TAP Vol 6 Issue 17

Managing Lymphomas

4, 9

| HPV-Positive Head and Neck Cancer

18

| Palliative Care Services

VOLUME 6, ISSUE 17

30

SEPTEMBER 25, 2015

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

World Conference on Lung Cancer

First-Line Nivolumab/Ipilimumab Combination in Non–Small Cell Lung Cancer Shown to Be Tolerable

Our Children’s Future Is Our Responsibility

By Caroline Helwick

By Ronald A. DePinho, MD

F

or advanced non–small cell lung cancer (NSCLC), first-line treatment with combined immune checkpoint blockade—in novel doses and schedules—was associated with deep and durable responses, encouraging progression-free survival, and much better tolerability than has been previously observed with nivolu­ mab (Opdivo) plus ipilimumab (Yervoy).

The results are from the CheckMate 012 trial and were presented at the 16th World Conference on Lung Cancer in Denver by Naiyer Rizvi, MD, Director of Thoracic Oncology and Immunotherapeutics in Medical Oncology at NewYork–Presbyterian/Columbia University Medical Center.1 The annual meeting is hosted by the International Association for the Study of Lung Cancer.

CheckMate 012 Details CheckMate 012 compared several dosing schedules for combining the programmed cell death pro-

tein 1 (PD-1) antibody nivolumab and the CTLA4 inhibitor ipilimumab for front-line use in treating advanced NSCLC. “We think that nivolu­ mab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 or 12 weeks Naiyer Rizvi, MD are the best schedules and the ones to move forward with,” Dr. Rizvi told The ASCO Post.

Previous phase III studies have shown an overall survival benefit for nivolumab, as compared to docetaxel, in previously treated patients with advanced NSCLC. “We decided to explore the safety and efficacy of nivolumab in the first-line setting, not just as monocontinued on page 3

Issues in Oncology

Making Their Voices Heard: 118 Oncologists Speak Out About Stemming the High Cost of Cancer Drugs A Conversation With S. Vincent Rajkumar, MD

By Jo Cavallo

I

with S. Vincent R ­ ajkumar, MD, one of the coauthors of the article.

Dr. Rajkumar is Professor of Medicine in the Department of Hematology at the Mayo Clinic in Rochester, Minnesota. In the article, the oncologists call for support of a grassroots effort to focus attention on the problem and detail solutions to mitigate the issue of the rapid rise of oncology drug prices.

“There is no relief in sight because drug comOftentimes the patients most panies keep challenging the market with even affected by high health-care costs higher prices,” wrote the are the ones who are uninsured or oncologists. “This raises the question of whether underinsured and have no voice. We current pricing of cancer need to be their voice. drugs is based on reason—S. Vincent Rajkumar, MD able expectation of return

n a bold move to shed light on the ramifications of the ever-increasing cost of cancer drugs for patients with cancer and for the health-care system, 118 prominent oncologists came together to write a commentary in Mayo Clinic Proceedings detailing their concerns.1 To learn more about these proposals and the reaction from the oncology community to the commentary, The ASCO Post recently talked

C

ancer prevention is a child-care issue.

With many of cancer’s instigators planting their seeds during childhood, we—as a profession and as a nation—must seize this important window of opportunity to protect the health and well-being of future generations.

Current estimates suggest that up to onehalf of cancers in Western populations can be prevented by adopting a healthy lifestyle during childhood and maintaining it across one’s life­ span. Yet, in America today, most adolescents who do smoke initiate smoking before age 18, childhood obesity rates remain high, vaccination rates for human papillomavirus (HPV) are continued on page 88

Dr. DePinho is President of The University of Texas MD Anderson Cancer Center in Houston.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage World Conference on Lung Cancer ������������������������������ 1, 3, 28 Debates and Didactics in Hematology and Oncology ������������ 4, 9, 18 Multinational Association of Supportive Care in Cancer �����������������������26 Big Data Workshop �����������������������������������27 Direct From ASCO �������������������������� 42–46 ASCO Statements Obesity ����������������������������������������������������6–8 Genetic and Genomic Testing ������������������ 76 Geriatrics for the Oncologist �������������������62 In Memoriam: Gianni Bonadonna, MD ����77

continued on page 48

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The ASCO Post | SEPTEMBER 25, 2015

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PAGE 3

World Conference on Lung Cancer Nivolumab/Ipilimumab continued from page 1

therapy but combined with other therapies, really pushing the envelope about where we should go next with immune checkpoint blockade,” Dr. Rizvi said.

CheckMate 012 studied nivolumab alone and in various combinations that involved platinum-based chemotherapy, erlotinib, bevacizu­ mab (Avastin), and ipilimumab. The combination with ipilimumab mirrored the dose and schedules used in metastatic melanoma (nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks or nivolumab at 3 mg/ kg plus ipilimumab at 1 mg/kg every 3 weeks). Response rates with these combinations were 13% and 20%, ­respectively.

Safety and Tolerability Grade 3/4 treatment-related adverse event rates were 58% and 44%, and 37% of patients discontinued this combination due to toxicity.

“The toxicity was more than that seen with single-agent nivolumab and more than we have observed with the combination in melanoma. It was clear

that lung cancer behaves differently, and different doses and schedules needed to be explored,” he said.

With safety and tolerability as the primary endpoint, Dr. Rizvi and colleagues therefore evaluated several new dosing schedules for this ­combination: • Nivolumab at 1 mg/kg every 3 weeks × 4 plus ipilimumab at 1 mg/ kg every 3 weeks × 4 plus nivolumab at 3 mg/kg every 2 weeks (n = 31) • Nivolumab at 1 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n = 40) • Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks (n = 38) • Nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n = 39).

“We found that the combination was very well tolerated in all the cohorts,” Dr. Rizvi said. “Few patients (3%–10%) discontinued treatment due to adverse events. This compares favorably to what we see with first-line monotherapy with nivolumab (10%).”

Grade 3/4 treatment-related adverse events occurred in 28% to 35% of patients and were “all quite manageable.”

Role of Nivolumab in NSCLC ■■ CheckMate 012 evaluated nivolumab in combination with ipilimumab in novel dosing schedules that greatly improved tolerability.

■■ Fewer than 10% of patients discontinued treatment because of treatmentrelated adverse events.

■■ Response rates ranged from 13% to 39%, with a number of partial responses not yet confirmed.

■■ Median progression-free survival ranged from 4.9 to 10.6 months.

There were no treatment-related deaths.

“The toxicity profile is very different from our initial experience with this combination,” Dr. Rizvi said.

High Response Rates “First-line therapy with nivolumab plus ipilimumab demonstrated a high level of clinical activity characterized by deep and durable responses in advanced lung cancer,” Dr. Rizvi ­reported.

Objective responses were confirmed in 13% to 39%, with additional unconfirmed partial responses observed. The highest response rate, 39%, occurred in the cohort receiving nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks.

EXPERT POINT OF VIEW

G

lenwood Goss, MD, FRCPC, FCPSA, Professor of Medicine and Director of Clinical and Translational Research at the Ottawa Hospital Cancer Centre and University of Ottawa, Canada, formally discussed the findings. He noted that this combination in advanced melanoma showed “limited progression-free survival improvement that comes at the price of toxicity,” ie, a 55% rate of grade 3/4 adverse events.

The adverse events [with the nivolumab/ipilimumab combination] have come down substantially and are acceptable. Those leading to discontinuations are no greater than those seen with nivolumab alone and are less than seen in the original combination cohort.

—Glenwood Goss, MD, FRCPC, FCPSA

Changing Scenario When combined in the doses and schedules used in advanced melanoma, the nivolumab/ipilimumab combination was not well tolerated, he emphasized, adding, “You’ve got to admire these investigators for persisting in their quest.”

The modification of the dosing schedule has appeared, at least early on, to have changed this scenario.

“The adverse events have come down substantially and are acceptable.

Those leading to discontinuations are no greater than those seen with

nivolumab alone and are less than seen in the original combination cohort,” Dr. Goss pointed out.

Note of Caution The response rates of 13% to 39% “are quite acceptable and appear somewhat better than with monotherapy. It looks as though the combination is better than nivolumab alone in terms of response, with comparable toxicity,” he continued.

“But I caution,” he added. “The numbers are small, there is limited follow-up, and no meaningful progression-free or overall survival data.

The response rate is at best 39%, there is a narrow therapeutic window between efficacy and toxicity, and the predictive relevance of PD-L1 [programmed cell death ligand 1] expression remains unanswered.” n

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

Efficacy by Tumor PD-L1 Expression Clinical activity was observed and those with tumors expressing programmed cell death ligand type 1 (PDL1) had better responses than those whose tumors did not express PD-L1.

The majority of all responders were still responding at data cutoff.

In patients with ≥ 1% PD-L1 expression, response rates ranged from 8% (nivolumab at 1 mg/kg every 3 weeks × 4 plus ipilimumab at 1 mg/kg every 3 weeks × 4) to 48% (nivolumab at 3 mg/ kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks, and nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks).

The response rate was higher in the PD-L1 positive vs PD-L1 negative cohorts overall but the majority of patients had PD-L1 expression greater than or equal to 1% (about 70%).

Median duration of response was not reached in any arm, regardless of PD-L1 expression. Median progression-free survival was not reached among PD-L1–positive patients receiving nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks and was 34.8 weeks for the cohort receiving nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/ kg every 12 weeks, which appeared longer than for PD-L1–negative patients in these cohorts.

A phase III trial, CheckMate 227, is currently comparing nivolumab or nivolumab plus ipilimumab vs platinum-based doublet chemotherapy in chemotherapy-naive stage IV or recurrent NSCLC. n

Disclosure: Dr. Rizvi received honoraria from Bristol-Myers Squibb, Roche, AstraZeneca, Merck, and Novartis.

Reference 1. Rizvi NA, Gettinger SN, Goldman JW, et al: Safety and efficacy of first-line nivolumab and ipilimumab in non-small cell lung cancer. 16th World Conference on Lung Cancer. Abstract ORAL02.05. Presented September 7, 2015.

The ASCO Post | SEPTEMBER 25, 2015

PAGE 4

Debates and Didactics in Hematology and Oncology Hematology

Double-Hit Lymphoma: Many Treatment Strategies, No Standard of Care

By Caroline Helwick

“D

ouble-hit lymphoma” represents a challenging malignancy without a standard-of-care treatment, although outcomes for some patients are better than was once believed, according to Jonathon B. ­Cohen, MD, Assistant Professor of Hematology and Medical Oncology at Emory University, Atlanta. Dr. Cohen shared his approach to double-hit lymphomas at the 2015 Debates and Didactics in Hematology and Oncology Conference, sponsored by Emory University, in Sea Island, Georgia.

Challenges in Evaluation “The evaluation and identification of these patients is harder than it looks. I see many patients where there’s been a lot of discussion as to whether the patient truly has a double-hit lymphoma.

The recent identification of [the] ‘double-expresser’ category makes it even more complicated,” said Dr. Cohen.

the detection of double-expressers. In a 2012 study, 33% of patients were MYCpositive, 53% were BCL2-positive, and 18% expressed both genes.1 Overall survival was significantly better for the double-expressers than for the doublehit group, and both groups had worse outcomes than patients lacking these alterations.

Part of the challenge in evaluation and diagnosis is that double-hit lymphoma is not, by itself, a recognized lymphoma classification according to the World Health Organization (WHO). Many patients fall into the Bcell lymphoma unclassifiable category or have morphologically diffuse large B-cell lymphoma but are subsequently shown by fluorescent in situ hybridization to have a MYC plus BCL2 (or BCL6) gene rearrangement—the criteria for double-hit lymphoma status.

The upcoming WHO reclassification should clarify these categories,

While we can have long-term survivors, patients who fail initial treatment are, in most cases, destined for a dismal outcome. You get one swing at bat. It’s important to figure out the most appropriate treatment.

—Jonathon B. Cohen, MD

Double-hit lymphoma is characterized by the presence of concurrent MYC (myelocytomatosis oncogene) and BCL2 (B-cell lymphoma 2) gene rearrangements. Double-expresser patients stain positive on immunohistochemistry for MYC and BCL2 expression. With standard therapy approaches for non-Hodgkin lymphoma, such as R-CHOP (rituximab [Rituxan]/cyclophosphamide/doxorubicin/vincristine/prednisone), both patient types have a worse prognosis than patients without these alterations.

Recent availability of the MYC immunohistochemistry stain has increased

but in the meantime, any patient with aggressive non-Hodgkin lymphoma should be assessed by fluorescent in situ hybridization to evaluate for MYC and BCL2/6 gene expression to give optimal treatment, he added.

Wide Range of Treatment Approaches “There are many approaches to treatment and no standard of care,” Dr. Cohen said. Key questions follow: What is the optimal induction regimen? Does stem cell transplant increase the chances for complete remission and long-term survival? The

Dr. Cohen’s Approach to Managing Double-hit Lymphoma • All patients with aggressive non Hodgkin lymphoma should be evaluated for MYC and BCL2/6 gene expression, if possible, by fluorescent in situ hybridization and immunohistochemistry.

• Several intensive treatment regimens are available. Dr. Cohen favors dose-adjusted R-EPOCH for patients with double-hit one universal truth, according to Dr. Cohen, is that R-CHOP alone is not adequate treatment, as it is unlikely to achieve long-term remission.

