressive and proactive strategy for managing [hand-foot skin reaction/syndrome], with the objective of reducing its incidence, duration, and severity, the authors noted. In the new trial, “sorafenib is initiated at a total daily dose of 600 mg (200 mg in the morning and 400 mg in the evening) and capecitabine at 1,000 mg/m2 twice a day for 14 of every 21 days, with the option of escalating the daily dose to 800 mg (400 mg twice a day) and 1,250  mg/m2 twice a day, respectively, as tolerated, or reducing the dose to manage toxicity. Because [hand-foot skin reaction/ syndrome] emerged early on during the SOLTI-0701 trial, RESILIENCE provides detailed guidance for prophylactic and symptomatic treatment and calls for patients to be monitored closely during the first few months of treatment. The RESILIENCE study will also provide a more robust assessment of [overall survival],” for which SOLTI-0701 was not sufficiently powered, according to the investigators. “The SOLTI-0701 results suggest a potential role for the combination of sorafenib plus capecitabine in HER2negative advanced breast cancer but will need to be confirmed in the phase III setting. These results should not be considered practice changing,” the authors stated. “The RESILIENCE study will definitively ascertain the efficacy and safety of this combination.” Baselga J, et al: J Clin Oncol. March 12, 2012 (early release online).

Benefit of Adjuvant Tamoxifen in ER-positive DCIS Retrospective analyses of hormone receptors among patients enrolled in the National Surgical

Adjuvant Breast and Bowel Project (NSABP) B-24 study showed that women with estrogen receptor (ER)-positive ductal carcinoma in situ (DCIS) who received tamoxifen after standard therapy had significant reductions in subsequent breast cancer. “The use of adjuvant tamoxifen should be considered for patients with DCIS,” concluded the researchers, who represented the NSABP and centers in the United States and the Netherlands. “The B-24 trial was initiated before hormone receptor status was routinely evaluated in DCIS, and patients were enrolled without this information. The current study was undertaken to evaluate, retrospectively, the relationship between adjuvant tamoxifen and receptor status in DCIS, with the expectation that the results would be similar to those in [invasive breast cancer],” the authors wrote. For the retrospective evaluation, ER and progesterone receptor (PgR) results were available for a subset of 732 patients, 41% of the original study population. ER was positive in 76% of those patients, and PgR was positive in 66%.

Preventive Effect “Patients with ER-positive DCIS treated with tamoxifen (vs placebo) showed significant decreases in subsequent breast cancer at 10 years (HR = 0.49; P = .001) and overall follow-up (HR = 0.60; P = .003), which remained significant in multivariable analysis (overall HR = 0.64; P = .003),” the researchers reported. “Results were similar, but less significant, when subsequent ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately.” Stratifying patients by PgR and by PgR and/or ER status was not more predictive than ER alone. “Tamoxifen reduced contralateral breast cancer in patients with ER-positive and ‑negative DCIS, as expected (ie, prevention),” the authors noted. “No ipsilateral benefit was observed in ER-negative disease, emphasizing that tamoxifen must bind to functional ER to exert its beneficial effect on preexisting residual tumor cells.” The study was supported by grants from the National Institutes of Health and by the Breast Research Founda-

tion and AstraZeneca.

Allred DC, et al: J Clin Oncol. March 12, 2012 (early release online).

PROSTATE CANCER PSA Screening Reduced Prostate Cancer–Specific but Not Overall Mortality “Analyses after 2 additional years of follow-up consolidated our previous finding that [prostate-specific antigen (PSA)]-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality,” investigators from the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported in The New England Journal of Medicine. At a median follow-up of 11 years in the core age group (55 to 69 years old), the relative reduction in the risk of death among the men randomly assigned to the PSA screening group was 21%, and 29% after adjusting for noncompliance. The ERSPC is a multicenter study that involved 182,160 men between the ages of 50 and 74 when they entered the study, including 162,388 men in the core age group. There were 299 deaths from prostate cancer in the screening group, corresponding to a death rate of 0.39 per 1,000 personyears, and 462 in the control group, corresponding to a death rate of 0.50. “The absolute reduction in mortality in the screening group was 0.10 deaths per 1,000 person-years or 1.07 deaths per 1,000 men who underwent randomization,” the investigators stated. “To prevent one death from prostate cancer at 11 years of follow-up, 1,055 men would need to be invited for screening and 37 cancers would need to be detected.” Overall mortality was similar among men who had PSA screening and those who did not. There were 18.2 deaths per 1,000 person-years in the screening group and 18.5 per 1,000 person-years in the control group.