Some commonly employed, more intensive treatment options include the following regimens: • Dose-adjusted R-EPOCH (rituximab plus etoposide/prednisone/ vincristine/cyclophosphamide/ doxorubicin) • R-hyperCVAD (rituximab plus cyclophosphamide/vincristine/doxorubicin/dexamethasone alternating with methotrexate/cytarabine) • R-CODOX-M/IVAC (rituximab/ cyclophosphamide/vincristine/ doxorubicin/methotrexate) (etoposide/cytarabine/ifosfamide) Dr. Cohen said for both double-hit and double-expressing patients, he favors dose-adjusted R-EPOCH, which is the only one of the three regimens that has been prospectively evaluated. The study on which he bases this preference, which was led by the National Cancer Institute, evaluated dose-adjusted REPOCH and found that progressionfree survival at 14 months was 79% for all MYC-positive patients with nonHodgkin lymphoma and 87% for the double-hit patients.2 Since newly diagnosed patients had to be stable enough to await the results of the fluorescent in situ hybridization assessment at the

lymphomas and for those classified as “double expressors.”

• All patients should be assessed for central nervous system disease with strong consideration for prophylaxis.

• Auto transplant’s role has not been established. Dr. Cohen recommends the pros and cons of stem cell transplant be discussed with each patient. n time of diagnosis, it is likely that very sick patients were not enrolled.

Dr. Cohen acknowledged, however, “This study suggests this regimen is very active. It’s still very early in followup, but these are encouraging data, and they look far better than our initial survival curves.”

Dr. Cohen also suggested that patients should be assessed for central nervous system involvement and considered for prophylaxis. If central nervous system disease is suspected at the time of diagnosis, he said he often alters his induction therapy. If there are no initial signs of central nervous system involvement, he uses prophylaxis, especially in MYC-positive patients.

Initial Treatment: Complete Response Is Key The variability in current treatment choices is illustrated by a review of 49 patients with MYC-positive diffuse large B-cell lymphoma (29 with double-hit lymphoma) at The Ohio State University.3 Of them, 17% received RCHOP, 28% received a “Burkitt-like regimen,” 48% received R-EPOCH, and 7% received another treatment; none received a transplant.

The most important factor in their outcomes was not whether they were MYC-positive or double-hit, but whether they achieved a complete remission.

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 5

Debates and Didactics in Hematology and Oncology After 4 years of follow-up, virtually all patients with complete remission remained alive, compared with none of the patients failing to achieve a complete remission, noted Dr. Cohen, a study co-investigator.

“This speaks to the fact that while we can have long-term survivors, patients who fail initial treatment are, in most cases, destined for a dismal outcome,” he commented. “You get one swing at bat. It’s important to figure out the most appropriate treatment.”

Transplant After Induction Therapy What has been less well established is whether consolidation and stem cell transplant provide further benefit. MD Anderson researchers retrospectively evaluated 129 patients with double-hit lymphoma receiving a range of treatments and found that 2-year event-free survival was highest (> 60%) among the R-EPOCH cohort.4 Upfront transplant did not influence event-free and overall survival among patients who achieved a complete remission, although the curves did separate at 2 years in this nonrandomized study. “The findings suggest, at least, that front-line transplant in all likelihood does not hurt,” he commented.

In a small study from British Columbia, 19 patients received R-CODOX-M/IVAC treatment followed by

stem cell transplant.5 This aggressive approach resulted in a 2-year progression-free survival of 60% and overall survival of 82%. “The findings would suggest this is an additional reasonable regimen for double-hit lymphoma,” Dr. Cohen offered.

A multicenter study of 311 patients further evaluated induction regimens and transplant.6 Patients received RCHOP (32%), R-hyperCVAD (21%), R-EPOCH (21%), R-CODOX-M/ IVAC (14%), and other regimens (13%), and 17% received an autologous transplant at first complete remission.

Intensive induction, as compared with R-CHOP, was also significantly associated with improved progressionfree survival (approximately 50% at 4 years; P = .001). Progression-free survival was highest with R-hyperCVAD (approximately 60% at 4 years; P = .0016). After adjustments for several high-risk features identified in the study, intensive induction also significantly improved overall survival.

Although stem cell transplant did not significantly improve survival (P = .140), the curves did separate, he noted, “suggesting there may be some benefit, though it was done in the minority of patients, who were selfselected to get to transplant. The role of transplant has not been established; therefore, I discuss the pros and cons with each ­patient.”

In support of transplant, one could

argue that transplant in first complete remission is generally low risk, that extrapolating from other studies suggests high-risk patients may benefit, and that when patients relapse after initial therapy, their outcomes are very poor (so preventing relapse is critical). Against transplant, one could argue that prospective studies are lacking and that patients who achieve complete remission after induction may well remain in remission and not ever need a transplant.

“The question has not been answered as to whether after intensive treatment, patients still need transplant,” he reiterated. “I typically consider transplant in patients with double-hit lymphoma who have several other IPI [International Prognostic Index] risk factors.

However, those who are not otherwise high risk who achieve a [complete remission] with intensive therapy can likely be observed.”

What is clearer is that with an appropriate intensive regimen, outcomes for patients with double-hit lymphoma “are not nearly as bad as we initially thought,” Dr. Cohen said. “The curve flattens out at about 40% [6 months post diagnosis], and some patients are likely cured.

Hopefully, with better treatment, we can move that bar higher.” n Disclosure: Dr. Cohen has served on advisory boards for Pharmacyclics, Millennium/Takeda, Seattle Genetics, and Celgene. He has received research funding from BMS and Pharmacyclics.

References 1. Johnson NA, Slack GW, Savage KJ, et al: Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:3452-3459, 2012.

2. Dunleavy K, Fanale M, LaCasce A, et al: Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. 2014 ASH Annual Meeting. Abstract 395. Presented December 8, 2014.

3. Cohen JB, Geyer SM, Lozanski G, et al: Complete response to induction therapy in patients with Myc-positive and doublehit non-Hodgkin lymphoma is associated with prolonged progression-free survival.

Cancer 120:1677-1685, 2014.

4. Oki Y, Noorani M, Lin P, et al: Double hit lymphoma: Br J Haematol 166:891-901, 2014.

5. Sun H, Savage KJ, Karsan A, et al: Outcome of patients with non-Hodgkin lymphomas with concurrent MYC and BCL2 rearrangements treated with CODOX-M/IVAC with rituximab followed by hematopoietic stem cell transplantation.

Clin Lymphoma Myeloma Leuk 15:341348, 2015.

6. Petrich AM, Gandhi M, Jovanovic B, et al: Impact of induction regimen and stem cell transplantation on outcomes in doublehit lymphoma: A multicenter retrospective analysis. Blood 124:2354-2361, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Arnaud Scherpereel, MD, on Bevacizumab and Standard Chemotherapy in Mesothelioma see page 28

Steve Reichert, MD, on Palliative Care Services in an Inner City Setting see page 30

Rowan T. Chlebowski, MD, PhD, on Breast Cancer Risk After Hormone Therapy see page 56

Lauren C. Harshman, MD, on Statin Use at the Start of Androgen-Deprivation Therapy see page 60

Sean Smith, MD, on the Need for Physiatry in a Cancer Care Plan see page 64

Mark E. Robson, MD, on ASCO’s Policy Update on Genetic and Genomic Testing for Cancer Susceptibility see page 76

Visit The ASCO Post online at ASCOPost.com

Scott N. Gettinger, MD, on Nivolumab in Heavily Pretreated Advanced Non-Small Cell Lung Cancer see page 54

Amy MacKenzie, MD, and Andrew Chapman, DO, on Geriatric Oncology Highlights at ASCO 2015 see page 62

The ASCO Post | SEPTEMBER 25, 2015

PAGE 6

JCO Spotlight Survivorship

ASCO Statement Addresses Recommendations for Obesity Clinical Trials in Cancer Survivors

By Matthew Stenger

A

s reported in the Journal of Clinical Oncology by Jennifer A. ­Ligibel, MD, of Dana-Farber Cancer Institute, and colleagues, ASCO has issued a statement providing recommendations for obesity clinical trials in cancer survivors.1 ASCO convened the Research Summit on Advancing Obesity Clinical Trials in Cancer Survivors in November 2014. The meeting involved stakeholders in the study of obesity and cancer, including obesity researchers, oncology providers, clinical trialists, patient advocates, governmental and private funding organizations, payers, and representatives from health systems.

As explained by the authors, the summit “sought to identify the

About the Summit

By Jennifer A. Ligibel, MD

T

he research summit was part of the ASCO Obesity Initiative, which sought to increase awareness of the links between obesity and cancer and to foster research in this area that evaluated the impact of weight loss and increased activity on cancer outcomes.

There have been hundreds of observational studies showing that obesity is associated with an increased risk of cancer and poor outcomes in many malignancies.

However, there are few trials that actually test whether weight loss, a better diet, or increased physical activity reduces the risk of cancer recurrence and cancerrelated mortality.

As rates of obesity continue to grow, obesity threatens to wipe out some of the advances we have made in improving cancer outcomes. A better understanding of the impact of obesity on cancer risk and outcomes is needed. Importantly, we also need to know if modification of lifestyle factors after cancer diagnosis can reduce the risk of cancer recurrence and improve survival rates in individuals with early-stage malignancies. n

knowledge gaps that clinical trials addressing energy balance factors in cancer survivors have not answered

and to develop a roadmap for the design and implementation of studies with the potential to generate data

that could lead to the evidence-based incorporation of weight management and physical activity programs into

ASCOPost.com  |   SEPTEMBER 25, 2015

PAGE 7

JCO Spotlight

standard oncology practice.�

The statement presents key conclusions of the summit and provides recommendations for the development of a coordinated research agenda for obesity trials. The basic recommendations are summarized here.

Large prospective randomized intervention trials are needed to generate

data on the impact of energy balance interventions on cancer outcomes. Recommendations for the components and structure of such trials include: Research teams: Include multidisciplinary teams of researchers with expertise in oncology, clinical trials, behavioral science, weight management, nutrition, and physical activity.

Target patient populations: Focus on populations with the most evidence and largest groups of cancer survivors.

Study design: Ensure adequate power to detect biologically plausible effect size.

Must take into account improvements in cancer prognosis. Must enroll patients with sufficient risk of recurrence.

Endpoints: Include cancer outcomes

(including disease-free and overall survival), comorbidities, feasibility of implementation, economic endpoints, and intermediate biomarkers.

Concomitant dissemination, translational, and other research efforts are needed to provide evidence in areas including: continued on page 8

The ASCO Post | SEPTEMBER 25, 2015

PAGE 8

JCO Spotlight Obesity Clinical Trials continued from page 7

• Long-term maintenance of behavioral change • Use of technology to facilitate referrals to energy balance intervention programs and support short- and longer-term behavioral change • Intervention approaches in special

populations (eg, elderly, pediatric, minority, and rural populations and those with specific cancer types) • Translational science to define mechanisms through which energy balance factors affect cancer

Recommendations Recommendations for the imple-

mentation of research initiatives include those in the following areas.

Study development: Foster transdisciplinary partnerships of investigators; bring stakeholders together through clinical trials planning meetings; guide new research to address critical gaps in knowledge through requests for applications targeting

specific areas (eg, dissemination of lifestyle interventions, development of lifestyle interventions targeting unique populations); network with and foster career development of new and early-career investigators.

Funding : Develop mechanisms to bring together different sources of funding (eg, public and private sources) to support the cost of lifestyle interventions and other costs unique to this area of research; develop new funding partnerships between organizations; create standing funds across organizations for joint projects; jointly fund dream teams; develop collaborative relationships with nontraditional funding partners (eg, insurance companies, Centers for Medicare & Medicaid Services, large employers); develop collaborative projects with groups that study other patient populations with common risk factors (eg, cardiology or endocrinology groups).

Stakeholder engagement: Identify key stakeholders for both research and dissemination aspects of lifestyle interventions in cancer survivors and ensure that a broad range of perspectives are included in design and conduct of lifestyle intervention trials.

Engagement of providers: Provide education and training sessions at national oncology and primary care meetings and within oncology fellowship training; develop interventions that can be implemented in diverse clinic settings and tested through National Cancer Institute Community Oncology Research Program practices; integrate lifestyle elements into electronic medical records; provide training for oncology personnel in communication skills for dealing with sensitive topics like weight loss; incorporate lifestyle interventions into survivorship care plans.

Engagement of patients: Involve large advocacy organizations and a diverse group of individual advocates in lifestyle intervention studies; consider convenience, cost, time commitment, and flexibility in intervention design (with integration into routine care appointments and assessments, as possible); include quality-of-life and other patient-reported outcomes. n Disclosure: Dr. Ligibel reported no potential conflicts of interest. For full disclosures of the statement authors, visit jco.ascopubs.org.

Reference 1. Ligibel JA, Alfano CM, Hershman D, et al: Recommendations for obesity clinical trials in cancer survivors. J Clin Oncol. August 31, 2015 (early release online).

ASCOPost.com | SEPTEMBER 25, 2015

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Debates and Didactics in Hematology and Oncology Hematology

Mantle Cell Lymphoma: Is Transplantation Still Necessary?

By Caroline Helwick

A

utologous stem cell transplantation has played a critical role in the treatment of mantle cell lymphoma, but in the age of novel treatments, is it always warranted? Two experts in the field explored the question at the 2015 Debates and Didactics in Hematology and Oncology Conference sponsored

by Emory University, Atlanta, and held in Sea Island, Georgia.