Controversy Renewed “The controversy regarding screening for prostate cancer has been renewed by the publication of the draft report of the U.S. Preventive Services Task Force, which after a literaturebased analysis of benefits and harms continued on page 88


American Society of Clinical Oncology

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Collaborating to Conquer Cancer


The ASCO Post  |   APRIL 15, 2012

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In the Literature

Emerging Clinical Data on Cancer Management continued from page 86

recommended against the use of PSA testing in asymptomatic men,” the authors noted in the discussion section of their study report. “Clearly, the issue can be resolved only on the basis of evidence that considers both the advantages and disadvantages of screening, data that are not available at this time,” they added. Schröder FH, et al: N Engl J Med 366:981-990, 2012.

GASTRIC CANCER Salvage Chemotherapy plus Best Supportive Care in Advanced Gastric Cancer Adding salvage chemotherapy to best supportive care was tolerated and improved overall survival among patients with advanced gastric cancer previously treated with both fluoropyrimidines and platinum, administered simultaneously or concurrently. The authors of the study report, published in the Journal of Clinical Oncology, noted that at the time the trial was designed there was no evidence that salvage chemotherapy in patients with advanced gastric cancer substantially prolonged overall survival, but there was a potential for toxicity from the treatment. A total of 202 patients were enrolled at eight tertiary care centers in Korea, where gastric cancer is the most frequently occurring malignan-

cy. They were randomly assigned in a 2:1 ratio to receive either salvage chemotherapy plus best supportive care or best supportive care alone. “Choice of [salvage chemotherapy]—either docetaxel … 60 mg/m2 every 3 weeks or irinotecan … 150 mg/m2 every 2 weeks—was left to the discretion of investigators,” the authors stated.

improve efficacy in this setting without compromising tolerability.

Major Findings

Eating more red meat appears to be associated with an increased risk of allcause mortality and death from cancer and cardiovascular disease, but substituting fish, poultry, nuts, legumes, lowfat dairy products, and whole grains for red meat is associated with a lower mortality risk, according to a study published online first by Archives of Internal Medicine. The study documented 23,926 deaths, including 9,464 deaths from cancer and 5,910 from cardiovascular disease among 37,698 men in the Health Professionals Follow-up Study (1986–2008) and 83,644 women in the Nurses’ Health Study (19802008) who were free of cancer and cardiovascular disease at baseline. “Diet was assessed by validated food frequency questionnaires and updated every 4 years,” the investigators reported. The elevated risk of total mortality in the pooled analysis for a one-serving-per-day increase was 12% for total red meat, 13% for unprocessed red meat, and 20% percent for processed red meat. “We found no statistically significant differences among specific unprocessed red meat items or among specific processed red meat items for the associations with total mortality,” the authors reported. “However, bacon and hot dogs tended to be associated with a higher risk than other items.”

Median overall survival was 5.3 months among 133 patients receiving salvage chemotherapy plus best supportive care, compared to 3.8 months among 69 patients receiving only best supportive care (one-sided P = .007). Salvage chemotherapy was generally well tolerated, and adverse events were similar in the two arms. The investigators found no median overall survival difference between docetaxel and irinotecan (5.2 vs 6.5 months; P = .116). “Despite recent advances, prognosis of patients with [advanced gastric cancer] remains poor,” the researchers noted in their conclusion. “It could be generalized with all the data available, including those from numerous phase  II trials, two phase III trials (one among Asian and another among white patients), and different chemotherapy regimens, that [salvage chemotherapy] should be considered a standard of care in patients with [advanced gastric cancer].” The addition of another drug to docetaxel or irinotecan, particularly a molecularly targeted agent, they continued, might

Kang JH, et al: J Clin Oncol. March 15, 2012 (early release online).