Amelia Langston, MD, is Professor of Hematology and Medical Oncology and Director and Section Chief of the Bone Marrow and Stem Cell Transplant Program at Emory. Christopher ­Flowers, MD, MS, is Associate Professor of Hematology and Medical Oncology and Director of the Emory Lymphoma Program.

According to Dr. Langston, “Autologous stem cell transplant should be part of the initial treatment strategy for ‘fit’ patients with mantle cell lymphoma. It is unclear whether this represents curative therapy, but it is our most powerful approach for prolonging progressionfree survival and time to next therapy.”

However, according to Dr. Flowers, robust new agents “may change the natural history of this disease” and eliminate the need for autologous stem cell transplant in some patients. “My position is that all young patients do not necessarily need to undergo [autologous stem cell transplant] for mantle cell lymphoma,” he maintained.

‘The Various Faces of Mantle Cell Lymphoma’ Dr. Langston gave a brief review of the disease state, noting that mantle cell lymphoma accounts for a relatively small proportion (3%–10%) of nonHodgkin lymphoma. Mantle cell lymphoma, which occurs mostly in elderly males, has several morphologic variants, including the aggressive blastoid variant. Genomic studies are beginning to “unravel the various faces of mantle cell lymphoma,” but such information has not yet been integrated into risk-adapted management strategies, she added.

Although a small proportion of patients will have indolent disease, the majority present with advanced disease. “Aggressive behavior is the rule for most, but not all, patients,” according to Dr. Langston.

Transplant for Initial Therapy Studies have consistently shown that response to conventional therapy for

intermediate- or high-grade lymphoma, ie, CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) with or without rituximab (Rituxan), is inadequate. Complete remission rates are low, and the duration of remission is short.

any induction regimen should include high-dose cytarabine, Dr. Langston said.

For example, the European Mantle Cell Lymphoma Network Induction Study compared R-CHOP for 6 cycles with R-CHOP for 3 cycles followed by R-DHAP (rituximab/dexamethasone/

Autologous stem cell transplant should be part of the initial treatment strategy for ‘fit’ patients with mantle cell lymphoma. It is unclear whether this represents curative therapy, but it is our most powerful approach for prolonging progression-free survival and time to next therapy.”

—Amelia Langston, MD

A study by the European Mantle Cell Lymphoma Network established autologous stem cell transplant as the standard of care. Patients receiving upfront CHOP or CHOP-like induction, followed by autologous stem cell transplant, had prolonged progressionfree survival, compared with those on interferon maintenance (P = .0108).1 The study also showed that patients who achieved complete remission, vs partial remission, had the greatest benefit, although there was a suggestion of benefit even with partial remission.

The study was not designed to evaluate overall survival, but a strong trend favored the transplant arm, she noted.

The weakness of this study was that it was initiated early in the rituximab era, and only one-quarter of patients received this drug. Another limitation was the use of CHOP or a CHOP-like regimen for induction, which is not optimal. Nevertheless, the study established autologous stem cell transplant as part of standard therapy for ‘fit’ patients with mantle cell lymphoma—ie, those up to 70 years of age who are otherwise healthy, said Dr. Langston.

What Is the Best Induction Regimen?

If R-CHOP is not the best induction regimen prior to autologous stem cell transplant, what is? Numerous phase II trials have suggested that complete remission rates are higher and disease-free survival is longer when high-dose cytarabine is incorporated into induction; therefore,

cytarabine/cisplatin) for 3 cycles, with responders in each arm proceeding to autologous stem cell transplant.2 Objective response rates were similar, but complete remission rates were significantly higher in patients receiving the cytarabine-containing regimen (54% vs 40%; P = .0003). Time to failure was also significantly longer with cytarabine (88 months vs 46 months; P = .038), as was overall survival (not reached vs 82 months; P = .045).

Whether autologous stem cell transplant can be “curative” is still unclear.

Although the plateauing of progressionfree and overall survival curves is encouraging, Dr. Langston added, patients with mantle cell lymphoma often relapse very late, out to 8 to 10 years, and so need to be followed continuously.

Rituximab Maintenance “The role of rituximab maintenance post [autologous stem cell transplant] needs a prospective study, but some data suggest it may produce improved response duration and survival,” Dr. Langston said. At the 2014 ASH Annual Meeting, a retrospective analysis of 157 patients from the Fred Hutchinson Cancer Center showed that rituximab maintenance reduced the risk of disease progression by 67% and the risk of dying by 60%.3 The results held up in the multivariate analysis.

Some May Not Need Transplant Dr. Flowers acknowledged the benefits of autologous stem cell transplant

but countered that all young patients do not need autologous stem cell transplant for mantle cell lymphoma. It appears that about 6% of patients can defer therapy and still have prolonged progression-free and overall survival.

He agreed with Dr. Langston that R-CHOP is inadequate for most patients and pointed to more powerful induction options. Studies in older patients suggest that bendamustine (Treanda)/rituximab may be superior to R-CHOP. A regimen that alternates R-hyperCVAD with R-M/A (rituximab/methotrexate/cytarabine) may also improve outcomes as an induction treatment without autologous stem cell transplant.4 Romaguera et al showed a marked complete remission rate (87%) and “profound” 3-year failure-free survival (64%) and overall survival (82%), suggesting this aggressive regimen produces durable remissions without autologous stem cell transplant, according to Dr. Flowers.

Treating Relapsed Disease Regardless of these findings, mantle cell lymphoma remains largely a relapsing/remitting disease. Fortunately, the list of treatment options for these patients is growing, Dr. Flowers said.

One appears to be the proteasome inhibitor bortezomib (Velcade). Although most patients do not respond to bortezomib, those who do can have durable remissions, according to the PINNACLE trial, which evaluated singleagent bortezomib in 155 patients with relapsed/refractory disease.5 Patients achieving complete remission continued treatment for 4 more cycles; those with partial responses or stable disease continued treatment for up to 17 cycles.

Among responders, progression-free survival was 91% at 1 year, and median overall survival was 35.4 months.6 “This treatment has been used for patients who relapsed even after an aggressive treatment like [autologous stem cell transplant],” said Dr. Flowers.

Lenalidomide (Revlimid) also produced meaningful complete remission rates and durable responses in those who relapsed after autologous stem cell transplant, according to a combined analysis of several trials.7 The complete remission rate was 10%, median progression-free survival was 5.4 months, and median overall survival was 23.9 months among 208 patients continued on page 13

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Limitation of Use: Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Giant Cell Tumor of Bone Xgeva is indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Hypercalcemia of Malignancy Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

DOSAGE AND ADMINISTRATION: Important Administration Instructions Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

Recommended Dosage: Bone Metastasis from Solid Tumors: The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Giant Cell Tumor of Bone: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Hypercalcemia of Malignancy: The recommended dose of Xgeva is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.

CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva.

Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva.

WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia.

Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently.

Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels, throughout Xgeva therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Osteonecrosis of the Jaw. Osteonecrosis of the jaw (ONJ) has been reported in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Consider temporary discontinuation of Xgeva therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating physician should guide the management plan of each patient based on individual risk/benefit assessment.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis.

EMBRYO-FETAL TOXICITY: Xgeva can cause fetal harm when administered to a pregnant woman.

Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time.

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia • Osteonecrosis of the Jaw The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental

procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female.

Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3) Zoledronic Acid Xgeva n = 2836 Body System n = 2841 % % GASTROINTESTINAL 32 31 Nausea 19 20 Diarrhea GENERAL Fatigue/ Asthenia 45 46 IN VESTIGATIONS Hypocalcemiab 9 18 20 32 Hypophosphatemiab NEUROLOGICAL Headache 13 14 RESPIRATORY 18 21 Dyspnea 15 15 Cough Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes.

• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53).

Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva.

Giant Cell Tumor of Bone The safety of Xgeva was evaluated in two single arm trials (Trials 4 and 5) in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Trial 5. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 304 patients who received Xgeva, 145 patients were treated with Xgeva for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14 (range: 1 to 60 doses) and the median number of months on study was 11 (range: 0 to 54 months).

Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13 to 83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age).

The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Trials 1, 2, and 3. The most common adverse reactions in patients (per-patient incidence ≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (per-patient incidence of 0.7%).

The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw (per-patient incidence of 0.7%), and tooth abscess or tooth infection (per-patient incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

Hypocalcemia and Hypophosphatemia • Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with Xgeva.

• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).

Osteonecrosis of the Jaw (ONJ) In Trials 4 and 5, ONJ was confirmed in 4 of 304 (1.3%) patients who received Xgeva. The median time to ONJ was 16 months (range: 13 to 20 months) [see Warnings and Precautions (5.4)].

Hypercalcemia of Malignancy Xgeva was evaluated in an open-label, single-arm trial (Trial 6) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled.

The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Trials 1, 2, 3, 4, and 5. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to Xgeva therapy.

Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.

• Hypersensitivity, including anaphylactic reactions.

• Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported.

Immunogenicity.

As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years and none of the 304 patients with giant cell tumor of bone in Trials 4 and 5 tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as a

assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect.

Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.

USE IN SPECIFIC POPULATIONS: Pregnancy: Category D. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva.

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation.

Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated.

Pediatric Use. The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Xgeva is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone.

Xgeva was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg. A total of two of six (33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/ kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth.

Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment. Two clinical trials were conducted in patients without cancer and with varying degrees of renal function. In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation.

Hypocalcemia was mild to moderate in severity in 96% of patients. Monitor calcium levels and, calcium and vitamin D intake.

Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk.

Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2014 Amgen Inc. All rights reserved.

Printed in USA. USA-162x-104118

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 13

Debates and Didactics in Hematology and Oncology Mantle Cell Lymphoma continued from page 9

with relapsed/refractory disease. Lenalidomide was active even in patients who had received bortezomib upon relapse, and the benefits of this drug apply as well to patients who have not had a transplant, Dr. Flowers noted.

survival was 13.9 months, and median overall survival was not reached. Durable responses were seen even in patients with prior exposure to bortezomib and lenalidomide.

Idelalisib also produced “appreciable responses” in mantle cell lymphoma, “albeit it was studied in a relatively

They [novel agents] may not necessarily cure mantle cell lymphoma, but we may be able to keep the disease away with less intensive therapies than [autologous stem cell transplant], and with less toxicity. With modern therapy, we may see a change in the natural history of this disease.

—Christopher Flowers, MD, MS

The most impressive new data, however, have been seen for the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica) and the PI3K inhibitor idelalisib (Zydelig), reported Dr. Flowers.

Response rates for ibrutinib were essentially twice those observed in the lenalidomide studies (68%, with 21% complete responses), in the study published in The New England Journal of Medicine.8 Median progression-free

small number of patients, and it is not approved for this indication,” Dr. Flowers added.

Two additional novel agents in earlyphase trials include the BCL-2 inhibitor venetoclax, which has shown singleagent activity and in vitro synergy with proteasome inhibitors (ibrutinib and rituximab) and the novel oral proteasome inhibitor ixazomib (MLN9708).

The availability of these novel agents allows for combinations and sequencing

of treatments in patients with relapsed/ refractory disease. “They may not necessarily cure mantle cell lymphoma, but we may be able to keep the disease away with less intensive therapies than [autologous stem cell transplant], and with less toxicity,” Dr. Flowers said. “With modern therapy, we may see a change in the natural history of this disease.” n

Disclosure: Dr. Flowers is an unpaid consultant for Genentech and Celgene; has received consulting fees from OptumRX and research support from AbbVie, Acerta, Celgene, Genentech, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Millennium/Takeda, Onyx Pharmaceuticals, Pharmacyclics, TG Therapeutics, and Spectrum.

References 1. Dreyling M, Lenz G, Hoster E, et al: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL Network. Blood 105:2677-2684, 2005.

2. Hermine O, Hoster E, Walewski J, et al: Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: Final analysis of the MCL Younger Trial of

the European Mantle Cell Lymphoma Network. 2012 ASH Annual Meeting. Abstract 151.

3. Graf SA, Stevenson PA, Holmberg LA, et al: Rituximab maintenance therapy after autologous stem cell transplantation improves survival of patients with mantle cell lymphoma. 2014 ASH Annual Meeting. Abstract 3985. Presented December 8, 2014.

4. Romaguera JE, Fayad L, Rodriguez MA, et al: High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 23:7013-7023, 2005.

5. Fisher RI, Bernstein SH, Kahl BS, et al: Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24:4867-4874, 2006.

6. Goy A, Bernstein SH, McDonald A, et al: Potential biomarkers of bortezomib activity in mantle cell lymphoma from the phase 2 PINNACLE trial. Leuk Lymphoma 51:1269-1277, 2010.

7. Witzig TE, Vose J, Zinzani PL, et al: Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. 2013 ASCO Annual Meeting.

Abstract 8533. Presented May 31, 2013.

8. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013.

Announcements

ASH Honors John C. Byrd, MD, With 2015 William Dameshek Prize

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he American Society of Hematology (ASH) will present the 2015 William Dameshek Prize to John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC– James) for his contributions to the development of transformative treatments for chronic lymphocytic leukemia (CLL).

This prize, named after the late William Dameshek, MD, a Past President of ASH and the original editor of Blood, recognizes a recent outstanding contribution to the field of hematology. Dr. Byrd will accept his award on Tuesday, December 8, during the 57th ASH Annual Meeting and Exposition in Orlando.

Dr. Byrd is the D. Warren Brown Chair of Leukemia Research at The Ohio State University College of Medicine, where he holds the academic rank of Professor of Internal Medicine; Medicinal Chemistry; Molecular, Cellu-

lar, and Developmental Biology; and Veterinary Bioscience. He is the Director of the Division of Hematology and Program Co-Leader of the Leukemia Research Program in the OSUCCC.

John C. Byrd, MD

Throughout his more than 20-year career, Dr. Byrd has revolutionized the way CLL is viewed and treated, yielding practice-changing therapies for patients with the disease. Early in his career, Dr. Byrd developed and defined the mechanism of action of the anti-CD20 antibody rituximab, the first therapy

to prolong survival in CLL. He led the preclinical and clinical development of the targeted therapy ibrutinib. Since the U.S. Food and Drug Administration approved ibrutinib in 2013, Dr. Byrd has continued to facilitate research addressing drug resistance and exploring alternative treatment strategies.

Dr. Byrd earned his medical degree at the University of Arkansas for Medical Sciences. He completed his internship and residency in internal medicine and fellowship in hematology, oncology, and bone marrow transplantation at the Walter Reed Army Medical Center in Washington, DC. Dr. Byrd received translational laboratory training at Johns Hopkins University under the mentorship of Michael Grever, MD, with whom he has continued to work closely throughout his career.

In 2001, Dr. Byrd joined OSUCCC, where he has transformed the Hematologic Malignancies Program from a

joint Hematology-Oncology Program with seven members into a distinct Division of Hematology with nearly 50 members. He is active in cooperative group research, serving as a member of the CLL Research Consortium and in several leadership roles within the Cancer and Leukemia Group B and Alliance for Clinical Trials in Oncology.

Dr. Byrd has been involved in ASH throughout his career, serving as faculty and Co-Director of the ASH Clinical Research Training Institute. He is also active in ASCO and AACR. “[ASH] is honored to recognize Dr. Byrd with the William Dameshek Prize for his outstanding contributions in the area of CLL that extend or improve the quality of life of hundreds of thousands of patients each year,” said ASH President David A. Williams, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School.” n

The ASCO Post | SEPTEMBER 25, 2015

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Announcements

Fred R. Hirsch, MD, PhD, Presented With 2015 Addario Lectureship Award

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he Bonnie J. Addario Lung Cancer Foundation (ALCF) honored Fred R. Hirsch, MD, PhD, with the 2015 Addario Lectureship Award for his continued leadership and expertise in lung cancer treatment and research. Dr. Hirsch, CEO of the International Association for the Study of Lung Cancer (IASLC), received the award at the 16th International Lung Cancer Congress held on July 30 to August 1 in Huntington Beach, California.

diligently to bridge international ties for lung cancer and recognizes it is a global disease that requires a global effort.”

Dr. Hirsch has been Professor of Medicine at the University of Colorado Cancer Center and Professor of

Medicine and Pathology at the University of Colorado, Denver since 1999.

He also serves as the Conference President for the World Conference on Lung Cancer. Dr. S:6.75” Hirsch received his medical degree and doctorate from the University of Copenhagen and served

as Chief Physician in the Department of Oncology at the Finsen Center (Copenhagen) from 1996–1999. He has been a supervisor for many European and Asian postdoctoral trainees in his laboratory at the University of Colorado Cancer Center. n

Fred R. Hirsch, MD, PhD

“Dr. Hirsch’s contribution and dedication to lung cancer research is truly remarkable,” said Bonnie J. A ­ ddario, 10-year lung cancer survivor and founder of the ALCF. “Dr. Hirsch is a cancer survivor, which makes him very sensitive to patients and increases his commitment to their survival. We are thrilled to present him with the eighth Addario Lectureship Award to highlight his commitment to eliminate lung cancer worldwide.”

Recognized by Colleagues Dr. Hirsch is known best for his research on the diagnostic tool fluorescent in situ hybridization (FISH).

Colleagues David Gandara, MD, Associate Director of Clinical Research at the UC Davis Cancer Center, and Roy Herbst, MD, PhD, Ensign Professor of Medicine and Chief of Medical Oncology at the Yale Cancer Center, have nicknamed him the “Big Fisherman.”

“There is no one in the world that has been more dedicated to IASLC and addressing lung cancer worldwide [than Dr. Hirsch],” said Paul Bunn, Jr, MD, Distinguished Professor, Division of Medical Oncology at the University of Colorado and James Dudley Chair in Lung Cancer Research. “[He] has a unique perspective—he is not only both a pathologist and a medical oncologist, but also has trained and practiced in both Europe and the United States. He has been involved in studies of lung cancer diagnosis, staging, prevention, early detection, and treatment that have revolutionized the care of lung cancer patients. He works

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.

Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%).

Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

© 2014 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA

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Announcements

Jinghui Zhang, PhD, Named Chair of Computational Biology at St. Jude

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t. Jude Children’s Research Hospital has named Jinghui Zhang, PhD, as the first Chair of the Department of Computational Biology. She will hold the St. Jude Endowed Chair in Bioinformatics.

Computational biology applies

mathematics and computer science to the study of genomics, systems biology, biologic image analysis, and structural and chemical biology. The 28,700 square-foot space will be named Brooks Brothers Computational Biology Center and will hold both laboratories and

S:6.75”

Jinghui Zhang, PhD

offices, while also being home to a stateof-the-art genome-sequencing laboratory. Under Dr. Zhang’s leadership, the department will grow to include nine faculty members during the next several years.

Dr. Zhang joined St. Jude in 2010. n

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

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• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

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31 3

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121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.

Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330).

Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.

Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

COMETRIQ.com

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PAGE 16

Announcements

NCI Awards SPORE Grant to Mayo Clinic Multiple Myeloma Research Team

A

team of Mayo Clinic Cancer Center scientists has been awarded a Specialized Program of Research Excellence (SPORE) grant in multiple myeloma from the National Cancer Institute. The Center is one of only three cancer centers to receive a SPORE grant

for multiple myeloma cancer research.

“With project leaders from Mayo campuses in Arizona, Rochester, and Florida, our SPORE team will study the genetic basis for myeloma, develop novel viral and immunologic therapies, and optimize the use of existing therapies

with a goal of controlling and eventually curing this deadly disease,” said lead investigator Leif Bergsagel, MD. “Starting from the pioneering work of Robert Kyle, MD, over theS:6.75” past half-century, the myeloma group at Mayo Clinic is one of the strongest in the world.”

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning.

Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.

Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.

Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment.

In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively.

All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients.

Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Renowned journalist and Mayo Clinic Trustee Tom Brokaw, diagnosed with multiple myeloma at Mayo Clinic in 2013, will serve as a patient advocate to the SPORE to represent the interests of patients and increase awareness of, and support for, myeloma research. n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in 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.

6. 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 safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days.

The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0.

Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5 Palmar-plantar erythrodysesthesia syndrome.

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Announcements

Yale Cancer Center Receives $11 Million SPORE Grant for Lung Cancer Research

PROD ED AE/AS CW CD

DATE

Visit The ASCO Post website at ASCOPost.com

SIGNOFF

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“This is an exciting time to do cancer research in areas like immunotherapy,” said Lieping Chen, MD, the United Technologies Corporation Professor in Cancer Research and Codirector of the Cancer Immunology Program at Yale Cancer Center. “With this award from the NCI, we hope to make a big difference in treating and preventing lung cancer.”

The Yale SPORE will conduct projects in immunotherapy, precision medicine, drug development, and smoking cessation. Teams will also work to identify new translational research avenues and train young physician-researchers for careers in lung cancer. Frank J. Slack, PhD, Director of the Institute for RNA Medicine at the Cancer Center at Beth Israel Deaconess Medical Center, will co-lead a project examining microRNAs as therapeutics for lung cancer. Dr. Slack was formerly on the faculty at Yale and retains a research affiliation.

Yale is 1 of 5 institutions in the country with a SPORE devoted to lung cancer and 1 of 13 institutions to house more than one SPORE. n S:9.75”

Stage 2: Systolic ≥160 mmHg or Diastolic ≥100 mmHg

Placebo N=1073 (%) 15

Roy S. Herbst, MD

AD

Table 3.

Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in 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. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).

8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are 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 COMETRIQ, 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.

8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.

8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility.

Cabozantinib impaired male and female fertility in animal studies.

8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal).

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established.

8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.

10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy.

• COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

and back again to develop even newer insights,” said principal investigator Roy S. Herbst, MD, the Ensign Professor of Medicine, Chief of the Medical Oncology Program at Smilow Cancer Hospital at Yale-New Haven, and Associate Director for the Translational Research Program at Yale Cancer Center. “This effort represents tremendous teamwork by investigators to combat this very common and all-too-fatal disease.”

TC

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3 Subjects with at least two blood pressure measurements after the first dose.

ology, and addiction science to collaborate on projects.

“The only way to approach a problem as big as lung cancer is to have experts in basic, translational, and clinical research working on several fronts taking the research from the lab to the clinic

QC

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

search program in non–small cell lung cancer.

The new research program harnesses the strengths of academic cancer centers by bringing together experts in onS:6.75” cology, immunobiology, pharmacology, molecular biology, pathology, epidemi-

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he National Cancer Institute (NCI) recently awarded Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven a Specialized Program of Research Excellence, or SPORE, grant worth $11 million.

The Yale SPORE will launch a new re-

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ASCOPost.com | SEPTEMBER 25, 2015

The ASCO Post | SEPTEMBER 25, 2015

PAGE 18

Debates and Didactics in Hematology and Oncology Head/Neck Cancer

HPV-Positive Head and Neck Cancer: When Can Chemotherapy Be Omitted?

By Caroline Helwick

A

re there patients with locally advanced squamous cell carcinoma of the head and neck associated with human papillomavirus (HPV) for whom chemotherapy can be omitted? Experts debated this question at the 2015 Debates and Didactics in Hematology and Oncology Conference in Sea Island, Georgia, sponsored by Emory University. Jonathan Beitler, MD, Professor of Radiation Oncology, Otolaryngology, Hematology, and Oncology at Emory, and Nabil Saba, MD, Professor of Hematology and Medical Oncology and Director of Head and Neck Medical Oncology at Emory, focused on the controversies surrounding the management of HPV-related head and neck cancer, especially in nonsmokers with N2b tumors.

Prognostic Effect of HPV Positivity Clearly, HPV status has a prognostic effect, but does it influence treatment?

In their 2010 report in The New England Journal of Medicine, Ang and colleagues found that HPV-positive patients, compared with their HPV-negative counterparts, had better progression-free survival and lower locoregional failure rates as well as improved 3-year overall survival (82.4% vs 57.1%; P < .001).1 The rate of distant metastasis, however, was not significantly different between the two groups (8.7% vs 14.6%; P = .21).

Subsequent to this important study, HPV-positive diagnoses have increased.

“While these patients are doing well with locoregional control,” according to Dr. Saba, “a new paradigm has emerged—more distant failures seen in patients being treated for locally advanced disease.”

Dr. Beitler added that similar findings were made in the TAX 324 trial, in which patients with HPV-16–associated tumors had far better survival outcomes than HPV-negative patients after treatment with sequential chemoradiation.2 The DAHANCA5 study also showed that HPV-associated tumors had better outcomes, this time after radiotherapy alone.3 Not only does HPV positivity confer a more favorable prognosis, it is “platform-independent,” Dr. Beitler told listeners. “These patients just do better regardless of whether they are treated with chemoradiation, radiation alone, or even surgery with or without adjuvant therapy.”

In a nutshell, concurrent chemoradiation is what we do in advanced disease.

—Jonathan Beitler, MD

Staging Issues With HPV Positivity A current problem for clinicians is that HPV positivity has not been incorporated into the current TNM staging system. Huang et al recently showed, among more than 600 subjects, that higher stage of disease was not associated with poor 5-year survival for patients with HPV-associated tumors, as it was for those with HPV-unrelated cancers— indicating “prognostic discordance.”4 A problem with the Huang analysis is that it included very few patients with stage I (1%) or II (4%) disease, and it did not utilize the stage IVa and IVb designations of the current AJCC (American Joint Committee on Cancer) system,5 according to Dr. Beitler.

“We don’t even know if extracapsular extension makes a difference in HPVrelated cancers,” he added.

The lack of an accurate staging system for these patients makes it impossible to identify those HPV-positive patients who truly need chemotherapy, Dr. Beitler said. It appears that patients most at risk for metastatic disease are those with N2c and N3 disease, a relatively infrequent subgroup.6

Benefit of Chemotherapy Still Debated Although the use of chemotherapy is supported in N3 and T3/4 disease, “mission creep” has occurred, and “somehow chemotherapy gets added in other stages, and that may not be appropriate,” Dr. Beitler explained. In many cases, he suggested, chemotherapy adds toxicity but not benefit. As a locoregional radiation sensitizer, it “is worth” about 12 Gy7 and “isn’t worth a heck of a lot” for protection against systemic disease, at least according to the MACH-NC meta-analysis.8 Regarding chemotherapy toxicity, the GORTEC 94-01 final analysis found significantly higher rates of teeth-related problems and numerically

higher rates of several other side effects.9 The percentage of patients with no evidence of disease but grade 3/4 late effects was 30% with radiotherapy alone and 56% with chemoradiation (although this was not statistically significant; P = .12). Other studies have indicated that as more chemotherapy is added, the relative risk of toxicity increases, Dr. Beitler said.