DIET AND NUTRITION Higher Intake of Red Meat Associated with Increased Risk of Mortality

Substitution Analyses In their substitution analyses, the authors estimated that replacing one serving of total red meat with one serving of fish, poultry, nuts, legumes, low-fat dairy products, or whole grains

The ASCO Post Wants to Hear from You

© Edward Koren/The New Yorker Collection/www.cartoonbank.com

daily was associated with a lower risk of total mortality: 7% for fish, 10% for legumes and for low-fat dairy products, 14% for poultry and for whole grains, and 19% for nuts. The investigators estimated that 9.3% of total deaths in men and 7.6% in women during follow-up could be prevented if all the participants consumed fewer than 0.5 servings per day of total red meat. “Regarding cancer mortality, red meat intake has been associated with increased risks of colorectal cancer and several other cancers,” the authors commented. “Several compounds in red meat or created by high-temperature cooking, including N-nitroso compounds (nitrosamines or nitrosamides) converted from nitrites, polycyclic aromatic hydrocarbons, and heterocyclic amines, are potential carcinogens. Heme iron and iron overload might also be associated with increased cancer risk through promotion of N-nitroso compound formation, increased colonic cytotoxicity and epithelial proliferation, increased oxidative stress, and iron-induced hypoxia signaling.”

‘Holy Cow!’ In an invited commentary, entitled “Holy Cow! What’s Good for You Is Good for Our Planet,” Dean Ornish, MD, of the University of California, San Francisco, wrote, “In addition to their health benefits, the food choices we make each day affect other important areas as well. What is personally sustainable is globally sustainable. What is good for you is good for our planet.” Pointing out that plant-based foods “are rich in phytochemicals, bioflavonoids, and other substances that are protective,” he noted, “what we include in our diet is as important as what we exclude, so substituting healthier foods for red meat provides a double benefit to our health.”

Pan A, et al: Arch Intern Med. March 12, 2012 (early release online). Ornish D: Arch Intern Med. March 12, 2012 (early release online).

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


Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

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Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2011 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-P400-R0 October 2011


BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions]. INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug. QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology]. Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology]. General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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]. Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. 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 clinical practice. Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies]. Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 2 2 -

(1) (1)

1 (<1) 3 (1.5) -

1 1

22 20 8 4 3 -

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

4 1

(2)

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

1 1 1 -

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

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

-

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. 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. Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge. DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions]. Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum. Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions]. Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. 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. In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in 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 from FARESTON, 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 There is no indication for use of FARESTON in pediatric patients. Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Race The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions]. Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions]. Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food. Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations]. Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions]. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology]. Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment. Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions]. Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2011 GTx, Inc. All rights reserved. 2E Rev. 03/2011


ASCOPost.com  |   APRIL 15, 2012

PAGE 91

In the News

Options for Preserving Fertility Should Be Considered Early to Maximize the Likelihood of Success By Charlotte Bath

M

ost cancer survivors prefer to have biologic offspring despite concerns about the possible effects of cancer treatment on the child, the child’s lifetime cancer risk, or their own longevity, according to an ASCO panel that developed guidelines on fertility preservation in patients with cancer.1 While sperm and embryo cryopreservation remain the methods of fertility preservation with the greatest likelihood of success—as they were when the guidelines were issued in 2006—newer methods have also shown success or promise. A constant, however, is the need for oncologists to discuss with patients in their reproductive years (or with the parents of younger patients) the risk of infertility and the options for fertility preservation.

Ann Partridge, MD, MPH

In an interview with The ASCO Post, Ann Partridge, MD, MPH, Director of the Program for Cancer Survivorship at Dana Farber Cancer Center in Boston and a member of the 2006 ASCO panel on fertility preservation, discussed some changes and advances since the guidelines were issued.

Oocyte Preservation For oocyte cryopreservation, eggs removed from a woman’s body are not fertilized with sperm to create embryos before being frozen. For this reason, oocyte cryopreservation may be a suitable option for women who do not have a partner, do not want to use donor sperm, or have religious or ethical objections to embryo cryopreservation. Embryo and oocyte cryopreservation both require approximately 2 weeks of daily injections of folliclestimulating hormone to stimulate the development of eggs.