In sum, he said that surgery, radiotherapy, and chemoradiation are all effective for HPV-associated cancers, but staging is not particularly useful in selecting the best approach for a given patient.

the benefit of induction chemotherapy in reducing distant metastases (HR = 0.73, P = .001) is significant in the meta-analysis. The concomitant schedules markedly improved locoregional control (HR = 0.74, P < .001), with a significant but less impressive improvement in distant control (HR = 0.88, P = .04).8 It is important to note that this meta-analysis was performed before HPV status became a factor, and therefore the distant metastatic rate by HPV status is not known, added Dr. Saba. Nevertheless, he suggested, “the findings suggest that systemic chemotherapy does help ameliorate the rate of distant metastasis.”

‘Unusual Pattern of Metastasis’ Dr. Saba emphasized the importance of this finding in the case of HPV-positive tumors, which have “an unusual pattern of metastasis.” He added, “We were the first to report on the unusual pattern of metastases in the HPV-positive oropharyngeal squamous cell carcinoma group.”10 In the large retrospective Princess Margaret Hos-

For smokers with T4, N2c, N3, and N2b disease, we agree that chemotherapy is clearly indicated. For N2b disease in nonsmokers, omitting chemotherapy is a step into the unknown.

—Nabil Saba, MD

Dr. Beitler pointed to data from the MACH-NC meta-analysis to support his opinion that concomitant chemoradiation is beneficial, but induction chemotherapy is not.8 MACH-NC, which included more than 17,000 patients from 93 randomized trials, found that concomitant chemotherapy and radiation significantly improved overall survival (hazard ratio [HR] = 0.81), but induction chemotherapy did not improve survival (HR = 0.96) and reduced distant failures by only 2% to 3%.

Concomitant therapy was also superior to induction chemotherapy for eventfree survival and locoregional failure.

“In a nutshell, concurrent chemoradiation is what we do in advanced disease,” Dr. Beitler said.

However, Dr. Saba had a different perspective on the study and argued that

pital data set, investigators also found a higher risk for multiple-organ failure in HPV-positive patients (not seen in HPV-negative patients).

A “fair proportion of these patients,” noted Dr. Saba, manifested a “disseminating” phenotype with spread to two or more organs that was relatively frequent (33%), although it was not seen in HPV-negative cases.

Of the HPV-positive patients who had distant metastases, 20% demonstrated an “explosive” character, with numerous metastatic lesions occupying almost the entire organ and developing rapidly. “Strikingly, 72% of the HPV-positive distant metastatic cases were without locoregional failure,” Dr. Saba added.

This finding, he continued, provokes continued on page 20

Trusted to take a bite out * of G-CSF acquisition costs GRANIX® has gained >34% share of the US short-acting G-CSF hospital market in its first 17 months1 » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)2 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)2 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)2 » Offering a presentation for self-administration

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information

» Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of March 2015. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

References: 1. This information is an estimate derived from the use of information under license from the following IMS Health Information Service: IMS National Sales Perspective, GRANIX micrograms by non-federal hospital channel March 2015. IMS expressly reserves all rights, including rights of copying, distribution, and republication (micrograms calculated as eaches x strength). 2. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40681 May 2015.

The ASCO Post | SEPTEMBER 25, 2015

PAGE 20

Debates and Didactics in Hematology and Oncology HPV-Positive Cancer continued from page 18

several questions: How and when does the transformed HPV-positive tumor cell clone escape from the primary site and disseminate? How can such “occult” distant metastasis be identified?

“We simply don’t know. Until we are proficient at this, the only way to target

these clones is with systemic therapy,” Dr. Saba said.

Is Deintensification an Acceptable Approach?

Is deintensification of chemotherapy an acceptable approach to treating HPV-related N2b cancers? Dr. Saba emphasized that deintensification is not

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

724-43395

DIGITAL

equivalent to omitting or even reducing the dose of chemotherapy. “It can take several forms,” he explained.

One approach is to modify systemic agents to relieve toxicity (as in RTOG 1016). Risk stratification after surgery is another means (as in ECOG 3311, which introduced a lower dose of radiation in low-risk patients). “Chemo

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Job Number: 21282 Revision No: 0

selection” is yet another approach that deintensifies treatment by reducing radiation based on response to appropriate chemotherapy agents.

Deintensification of radiotherapy was shown to be effective in the E1308 trial, which evaluated induction chemotherapy followed by cetuximab ­(Erbitux) with low-dose vs standarddose radiotherapy in stage III/IV HPVpositive patients.11 Patients deemed to have the best prognosis (< T4, T1– N2b, < 10 pack-years of smoking) did very well when they received a reduced radiation dose (54 Gy). Dr. Beitler pointed out that E1308 did not quite meet its own minimal threshold for overall 2-year disease-free survival.

In 62 patients in the low-dose group, 2-year progression-free survival was 84%, and 2-year overall survival was 95%. Patients with ≤ 10 pack-years of smoking had slightly higher rates: 96% for progression-free survival and 97% for overall survival. For higher-risk patients who received full-dose intensitymodulated radiation therapy, 2-year progression-free survival was 65%, and overall survival was 87%.

“The trial showed that in the group we are discussing—the low-risk group, including nonsmokers with N2b disease—we can reduce the radiotherapy dose if we give enough systemic therapy upfront,” Dr. Saba said.

Dr. Saba did express some concerns that the increasing use of deintensification may be contributing to the distant failure rate seen with HPV-positive tumors. A combined analysis of RTOG 0129 and RTOG 0522 showed distant failure to be the predominant pattern of failure, occurring in 41% of HPV-positive patients and 38% of HPV-negative patients.12 It appeared that in HPV-negative tumors, the risk of distant metastases plateaued at about 2 years, but in HPV-positive tumors, the risk seemed to persist for a longer time. “This is a topic of concern for medical oncologists, as far as omitting systemic therapy in their treatment,” Dr. Saba said.

Radiotherapy Alone for Some Tumors For small primary tumors (T1–2, N1–2a), outcomes with radiation alone (66 Gy in 30 fractions) can be excellent, Dr. Beitler said. MD Anderson has reported a 5-year locoregional control rate of 98%. The addition of a systemic radiosensitizer did not improve results in patients with intermediate-stage oropharyngeal disease, even without accounting for HPV status.

Similarly, data from Princess Mar-

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 21

Debates and Didactics in Hematology and Oncology garet Hospital in Toronto have shown radiotherapy to be at least as effective as chemoradiation therapy, in a large series of patients. However, Dr. Saba responded that in the Princess Margaret Hospital cohort, distant and local disease control for patients with N2b disease was lower with radiotherapy alone, and some of these patients were nonsmokers, raising concerns about the control arm of NRG HN002 for patients with N2b disease.

“As medical oncologists, we have to ask, if we have patients with N2b disease who are nonsmokers, are we comfortable omitting chemotherapy? We in our group have said no. We are not comfortable giving radiation therapy only to these patients,” Dr. Saba said. “For smokers with T4, N2c, N3, and N2b disease, we agree that chemotherapy is clearly indicated. For N2b disease in nonsmokers, omitting chemotherapy is a step into the unknown.”

Clinical Trials May Offer Answers Two important clinical trials may provide some answers to guide clinicians in treating HPV-positive locally advanced disease. ECOG 3311 has en-

rolled HPV-16–positive patients with stage III/IV disease (cT1–3, N1–2b [no T1N1]), stratifying them by risk. Lowrisk patients will be observed; high-risk patients will be treated with radiotherapy and chemotherapy; and intermediaterisk patients will be randomized to two different radiotherapy schedules. Patients will be evaluated at 2 years.

The NRG HN002 trial has enrolled HPV-16–positive, nonsmoking patients with locoregionally advanced oropharyngeal cancer to receive radiotherapy alone (60 Gy, 6 fractions per week for 5 weeks, ie, slightly accelerated) or radiotherapy (60 Gy in 6 weeks) plus cisplatin 40 mg/m2 weekly for 6 cycles.

“Hopefully, we are embarking on randomized trials that will change preconceptions,” Dr. Beitler said. n

Disclosure: Drs. Beitler and Saba reported no potential conflicts of interest.

References 1. Ang KK, Harris J, Wheeler R, et al: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24-35, 2010.

2. Posner MR, Lorch JH, Goloubeva O, et al: Survival and human papillomavirus

in oropharynx cancer in TAX 324: A subset analysis from an international phase III trial. Ann Oncol 22:1071-1077, 2011.

3. Lassen P, Eriksen JG, HamiltonDutoit S, et al: Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 27:1992-1998, 2009.

4. Huang SH, Xu W, Waldron J, et al: Refining American Joint Committee on Cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol 33:836-845, 2015.

5. Beitler JJ, Mikell JL, Switchenko J: Human papillomavirus-related oropharyngeal cancer: Agree with a new staging system, but the devil is in the details. J Clin Oncol. July 27, 2015 (early release online).

6. O’Sullivan B, Huang SH, Siu LL, et al: Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 31:543550, 2013.

7. Kasibhatla M, Kirkpatrick JP, Brizel DM: How much radiation is the chemotherapy worth in advanced head and neck cancer? Int J Radiat Oncol Biol Phys

Visit ASCOPost.com for Interviews Filmed Live During the IASLC 16th World Conference on Lung Cancer The ASCO Post Newsreels presents these and other important discussions: ■■

New Kinase Targets for Treating Advanced Disease

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Genomics of Young Lung Cancer Study

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Integration of Next Generation Data Into the Clinic

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Screening for Lung Cancer in Those at High Risk Visit The ASCO Post online at ASCOPost.com

68:1491-1495, 2007.

8. Pignon JP, le MaîtreA, Maillard E, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4-14, 2009.

9. Denis F, Garaud P, Bardet E, et al: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69-76, 2004.

10. Müller S, Khuri FR, Kono SA, et al: HPV positive squamous cell carcinoma of the oropharynx: Are we observing an unusual pattern of metastases? Head Neck Pathol 6:336-344, 2012.

11. Cmelak A, Li S, Marur S, et al: E1308: Reduced-dose IMRT in human papillomavirus-associated resectable oropharyngeal squamous carcinomas after clinical response to induction chemotherapy. 2014 ASCO Annual Meeting. Abstract LBA6006. Presented May 30, 2014.

12. Misiukiewicz K, Camille N, Gupta V, et al: The role of HPV status in recurrent/ metastatic squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol 12:812-819, 2014.

Š 2015 Celgene Corporation

03/15

US-CELG140284

IN MULTIPLE MYELOMA

RESIDUAL DISEASE AND IMMUNE DYSFUNCTION FORM A GROWING RISK OF RELAPSE An increased understanding of multiple myeloma has helped advance myeloma care over the past several decades.1,2 Despite a significant improvement in 5-year relative survival rates, patients still experience multiple periods of relapse and remission.2,3 Do residual disease and immune dysfunction form a cycle that complicates our strategies?

EVEN WITH THE ACHIEVEMENT OF A COMPLETE RESPONSE, 100 MILLION MYELOMA CELLS MAY REMAIN.4

~

The majority of patients with multiple myeloma have persistent levels of residual disease (minimal residual malignant cells) that are below the sensitivity of most protein and bone marrow diagnostic tests.5-7 Even in patients who achieve a complete response (by current International Myeloma Working Group criteria), residual disease may persist.4 In addition, dominant and minor clones continue to evolve, putting the patient at increased risk for relapse.8,9

IMMUNE DYSFUNCTION ALLOWS RESIDUAL DISEASE TO PROLIFERATE, FURTHER WEAKENING THE IMMUNE SYSTEM, AND MAY CAUSE A CYCLE OF DISEASE THAT RESULTS IN RELAPSE.5, 9-14 Myeloma tumor cells crowd out healthy cells in the bone marrow, leading to a compromised immune system and decreased immune surveillance—the immune system’s ability to identify and eliminate tumor cells.9-13 When immune surveillance is impaired, residual cells may proliferate and evolve, permitting a cycle that can lead to relapse.9,10,13

CONTINUOUS SUPPRESSION OF RESIDUAL DISEASE AND SUPPORT OF IMMUNE FUNCTION ARE IMPORTANT CONSIDERATIONS WHEN CREATING A LONG-TERM STRATEGY.13,15,16 Visit mmrelapserisk.com to learn more.

References: 1. Kumar SK, et al. Leukemia. 2014;28:1122-1128. 2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER cancer statistics review 1975-2011. Available at http://www.seer.cancer.gov. Accessed October 22, 2014. 3. Hajek R. Multiple myeloma – a quick reflection on the fast progress. InTech; 2013. Available at http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-onthe-fast-progress. Accessed December 12, 2014. 4. Poon ML, et al. Cancer Therapy. 2008;6:275-284. 5. Hart AJ, et al. Biol Blood Marrow Transplant. 2012;18:1790-1799. 6. Rajkumar SV, et al. Blood. 2011;117:4691-4695. 7. Martinez-Lopez J, et al. Blood. 2014;123:30733079. 8. Keats JJ, et al. Blood. 2012;120:1067-1076. 9. Morgan GJ, et al. Nat Rev Cancer. 2012;12:335-348. 10. Katodritou E, et al. Am J Hematol. 2011;86:967-973. 11. Braga WM, et al. Clin Dev Immunol. 2012;2012:Mar 27 EPub. 12. Kyle RA, et al. N Engl J Med. 2004;351:18601873. 13. Pratt G, et al. Br J Haematol. 2007;138:563-579. 14. Favaloro J, et al. Leuk Lymphoma. 2014. May 12:1-8. [Epub ahead of print].

15. Roschewski M, et al. Blood. 2013;122:486-490. 16. Pessoa de Magalhães RJ, et al. Haematologica. 2013;98:79-86.

The ASCO Post | SEPTEMBER 25, 2015

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In the Clinic Supportive Care

Rolapitant for Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting

By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n September 2, 2015, rolapitant (Varubi) was approved for use in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and subsequent courses of emetogenic chemotherapy for cancer, including, but not limited to, highly emetogenic chemotherapy. (See page 38 for news of FDA approval).

Supporting Efficacy Data Approval was based on results of three double-blind phase III trials: two in patients receiving cisplatin-based highly emetogenic chemotherapy1,2 and one in patients receiving moderately emetogenic chemotherapy.1,3 These results showed that the addition of oral rolapitant to the 5-hydroxytryptamine 3 (5-HT3) antagonist granisetron and dexamethasone resulted in higher complete response rates (no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) during

OF NOTE Rolapitant is a selective and competitive antagonist of human substance P/neurokinin-1 (NK1) receptors.

cycle 1 of chemotherapy.

In one highly emetogenic chemotherapy trial, complete response rates during the delayed phase were 72.7% in the rolapitant group (n = 264) vs 58.4% in the control group (n = 262; difference = 14.3%, P < .001). In the second highly emetogenic chemotherapy trial, complete response rates were 70.1% in the rolapitant group (n = 271) vs 61.9% in the control group (n = 273; difference = 8.2%, P = .043). In the moderately emetogenic chemotherapy trial, in which approximately 50% of patients received anthracycline-cyclophosphamide combinations (now considered

highly emetogenic), complete response rates were 71.3% in the rolapitant group (n = 666) vs 61.6% in the control group (n = 666; difference = 9.8%, P < .001).

How It Works Rolapitant is a selective and competitive antagonist of human substance P/ neurokinin-1 (NK1) receptors. It does not have significant affinity for NK2 or NK3 receptors or for a variety of other receptors, transporters, enzymes, and ion channels.

How It Is Given The recommended dose of rolapitant is 180 mg given approximately 1 to 2 hours prior to the start of chemotherapy on day 1. It is given prior to the

breast cancer resistance protein (BCRP) and an inhibitor of P-glycoprotein (P-gp). Increased exposure to BCRP substrates with a narrow therapeutic index (eg, methotrexate, topotecan, irinotecan) may result in potential adverse reactions, requiring monitoring if concomitant use cannot be avoided.

The lowest dose of rosuvastatin (Crestor) should be given if concomitant use cannot be avoided. Increased exposure to P-gp substrates with a narrow therapeutic index, such as digoxin, may result in potential adverse reactions, requiring monitoring if concomitant use cannot be avoided.

No dosage adjustment is needed in patients with mild or moderate hepatic impairment. There are no data in

Rolapitant for Delayed Nausea and Vomiting ■■ Rolapitant (Varubi) was approved for use in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and subsequent courses of emetogenic chemotherapy for cancer, including, but not limited to, highly emetogenic chemotherapy.

■■ The recommended dose of rolapitant is 180 mg given approximately 1 to 2 hours prior to the start of chemotherapy on day 1.

initiation of each chemotherapy cycle but at no less than 2-week intervals. It is administered in combination with dexamethasone and a 5-HT3 receptor antagonist. No dosage adjustment for dexamethasone is required.

Rolapitant is not an inhibitor or inducer of CYP3A4. Thus, no dose adjustments are needed for coadministration of the CYP3A4 substrate dexamethasone or other substrates such as midazolam and ondansetron. Strong CYP3A4 inducers (eg, rifampin) reduce plasma levels of rolapitant; use of rolapitant should be avoided in patients requiring chronic treatment with such drugs.

Rolapitant is a moderate CYP2D6 inhibitor. Caution is warranted in considering the concomitant use of CYP2D6 substrates with a narrow therapeutic index. Concomitant use increased exposure to dextromethorphan.

Concomitant treatment with thioridazine is contraindicated. Concomitant use of pimozide should be avoided; if it cannot be avoided, patients should be monitored for QT prolongation.

Rolapitant is an inhibitor of the

patients with severe hepatic impairment; patients with severe hepatic impairment should be monitored for adverse reactions if use of rolapitant cannot be avoided.

Safety Profile Overall, adverse events were reported in approximately 7% of rolapitant patients and 6% of control patients during cycle 1 of the phase III trials. The most common adverse events of any grade that occurred more frequently in rolapitant patients during cycle 1 in the highly emetogenic chemotherapy trials were neutropenia (9% vs 8% in control group), hiccups (5% vs 4%), and abdominal pain (3% vs 2%). The most common adverse events in the moderately emetogenic chemotherapy trial were decreased appetite (9% vs 7%), neutropenia (7% vs 6%), dizziness (6% vs 4%), dyspepsia (4% vs 2%), urinary tract infection (4% vs 3%), stomatitis (4% vs 2%), and anemia (3% vs 2%).

Among 1,198 rolapitant recipients who continued in an optional multiple-cycle extension for up to 6 cycles of chemo-

OF NOTE Rolapitant carries warnings/ precautions for interaction with ­CYP2D6 substrates with a narrow therapeutic index.

therapy, adverse events were generally similar to those observed in cycle 1.

Rolapitant carries warnings/precautions for interaction with CYP2D6 substrates with a narrow therapeutic index.

The inhibitory effect of a single dose of rolapitant on CYP2D6 persists for at least 7 days. Concurrent use of rolapitant with the CYP2D6 substrate thioridazine is contraindicated. n References 1. Varubi (rolapitant) tablets prescribing information, Tesaro, Inc, September 2015. Available at http://varubirx.com/.

Accessed September 9, 2015.

2. Rapoport BL, Chasen MR, Gridelli C, et al: Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: Two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol. August 10, 2015 (early release online).

3. Schwartzberg LS, Modiano MR, Rapoport BL, et al: Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer. Lancet Oncol. August 10, 2015 (early release online).

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 www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

-ADVERTORIAL-

Innovation in squamous non-small cell lung cancer therapy There is an urgent need for effective treatment options to improve outcomes for patients with squamous non-small cell lung cancer (NSCLC). The importance of incremental improvements in squamous carcinoma therapies should not be underestimated.

Despite the wealth of medical knowledge afforded by years of scientific research, lung cancer continues to have one of the highest incidence rates and the highest mortality rate of any cancer.1 In 2012, lung cancer was responsible for 1.825 million new cases and 1.59 million deaths worldwide.1 Despite changes in patient behaviors, such as reduced tobacco smoking, the number of people dying from this disease is expected to increase to 2.95 million over the next 20 years.1 Squamous NSCLC is an aggressive form of lung cancer that is hard to treat.

NSCLC accounts for 85% to 90% of all lung cancers and comprises several subtypes.2 These subtypes include nonsquamous and squamous, which represent two-thirds and one-third of all NSCLC cases, respectively.2 Nonsquamous NSCLC can be further divided into different subtypes, including adenocarcinoma (approximately 40% of all NSCLC cases), large cell carcinoma (approximately 10% to 15% of all NSCLC cases), and other less common subtypes.2 Tumors in squamous NSCLC are often centrally located, making them more likely to invade larger blood vessels and bronchi, leading to potentially fatal complications.3,4 Squamous NSCLC tumors also grow quickly5,6 and commonly metastasize to other parts of the body.7 Furthermore, patients with squamous NSCLC are more likely to have a history of smoking and serious comorbidities, factors that make the disease more challenging to treat.8 In the 1st-line treatment of this disease, overall survival (OS) is approximately 8 to 10 months.9,10 There is, therefore, an urgent need for effective therapies that will

improve outcomes for patients with squamous NSCLC. In the 1st-line setting, progress in squamous NSCLC is lagging behind progress in nonsquamous NSCLC. For the majority of patients with advanced squamous NSCLC, platinum-based doublet chemotherapy remains the standard of care in 1st line,11,12 with an OS of approximately 8 to 10 months.9,10 This is in contrast to the progress made in nonsquamous NSCLC, where treatment advances—including therapies targeting oncogenic drivers—have extended survival.10,13,14 These oncogenic drivers— mutations in the epidermal growth factor receptor kinase and fusions involving anaplastic lymphoma kinase—rarely occur in squamous NSCLC, and as a result, few patients with squamous NSCLC can benefit from these treatments.15,16 Improved outcomes for patients with squamous NSCLC are needed.

While chemotherapy produces a moderate survival improvement in patients with advanced squamous NSCLC, no regimen is associated with a clear survival benefit in this group of patients.9 It is likely that improved outcomes will continue to occur in modest, stepwise increments in unselected squamous NSCLC patients,13,14,17,18 although efforts to identify clinical or molecular signatures with potential predictive value for currently available treatments are continuing.19,20 Ongoing genomic studies may identify novel therapeutic targets.21 Current clinical trials testing immune checkpoint inhibitors and agents to improve supportive care20 may also provide new, individual therapeutic strategies that have the potential to enhance the effectiveness of currently available treatments. More treatment options are needed for patients with squamous NSCLC.

Visit SQUAMOUSNSCLC.COM to learn more.

CONTRIBUTING AUTHORS: David R. Spigel, MD SCRI (Sarah Cannon Research Institute) Nashville, TN Philip Bonomi, MD Rush University Medical Center Chicago, IL Edward Kim, MD Levine Cancer Institute Carolinas HealthCare System Charlotte, NC

References 1. From Ferlay J., Soerjomataram I., Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 2. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-whatis-non-small-cell-lung-cancer. Accessed December 4, 2014. 3. Rosado-de-Christenson ML, Templeton PA, Moran CA. Bronchogenic carcinoma: radiologic-pathologic correlation. Radiographics. 1994;14(2):429-446. 4. Nichols L, Saunders R, Knollmann FD. Causes of death of patients with lung cancer. Arch Pathol Lab Med. 2012;136(12):1552-1557. 5. Wilson DO, Ryan A, Fuhrman C, et al. Doubling times and CT screen-detected lung cancers in the Pittsburgh lung screening study. Am J Respir Crit Care Med. 2012;185(1):85-89.

6. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med. 2012;157(11):776-784. 7. Rubin E, Reisner HM, eds. Essentials of Rubin’s Pathology. 5th ed.

Philadelphia, PA: Lippincott Williams & Wilkins; 2009:268-270. 8. Asmis TR, Ding K, Seymour L, et al. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol. 2008;26(1):54-59. 9. Hoang T, Dahlberg SE, Schiller JH, Johnson DH. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 10. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):12771280. 11. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed December 4, 2014.

To view the most recent and complete version of the guidelines, go online to http://nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 12. Reck M, Popat S, Reinmuth N, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3):iii27-iii39. 13. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551. 14. Morgensztern D, Waqar S, Subramanian J, Gao F, Govindan R. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol. 2009;4:1524-1529. 15. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175-180. 16. Perez-Moreno P, Brambilla E, Thomas R, Soria JC. Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res. 2012;18(9):2443-2451 17. Schiller JH, Harrington D, Belani CP, et al.

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-98. 18. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062. 19. Aydiner A, Yildiz I, Seyidova A. Clinical outcomes and prognostic factors associated with the response to erlotinib in non-small-cell lung cancer patients with unknown EGFR mutational status. Asian Pac J Cancer Prev. 2013;14:3255-3261. 20. Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21:80-89. 21. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519-525.

GLOONC00049a APRIL 2015

The ASCO Post | SEPTEMBER 25, 2015

PAGE 26

MASCC/ISOO International Symposium Supportive Care

Managing High-Risk Patients With Febrile Neutropenia

By Meg Barbor

F

ebrile neutropenia is of particular concern in high-risk patients who have undergone stem cell transplant, according to William J. Hogan, MB, BCh, Assistant Professor of Medicine at the Mayo Clinic in Rochester, Minnesota.

Dr. Hogan delivered an update on febrile neutropenia management in this population at the 2015 Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology (MASCC/ISOO) International Symposium on Supportive Care in Cancer, held recently in Copenhagen.1

Who Is at Risk?

Neutropenia is often defined as an absolute neutrophil count < 1,500 × 106/L. Those with severe neutropenia—an absolute neutrophil count < 500 × 106/L and especially < 100 × 106/L—are particularly at risk. Prolonged neutropenia generally refers to a duration of 7 days or longer.

Dr. Hogan. “Part of the issue is getting the patients to medical care quickly, and even when they get there, there are often extended delays before they get their first dose of intravenous [IV] antibiotics. So we really have to do better.”

Principles of Effective Management Dr. Hogan recommended triaging the patient quickly, assessing for risk, and instituting therapy immediately (< 60 minutes) for high-risk patients.

Risk assessment is crucial, as it determines patient prognosis and management (ie, inpatient vs outpatient, intensive care unit [ICU] vs non-ICU, and necessity and choice of IV antibiotics). “There are a number of risk assessment scores available, but the MASCC risk index scores are very useful,” he added.2 Next, consider sepsis protocol and

Antibiotic resistance has become a reality for all of us.

—William J. Hogan, MB, BCh

According to Dr. Hogan, certain populations are at greater risk for neutropenia-related poor outcomes. Patients undergoing therapies sufficient to impact myelopoiesis and gastrointestinal integrity, such as induction chemotherapy for acute leukemia or myeloablative conditioning regimens, are in that high-risk cohort.