Ovarian Suppression Oocyte cryopreservation is “much improved,” Dr. Partridge said. “When we wrote the guidelines in 2006, it was very experimental, with very low success rates.” But now “some centers are finding better success rates with oocyte preservation,” and there is “more and more success in terms of having a pregnancy after oocyte cryopreservation,” she added. “The jury is still out” on ovarian suppression, using hormonal therapies to prevent premature menopause and infertility in patients being treated with chemotherapy or radiation therapy, Dr. Partridge said. A randomized trial testing the potential benefits of using the gonadotropinreleasing hormone (GnRH) agonist triptorelin (Trelstar) to prevent chemotherapy-induced amenorrhea among premenopausal women with breast cancer found that amenorrhea rates were comparable in the triptorelin and control groups. That study was published in the Journal of Clinical Oncology 2 ( JCO) and reported in the Los Angeles Times. In an editorial3 accompanying the journal article and a podcast on the journal website, Dr. Partridge, who works mainly with patients who have breast cancer, noted that the use of GnRH agonists “is appealing, given that they are readily available and are generally less cumbersome than available alternative strategies including in vitro fertilization and embryo cryopreservation before treatment.” Data on GnRH agonists, however, “have been mixed,” Dr. Partridge noted. The triptorelin study reported in JCO is one of six recently completed or ongoing studies on GnRH agonists. Two other studies also had negative results; two had positive results; and the results of one trial have not yet been reported. That trial, the Prevention of Early Menopause Study (POEMS; Southwest Oncology Group [SWOG] study 0230), is a large international multicenter trial testing goserelin (Zoladex) with standard adjuvant chemotherapy. “Critically, the confounding effects of tamoxifen treatment should not be an issue in this study, which includes only women with hormone receptor– negative disease,” Dr. Partridge wrote

Expect and Encourage Questions from Your Patients

T

he oncologist has an important role in advising patients about infertility as a potential risk of cancer treatment and answering basic questions about fertility preservation options, according to the ASCO Recommendations on Fertility Preservation in People Treated for Cancer. An ASCO slide set associated with the published recommendations lists the following Points of Discussion Between the Patient and Physician: 1. Cancer and cancer treatments vary in their likelihood of causing infertility. 2. Consider preservation options early to maximize the likelihood of success. 3. Sperm cryopreservation and embryo freezing are the See Page 93 methods of fertility preservation with the highest likelihood of success. 4. There appears to be no detectable increased risk of disease recurrence associated with most fertility preservation methods and pregnancy. 5. Aside from hereditary genetic syndromes and in-utero exposure to chemotherapy, there is no evidence that a history of cancer, cancer therapy, or fertility interventions increase the risk of cancer or congenital abnormalities in the progeny. 6. Treatment-related infertility may be associated with psychosocial distress. The ASCO guidelines also suggest that oncologists refer patients to psychosocial providers and reproductive specialists as needed.

Reprinted with permission from an ASCO slide set associated with Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients. J Clin Oncol 24:2917-2931, 2006. Copyright © 2006 by the American Society of Clinical Oncology. The slide set and full text of the ASCO Clinical Practice Guideline are available at www.asco.org/guidelines/fertility.

in the editorial. “Given the current level of evidence,” she continued, “women who are interested in future fertility and the providers who are assisting them in these often difficult decisions should not rely on GnRH agonist treatment during chemotherapy for preservation of menstrual and ovarian function or fertility.”

More Limited Options for Prepubescent Patients Sperm banking is still the most commonly used method of fertility preservation for male patients. “It’s easy and cheap and relatively reliable,” Dr. Partridge said. It is not an option, however, for prepubescent males with immature sperm. “Testicular tissue freezing is the only option available before puberty,” according to Fertile Hope, a LIVESTRONG initiative “dedicated to providing reproductive information, support, and hope to cancer patients and survivors whose medical treatments present the risk of infertility.” As material posted on the Fertile

Hope website notes, “While this procedure shows a lot of promise, it is still experimental. There has not been a successful pregnancy yet.”4 Testicular shielding prior to radiation therapy can also help preserve fertility. Embryo or oocyte cryopreservation cannot be used to preserve fertility in females who have not entered puberty “For prepubescent girls, really the only option is to take pieces of the ovaries,” Dr. Partridge said, and then freeze the tissue until it can be reimplanted. “You would have to consider the risks of infertility from the regimen vs the risk of taking a piece of the ovary,” Dr. Partridge said, as well as dealing with the additional surgery. “In successful transplants, the tissue starts producing hormones and maturing eggs,” according to Fertile Hope. “While ovarian tissue freezing holds a lot of promise, it is still experimental.”4 Ovarian shielding or ovarian transposition (oophoropexy) can be used to help decrease radiation to the ovaries and damage to fertility. If transpocontinued on page 92


The ASCO Post  |   APRIL 15, 2012

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In the News

Preserving Fertility Should Be Considered Early continued from page 91

sition is used to surgically reposition the ovaries away from the radiation field, it should be performed just before radiation therapy to prevent remigration of the ovaries to their for-

mer position, according to the ASCO guidelines.

Threats to Fertility Fertility can be compromised by cancers directly affecting the reproductive organs and by cancer treatments. For women and men, the most

common cause for concern is receiving sterilizing, systemic therapy, Dr. Partridge said. “Bone marrow transplants, radiation to the gonads, and regimens including alkylating agents are the most toxic to the gonads—anything that either systemically or directly kills off cells is going to have a propensity to

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kill off developing cells, and of course the ovaries and the testes have lots of developing cells.” Bone-marrow transplantation regimens “tend to be the most gonadotoxic—they cause immediate sterilization for most, but not all, patients,” she said. Surgical treatment can affect fertility by removing organs directly involved with the production of eggs or sperm or parts of their pathways, such as the uterus or penis. “The other way cancer treatment can interfere is by getting in the way of the hormonal axes,” Dr. Partridge said, citing pituitary surgery as an example. “If you have pituitary disruption, that would get in the way of the hormonal axes that prime the ovaries to make an egg each month in premenopausal women.” The Fertile Hope website has a risk calculator tool that provides information about the risk of amenorrhea or azoospermia based on specific treatment regimens for selected cancers (see sidebar, Internet Tool to Calculate Risks to Fertility).

Additional Studies Dr. Partridge is involved in several ongoing and upcoming studies

Internet Tool to Calculate ‘Risks to Fertility’ Today in Oncology Stay up to date on breaking reports from major oncology meetings, summaries of recently published research, developments in health-care policy and health information technology, and essential information on the latest drug approvals and practice guidelines.

Featured Columnists Consider the state of cancer care, examine significant controversies in ethics and cost of care, and find invaluable perspectives on emerging trends.

Expert Opinions Access viewpoints on the ever-evolving landscape of cancer research and practice. Look for in-depth analysis of pivotal trial data and other recently reported findings that may prove critical to quality patient care.

Launching this June at the 2012 ASCO Annual Meeting

The ASCO Post on Twitter Check out the latest tweets from the @ASCOPost page on Twitter.

T

he risk calculator available at the Fertile Hope website (www. See Page 93 fertilehope.org) lets patients know whether specific treatment regimens would put them at high, intermediate, low, very low/no risk, or unknown risk for azoospermia or amenorrhea. Both Fertile Hope and the ASCO fertility recommendations point out, however, that fertility can be compromised even with the maintenance or resumption of cyclic menses. The risk calculator lists more than 15 different types of cancer each for men and women and more than 30 types of treatment, including single and combination chemotherapies and radiation therapy. To access the risk calculator, go to www.fertilehope.org/tool-bar/risk-calculator.cfm.


ASCOPost.com  |   APRIL 15, 2012

PAGE 93

In the News

of fertility issues among patients with cancer. One large study just starting is aimed at increasing awareness of these issues. Following up on a pilot study that addressed gaps in care for young women being treated for breast cancer, Dr. Partridge is launching a randomized controlled trial of educational and supportive care interventions. “One of the additional questions we are asking in a longitudinal cohort study of very young women with breast cancer is whether or not they feel pressured to have additional children,” Dr. Partridge said. “So we’ll get at that question of who’s pushing this issue: patients? their loved ones? When considering this issue for young patients, it may be their parents, and maybe that is appropriate.” The LIVESTRONG Cancer Clinical Trial Matching Service maintains a list of trials relevant to cancer and fertility that are currently seeking patient participation, and offers assistance in searching for clinical trial options that match a specific diagnosis and treatment history. To search for trials, go to www.fertilehope.org/learn-more/ research-and-trials/ or call 800-6206167, Monday to Friday, 7:00 AM to

Using QR Codes

5:30 PM Central Time (except holidays).

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

References 1. Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncol-

ogy Recommendations on Fertility Preservation in Cancer Patients. J Clin Oncol 24:2917-2931, 2006. 2. Munster PN, Moore AP, Ismail-Khan R, et al: Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:533-538, 2012.

Breast Cancer Symposium

breaSt cancer education at itS beSt

September 13-15, 2012 San FranciSco marriott marquiS | San FranciSco, caLiFornia

meet Some oF the expertS behind t h e S ym p o S i u m

Key Dates now open abstract Submitter housing & registration

Top Left to Bottom Right: banu arun, MD Anderson; clifford hudis, Memorial Sloan-Kettering Cancer Center; Lori Goldstein, MD, Fox Chase Cancer Center; dan hayes, University of Michigan; Gabriel hortobagyi, MD Anderson; eric Winer, Dana-Farber Cancer Center; Lori pierce, University of Michigan; Gary Levine, Hoag Memorial Hospital Presbyterian; Shawna Willey, Georgetown University Hospital

may 15, 2012 abstract Submission deadline

1

When you see a code that you would like to scan, start your code-reading application.