Additionally, neutropenia tends to be of particular concern in patients with refractory leukemia requiring multiple induction attempts. “This leaves patients very vulnerable to neutropenic fever and the consequence of neutropenic sepsis,” he stated. “Delayed engraftment or graft failure after transplant is also associated with very significant risk.”

Finally, patient-specific factors such as greater comorbidities and advanced age put patients at higher risk for poor outcomes. “Studies show that half of those patients with four comorbidities die in the hospital with neutropenic fever, so this really is a serious medical issue,” said

transfer to the ICU if necessary, he told the audience. “If a patient has hypotension, hypoxia, change in mental status, or increased lactate, he or she is at high risk and needs urgent assessment and consideration for ICU care,” he advised.

Finally, consider the prophylaxis used and prior colonization to determine antibiotic choice. “Also consider local resistance patterns based on your previous antibiotic use and what you see typically,” Dr. Hogan added. “That helps inform the decision about prophylaxis choices as well.”

Additionally, Dr. Hogan recommended a diagnostic evaluation performed through a thorough history assessment and clinical exam, appropriate labs (complete blood cell count, chemistry, markers of sepsis, organ function), cultures (peripheral blood and catheter, urine), and imaging. “Imaging can be misleading in patients with neutropenia because they don’t have white cells to provoke an inflam-

Febrile Neutropenia in Patients With Cancer ■■ Febrile neutropenia is of particular concern in high-risk stem cell transplant patients.

■■ Initial monotherapy with antipseudomonal therapy is recommended.

■■ Antibiotic resistance is increasing and should be kept in mind when treating patients with cancer.

matory response; so radiologic imaging of the chest may not be as quickly positive as it is in non-neutropenic patients,” he warned. “Also, urine may not show pyuria in the absense of neutrophils, so you do have to bear these things in mind.”

Initial Antimicrobial Regimen As to an initial antimicrobial regimen for febrile neutropenia, “there are regional differences, but, in general, initial monotherapy with antipseudomonal therapy is recommended,” said Dr. Hogan.

“Cefepime has been our standard because it offers excellent gram-negative coverage and quite good grampositive coverage. Meropenem and imipenem are excellent drugs, and we tend to use piperacillin/tazobactam more on patients with risk factors for anaerobic infection.”

Consider double–gram-negative coverage for a complicated presentation (addition of a quinolone if not used for prophylaxis or an aminoglycoside), and expand gram-positive coverage (eg, with vancomycin) if there is a softtissue or central-line infection. If there is clinical evidence for anaerobic infection from neutropenic enterocolitis or perirectal infection, then anaerobic cover could be an important part of the regimen as well, he advised.

quently is whether to remove the central catheter in a patient with infection,” said Dr. Hogan. The catheter can frequently be salvaged, but its removal should be considered if any of the following conditions is present: • Catheter culture result becomes positive significantly before peripheral cultures.

• Persistently positive cultures do not clear.

• The patient has sepsis, tunnel infection, or endocarditis.

• Specific organisms known to be difficult to clear in the presence of a catheter (Pseudomonas aeruginosa, Staphalococcus aureus, rapidly growing mycobacteria, Candida spp) are present.

“Antibiotic resistance has become a reality for all of us,” said Dr. Hogan.

The most common antibiotic-resistant bacteria are vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSA), extendedspectrum beta-lactamase–producing bacteria (ESBL), and Klebsiella-producing carbapenemase. “[Klebsiella-producing carbapenemase] is a challenging problem,” he added. “This is a very virulent, highly resistant organism. It may be responsive to tigecycline, but the options for treating it are very limited, so we need to try and prevent it from spreading.” n Disclosure: Dr. Hogan reported no potential conflicts of interest.

Modifications to Initial Therapy If the patient is hemodynamically unstable, broadening the coverage to include resistant organisms and fungi might be necessary (especially if > 5 days of fever, prolonged neutropenia).

But keep in mind that persistent fever may not require a change in therapy— consider other etiologies (eg, fungal, viral) and noninfectious causes (eg, malignancy, drugs, engraftment). Positive culture results may require expansion or modification based on the organism or resistance pattern.

“One question that comes up fre-

References 1. Hogan W: Febrile neutropenia: An update of management of high risk stem cell transplantation patients. 2015 MASCC/ISOO International Symposium on Supportive Care in Cancer. Parallel Session PS05. Presented June 26, 2015.

2. Multinational Association of Supportive Care in Cancer: Identifying patients at low risk for FN complications: Development and validation of the MASCC Risk Index Score. Available at www.mascc.org/ mascc-fn-risk-index-score. Accessed September 2, 2015.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY

In appropriate patients with advanced melanoma

KEYTRUDA:

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%).

86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer.

Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or diseaserelated symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

SELECTED SAFETY INFORMATION • Immune-mediated adverse reactions occurred with KEYTRUDA, including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism.

Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information on the next page.

Please see additional Selected Safety Information on the next page and the Brief Summary of Prescribing Information on the adjacent pages.

For patients For patientswith withunresectable unresectableorormetastatic metastaticmelanoma melanomaand anddisease diseaseprogression progressionfollowing followingipilimumab ipilimumaband, and, if BRAF V600 if BRAF V600mutation mutationpositive, positive,a aBRAF BRAFinhibitor inhibitor

KEYTRUDA: KEYTRUDA: DURABILITY DURABILITY OF OF RESPONSE RESPONSE 24% 24%overall overallresponse responserate rate(complete (completeresponse+partial response+partialresponse) response) with withsingle-agent single-agentKEYTRUDA KEYTRUDA(95% (95%CI, CI,15–34) 15–34) Data Datafor for2 2mg/kg mg/kgevery every33weeks weeks(n=89) (n=89)

11%% 23 23%%

• •There Therewere wereobjective objectiveresponses responsesininpatients patientswith withand and without withoutBRAF BRAFV600 V600mutation–positive mutation–positivemelanoma. melanoma.

Complete CompleteResponse Response(CR) (CR)(n=1) (n=1)

Partial PartialResponse Response(PR) (PR)(n=20) (n=20) (%(% ofof patients) patients)

• •Similar Similaroverall overallresponse responserate rateresults resultswere wereobserved observed in in the the10-mg/kg 10-mg/kgarm. arm.

• •Patients Patientscontinued continuedtreatment treatmentwith with KEYTRUDA KEYTRUDA until until unacceptable unacceptable toxicity toxicity or or disease disease progression progression that that was wassymptomatic, symptomatic,was wasrapidly rapidlyprogressive, progressive, required required urgent urgent inter intervention, vention, occurred occurred with with aa decline decline in in performance performancestatus, status,ororwas wasconfirmed confirmedat at44to to66 weeks weeks with withrepeat repeatimaging. imaging.

Study design: AA multicenter, open-label, Study design: multicenter, open-label,randomized, randomized,dose-comparative dose-comparativestudy studycohort cohortofofthe theongoing ongoingKEYNOTE-001 KEYNOTE-001Phase Phase1b1btrial trialininpatients patientswith with unresectable or or metastatic melanoma and progression unresectable metastatic melanoma and progressionofofdisease. disease.Key Keyeligibility eligibilitycriteria criteriaincluded includedprior priortreatment treatmentwith withipilimumab ipilimumab(2(2orormore moredoses doses at at 3 mg/kg or or higher) and a BRAF oror MEK inhibitor, if BRAF 3 mg/kg higher) and a BRAF MEK inhibitor, if BRAFV600 V600mutation–positive; mutation–positive;and anddisease diseaseprogression progressionwithin within2424weeks weeksfollowing followingthe thelast lastdose dose of of ipilimumab.

Patients were randomized to toreceive ipilimumab.

Patients were randomized receive2 mg/kg 2 mg/kg(n=89) (n=89)oror1010mg/kg mg/kg(n=84) (n=84)ofofKEYTRUDA KEYTRUDAevery every3 3weeks weeksuntil untilunacceptable unacceptabletoxicity toxicityoror disease progression.

The major efficacy disease progression.

The major efficacyoutcome outcomemeasures measureswere wereconfirmed confirmedoverall overallresponse responserate, rate,asasassessed assessedbybyblinded blindedindependent independentcentral central review using Response Evaluation Criteria in in Solid review using Response Evaluation Criteria SolidTumors Tumors(RECIST (RECIST1.1), 1.1),and andduration durationofofresponse. response.Tumor Tumorresponse responsewas wasassessed assessedevery every1212weeks. weeks.

SELECTED SELECTEDSAFETY SAFETYINFORMATION INFORMATION • Pneumonitis • Pneumonitisoccurred occurredin in1212(2.9%) (2.9%)ofof411 411patients, patients,including including Grade 2 or 3 cases in in 8 (1.9%) and 1 (0.2%) Grade 2 or 3 cases 8 (1.9%) and 1 (0.2%)patients, patients,respectively, respectively, receiving KEYTRUDA. Monitor patients forfor signs and receiving KEYTRUDA. Monitor patients signs andsymptoms symptomsofof pneumonitis.

Evaluate pneumonitis.

Evaluatesuspected suspectedpneumonitis pneumonitiswith withradiographic radiographic imaging. imaging.Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater pneumonitis.

TRUDA pneumonitis.Withhold WithholdKEY KEY TRUDAforforGrade Grade2;2;permanently permanently discontinue KEYTRUDA forfor Grade 3 or 4 pneumonitis. discontinue KEYTRUDA Grade 3 or 4 pneumonitis.

• Colitis • Colitis(including (includingmicroscopic microscopiccolitis) colitis)occurred occurredinin4 4(1%) (1%)ofof411 411 patients, including patients, includingGrade Grade2 2oror3 3cases casesinin1 1(0.2%) (0.2%)and and2 2(0.5%) (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients, respectively, receiving KEYTRUDA. Monitorpatients patientsforfor signs and symptoms signs and symptomsofofcolitis. colitis.Administer Administercorticosteroids corticosteroidsfor for Grade 2 or greater colitis.

Withhold Grade 2 or greater colitis.

WithholdKEYTRUDA KEYTRUDAforforGrade Grade2 2oror3;3; permanently discontinue KEYTRUDA forfor Grade 4 colitis. permanently discontinue KEYTRUDA Grade 4 colitis.

• Hepatitis (including autoimmune hepatitis) occurred • Hepatitis (including autoimmune hepatitis) occurredinin2 (0.5%) 2 (0.5%)ofof 411411 patients, including a Grade 4 case in in 1 (0.2%) patient, receiving patients, including a Grade 4 case 1 (0.2%) patient, receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforchanges changesininliver liverfunction. function.

Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greaterhepatitis hepatitis and, based onon severity ofof liver enzyme elevations, and, based severity liver enzyme elevations,withhold withholdoror discontinue KEYTRUDA. discontinue KEYTRUDA. • Hypophysitis occurred in in 2 (0.5%) ofof 411411 patients, including • Hypophysitis occurred 2 (0.5%) patients, includinga aGrade Grade2 2 case in in 1 and a Grade 4 case case 1 and a Grade 4 casein in1 (0.2% 1 (0.2%each) each)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforsigns signsand andsymptoms symptomsofof hypophysitis.

Administer hypophysitis.

Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater hypophysitis. hypophysitis.Withhold WithholdKEYTRUDA KEYTRUDAforforGrade Grade2;2;withhold withholdoror discontinue forfor Grade 3; 3; and permanently discontinue discontinue Grade and permanently discontinueKEYTRUDA KEYTRUDA forfor Grade 4 hypophysitis.

Grade 4 hypophysitis.

• Nephritis • Nephritisoccurred occurredinin3 3(0.7%) (0.7%)patients, patients,consisting consistingofofone onecase caseofof Grade Grade2 2autoimmune autoimmunenephritis nephritis(0.2%) (0.2%)and andtwo twocases casesofofinterstitial interstitial nephritis nephritiswith withrenal renalfailure failure(0.5%), (0.5%),one oneGrade Grade33and andone oneGrade Grade4.4.

Monitor Monitorpatients patientsfor forchanges changesininrenal renalfunction. function. Administer Administer corticosteroids corticosteroidsfor forGrade Grade2 2ororgreater greater nephritis. nephritis. Withhold Withhold KEYTRUDA KEYTRUDAfor forGrade Grade2;2;permanently permanentlydiscontinue discontinueKEYTRUDA KEYTRUDAfor for Grade Grade3 3oror4 4nephritis. nephritis.

• Hyperthyroidism • Hyperthyroidismoccurred occurredinin5 5(1.2%) (1.2%)ofof411 411patients, patients,including including Grade Grade2 2oror3 3cases casesinin2 2(0.5%) (0.5%)and and1 1(0.2%) (0.2%)patients, patients,respectively, respectively, receiving receivingKEYTRUDA. KEYTRUDA.Hypothyroidism Hypothyroidismoccurred occurredinin34 34(8.3%) (8.3%)ofof411 411 patients, patients,including includinga aGrade Grade3 3case caseinin11(0.2%) (0.2%)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Thyroid Thyroiddisorders disorderscan canoccur occuratatany anytime timeduring during treatment. treatment.Monitor Monitorpatients patientsfor forchanges changesininthyroid thyroidfunction function(at (atthe the start startofoftreatment, treatment,periodically periodicallyduring duringtreatment, treatment,and andas asindicated indicated based basedononclinical clinicalevaluation) evaluation)and andfor forclinical clinicalsigns signsand andsymptoms symptomsofof thyroid thyroiddisorders. disorders.Administer Administercorticosteroids corticosteroidsfor forGrade Grade33ororgreater greater hyperthyroidism. hyperthyroidism.Withhold WithholdKEYTRUDA KEYTRUDAfor forGrade Grade3;3;permanently permanently discontinue TRUDA for discontinueKEY KEYTRUDA forGrade Grade4 4hyperthyroidism. hyperthyroidism.Isolated Isolated hypothyroidism hypothyroidismmay maybebemanaged managed with with replacement replacement therapy therapy without withouttreatment treatmentinterruption interruptionand andwithout withoutcorticosteroids. corticosteroids.