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The code will scan automatically.

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Position your device in front of the code so that it fills about half your screen.

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If the scan is successful, you will be rerouted to the targeted link.

3. Partridge AH: Ovarian suppression for prevention of premature menopause and infertility: Empty promise or effective therapy? J Clin Oncol 30:479-481, 2012. 4. Fertile Hope/LIVESTRONG: Pediatrics: Information for Parents. Available at www.fertilehope.org. Accessed March 19, 2012.

- all-access learning with the top minds in breast cancer treatment

For meeting updates, visit breastcasym.org.

- answers for practicing oncologists - address real challenges in translational research

This live activity has been approved for AMA PRA Category 1 Credit.™

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PAGE 94

The ASCO Post  |   APRIL 15, 2012 AVASTIN® (bevacizumab)

News

Solution for intravenous infusion Initial U.S. Approval: 2004

Report to the Nation Finds Continuing Declines in Cancer Death Rates

D

eath rates from all cancers combined for men, women, and children continued to decline in the United States between 2004 and 2008, according to the Annual Report to the Nation on the Status of Cancer, 19752008. Overall cancer incidence rates among men decreased by an average of 0.6% per year between 2004 and 2008.  Overall cancer incidence rates among women declined 0.5% per year from 1998 through 2006, with rates leveling off from 2006 through 2008. The report is co-authored by researchers from the Centers for Disease Control and Prevention, the North American AssociaSee Page 93 tion of Central Cancer Registries, the National Cancer Institute, and the American Cancer Society. It was published online in the journal Cancer. The effects of excess weight and lack of physical activity on cancer risk were highlighted in a special section in the report. Esophageal adenocarcinoma, cancers of the colon and rectum, kidney cancer, pancreatic cancer, endometrial cancer, and breast cancer among postmenopausal women are associated with being overweight or obese. Several of these cancers also are associated with not being sufficiently physically active.

Impact of Unhealthy Behaviors “This report demonstrates the value of cancer registry data in iden-

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

Thomas R. Frieden, MD

tifying the links among physical inactivity, obesity, and cancer,” said CDC Director Thomas R. Frieden, MD. “It also provides an update of how we are progressing in the fight against cancer by identifying populations with unhealthy behaviors and high cancer rates that can benefit from targeted, lifesaving strategies, and interventions to improve lifestyle behaviors and support healthy environments,” Dr. Frieden said. Since the 1960s, tobacco use has declined by a third while obesity rates have doubled, significantly impacting the relative contributions of these factors to the disease burden.  Excess weight and lack of sufficient physical activity have been linked to increased risk of cardiovascular disease, hypertension, diabetes, and arthritis, as well as many cancers.

Reference 1. Eheman, C, Henley SJ, Ballard-Barbash R, et al: Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer. March 28, 2012 (early release online).

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade  1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13  (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4  weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade  2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy

AVASTIN® (bevacizumab) was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate >  10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 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 below reflect exposure to Avastin in 3795 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60  days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]


AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab) Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer MBC, an indication for which Avastin is not approved, the incidence of Grade 3–4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL ++ Placebo (n = 396) 74%

Arm 2 IFL ++ Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade  3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥  2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

55% 55% 19%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 );

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500  patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

10 OVERDOSAGE The highest dose tested in humans (20  mg/kg IV) was associated with headache in nine of 16  patients and with severe headache in three of 16 patients.

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. 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. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8  patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

01/12 AVA0000765901 10127309 Initial U.S.Approval: February 2004 Code Revision Date: December 2011 Avastin® is a registered trademark of Genentech, Inc. ©2012 Genentech, Inc.


To confront a common threat across approved indications...

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Because anti-angiogenesis matters Avastin is designed to directly inhibit the VEGF ligand to specifically inhibit angiogenesis1*

VEGF=vascular endothelial growth factor. *The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Most common adverse events

Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,† the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Avastin is not approved for use in combination with irinotecan.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. December 2011.

©2012 Genentech USA, Inc.     All rights reserved.     AVA0000488401     Printed in USA.     (01/12)

www.avastin.com


TAP Vol 3 Issue 6