• Other • Otherclinically clinicallyimportant importantimmune-mediated immune-mediatedadverse adverse reactions reactions can canoccur. occur.The Thefollowing followingclinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsoccurred occurredininless lessthan than1% 1%ofofpatients patientstreated treated with withKEYTRUDA: KEYTRUDA:exfoliative exfoliativedermatitis, dermatitis,uveitis, uveitis,arthritis, arthritis,myositis, myositis, pancreatitis, pancreatitis,hemolytic hemolyticanemia, anemia,partial partialseizures seizuresarising arisingininaapatient patient with withinflammatory inflammatoryfoci fociininbrain brainparenchyma, parenchyma,adrenal adrenalinsufficiency, insufficiency, myasthenic myasthenicsyndrome, syndrome,optic opticneuritis, neuritis,and andrhabdomyolysis. rhabdomyolysis.

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

(n=18/21) (n=18/21)

Of responses were ongoing in patients patients who who responded responded to KEYTRUDA

••Among progression of of disease disease 2.8, 2.8, 2.9, 2.9, and and 8.2 8.2 months months Among the the 21 21 patients patients with with an an objective response, 3 (14%) had progression after after initial initial response. response.

•• The durations ranging ranging from from 1.4+ 1.4+ to to 8.5+ 8.5+ months, months,which which The remaining remaining 18 18 patients patients (86%) (86%) had ongoing responses with durations included included 88 patients patients with with ongoing ongoing responses of 6 months or longer.

•• One first tumor tumor assessment assessment concurrent concurrentwith withaa Oneadditional additional patient patient developed developed 2 new asymptomatic lesions at the first 75% 75% decrease decrease in in overall overall tumor tumor burden.

—KEYTRUDA was durable durable for for 5+ 5+ months. months.

—KEYTRUDA was was continued continued and and this reduction in tumor burden was

SELECTED SELECTED SAFETY SAFETY INFORMATION INFORMATION (CONTINUED) common adverse adverse reactions reactions (reported (reported inin at at least least ••For For suspected suspected immune-mediated immune-mediated adverse reactions, ensure • The most common patients) were were fatigue fatigue (47%), (47%), cough cough (30%), (30%), nausea nausea adequate 20% of patients) adequate evaluation evaluation to to confirm confirm etiology or exclude other pruritus (30%), (30%), rash rash (29%), (29%), decreased decreasedappetite appetite(26%), (26%), causes.

(30%), pruritus causes.Based Basedon on the the severity severity of of the the adverse reaction, withhold (21%), arthralgia arthralgia (20%), (20%),and anddiarrhea diarrhea(20%).

(20%).

KEYTRUDA constipation (21%), KEYTRUDA and and administer administer corticosteroids. corticosteroids. Upon improvement of ofthe theadverse adversereaction reaction to to Grade Grade 11 or or less, initiate corticosteroid • It is not known known whether whether KEYTRUDA KEYTRUDA isis excreted excreted ininhuman humanmilk. milk. taper taper and and continue continue to to taper taper over over at least 1 month. Restart drugsare areexcreted excretedin inhuman humanmilk, milk,instruct instructwomen women Because many drugs KEYTRUDA KEYTRUDA ifif the the adverse adverse reaction reaction remains at Grade 1 or less. nursing during during treatment treatmentwith withKEYTRUDA. KEYTRUDA. to discontinue nursing Permanently Permanently discontinue discontinue KEYTRUDA KEYTRUDA for any severe or Grade 3 effectiveness of KEYTRUDA have notbeen been • Safety and effectiveness of KEYTRUDA have not immune-mediated immune-mediated adverse adverse reaction reaction that recurs and for any lifeestablished in pediatric pediatric patients. patients. threatening immune-mediated adverse reaction. threatening immune-mediated adverse ••Based Based on on its its mechanism mechanism of of action, action, KEYTRUDA may cause the Brief Brief Summary Summary of of the the Please see the fetal fetal harm harm when when administered administered to to aa pregnant woman. If used Information on on the the adjacent adjacent pages. pages.

Prescribing Information during during pregnancy, pregnancy, or or ifif the the patient patient becomes pregnant during treatment, treatment,apprise apprise the the patient patient of of the the potential hazard to a fetus. Merck Oncology Oncology Advise Advisefemales females of of reproductive reproductive potential potential to use highly effective 2014 Merck Merck Sharp Sharp && Dohme DohmeCorp., Corp., Copyright © 2014 contraception contraception during during treatment treatment and and for 4 months after the last a subsidiary of of Merck Merck & & Co., Co., Inc. Inc. dose doseof ofKEYTRUDA. KEYTRUDA. All rights reserved. reserved. ONCO-1116177-0000 ONCO-1116177-000011/14 11/14 keytruda.com keytruda.com

Questions Questions about about access for KEYTRUDA? Call Call The The Merck Merck Access Access Program at 855-257-3932.

Scan Scan here here or visit keytruda.com keytruda.com to to learn learn more.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use INDICATIONS AND USAGE KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis: Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks–9.9 months). The median duration was 4.9 months (range 1 week–14.4 months).

Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1–34) followed by a corticosteroid taper.

Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 2–3 pneumonitis.

Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) pneumonitis.

Immune-Mediated Colitis: Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3– 9.8). The median duration was 2.6 months (range 0.6 weeks–3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4–41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event.

Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis.

Immune-Mediated Hepatitis: Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1.

The time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months.

The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event.

Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Immune-Mediated Hypophysitis: Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose.

Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis, withhold or discontinue KEYTRUDA for severe (Grade 3) hypophysitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hypophysitis.

Renal Failure and Immune-Mediated Nephritis: Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3–4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.

Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2) nephritis, and permanently discontinue KEYTRUDA for severe (Grade 3), or life-threatening (Grade 4) nephritis.

Immune-Mediated Hyperthyroidism and Hypothyroidism: Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5 months (range 0.5–2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with highdose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event.

Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks–19 months). All but two of the patients with hypothyroidism were

treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.

Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold KEYTRUDA for severe (Grade 3) hyperthyroidism, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other Immune-Mediated Adverse Reactions: Other clinically important immune-mediated adverse reactions can occur.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal insufficiency.

Across clinical studies with KEYTRUDA in approximately 2000 patients, the following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Embryofetal Toxicity: Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail above.

• Immune-mediated pneumonitis.

• Immune-mediated colitis.

• Immune-mediated hepatitis.

• Immune-mediated hypophysitis.

• Renal failure and immune-mediated nephritis.

• Immune-mediated hyperthyroidism and hypothyroidism.

• Immune-mediated 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 described in the WARNINGS and PRECAUTIONS section reflect exposure to KEYTRUDA in Trial 1, an uncontrolled, open-label, multiple cohort trial in which 411 patients with unresectable or metastatic melanoma received KEYTRUDA at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18–94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease.

KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis.

Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18–88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater than 6 months and 21% for greater than 1 year.

KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use (continued)

DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

THE 1 ST FDA-APPROVED ANTI–PD-1 THERAPY USE IN SPECIFIC POPULATIONS Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic Melanoma

Pregnancy: Pregnancy Category D.

Risk Summary: Based on its mechanism of action, KEYTRUDA may cause fetal harm when In appropriate patients with advanced melanoma administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway KEYTRUDA 2 mg/kg every 3 weeks N=89

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data: Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects General Disorders and Administration Site Conditions on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve Fatigue 47 7 pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 Peripheral edema 17 1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus Chills 14 0 and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA Pyrexia 11 0 during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, Gastrointestinal Disorders there were no malformations related to the blockade of PD-1 signaling in the offspring of Nausea 30 0 these animals; however, immune-mediated disorders occurred in PD-1 knockout mice.

Constipation 21 0 Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab Diarrhea 20 0 has the potential to be transmitted from the mother to the developing fetus. Based on its Vomiting 16 0 mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing Abdominal pain 12 0 immune-mediated disorders or of altering the normal immune response.

Respiratory, Thoracic And Mediastinal Disorders Nursing Mothers: It is not known whether KEYTRUDA is excreted in human milk. No studies Cough 30 1 have been conducted to assess the impact of KEYTRUDA on milk production or its presence in Dyspnea 18 2 breast milk. Because many drugs are excreted in human milk, instruct women to discontinue Skin And Subcutaneous Tissue Disorders nursing during treatment with KEYTRUDA. Pruritus 30 0 Pediatric Use: Safety and effectiveness of KEYTRUDA have not been established in Rash 29 0 pediatric patients.

Vitiligo 11 0 Geriatric Use: Of the 411 patients treated with KEYTRUDA, 39% were 65 years and over.

Metabolism and Nutrition Disorders No overall differences in safety or efficacy were reported between elderly patients and Decreased appetite 26 0 younger patients.

Musculoskeletal and Connective Tissue Disorders Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is Arthralgia 20 0 needed for patients with renal impairment.

Pain in extremity 18 1 KEYTRUDA is indicated of patients with pharmacokinetic unresectable Hepatic Impairment: Based on a population analysis, noor dosemetastatic adjustment is Myalgia 14 for the 1 treatment needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN Back pain 12 1 melanoma and disease progression following ipilimumab and, if BRAF V600 mutation and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has Nervous System Disorders not been studied in patients withunder moderate (TB greater than 1.5 to 3 times ULN and anybased AST) positive, a BRAF inhibitor.

This indication is approved accelerated approval Headache 16 0 or severe (TB greater than 3 times ULN and any AST) hepatic impairment. on tumor response rate11and durability of response. An improvement in survival or diseaseDizziness 0 Females and Males of Reproductive Potential: Based on its mechanism of action, KEYTRUDA Blood and Lymphatic System Disorders related symptoms has not yet been established.

Continued approval this may may cause fetal harm when administered to a pregnant for woman.

Adviseindication females of Anemia 14 5 reproductive potential to use highly effective contraception during treatment with KEYTRUDA of clinical benefit in the confirmatory trials.

Psychiatric Disordersbe contingent upon verification and description and for at least 4 months following the last dose of pembrolizumab.

Insomnia 14 0 OVERDOSAGE Infections and Infestations There is no information on overdosage with KEYTRUDA. Upper respiratory tract infection 11 1 *There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was reported as Grade 4.

PATIENT COUNSELING INFORMATION

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%).

86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer.

Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response.

Other clinically important adverse reactions observed in up to 10% of patients treated with KEYTRUDA were: Infections and infestations: sepsis Table 2: Laboratory Abnormalities Increased from Baseline in ≥20% of Patients with Unresectable or Metastatic Melanoma KEYTRUDA 2 mg/kg every 3 weeks N=89 Laboratory Test

All Grades (%)

Grades 3–4 (%)

Chemistry Hyperglycemia 40 2* Hyponatremia 35 9 Hypoalbuminemia 34 0 Hypertriglyceridemia 25 0 Increased Aspartate Aminotransferase 24 2* • Immune-mediated adverse24reactions Hypocalcemia 1 Hematology occurred with KEYTRUDA, including Anemia 55 8*

SELECTED SAFETY INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

• Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA, including: — Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath.

—Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain.

—Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding.

—Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes.

—Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

—Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism.

• Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests.

• Advise women that KEYTRUDA may cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of KEYTRUDA.

pneumonitis, colitis, hepatitis, hypophysitis, • Advise nursing mothers not to breastfeed while taking KEYTRUDA. For more detailed information, please read the Prescribing Information. nephritis, hyperthyroidism, and hypothyroidism. uspi-mk3475-iv-1409r000 Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity.

Based on the severity of the adverse reaction, Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) Revised: 09/2014 assay results, a subset analysis was performed in the patients with a concentration KEYTRUDA should be withheld or ofdiscontinued pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. corticosteroids For moreCopyright information analysis, none of and the 97 patients who were treated with administered.

2 mg/kg every 3 weeks tested All rights reserved. positive for treatment-emergent anti-pembrolizumab antibodies. regarding immune-mediated adverse reactions, please 11/14 read ONCO-1116177-0000 The detection of antibody formation is highly dependent on the sensitivity and specificity of the additional Selected Safety Information on the next page. the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) *Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate aminotransferase, and anemia (one patient each).

positivity in an assay may be influenced by several factors including assay methodology, sample handling,Please timing of sample concomitant medications, and underlying see collection, additional Selected Safety Information on the disease. For these reasons, comparison of incidence of antibodies to KEYTRUDA with the next page and the Brief Summary of Prescribing Information incidences of antibodies to other products may be misleading.

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

855-257-3932 • Speak with a dedicated representative Monday to Friday between 8 AM and 8 PM ET.

• Ask to be contacted by a field reimbursement associate.

Merck Oncology Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1116177-0000 11/14

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 27

Big Data Workshop Health Information Technology

Radiation Oncology Looks to Collaboration for Big Data Systems

By Kirsten Boyd Goldberg

R

adiation oncologists dream of a day when, faced with a new patient sitting in their office, they can quickly consult a computer database offering specific treatment recommendations based on accurate, freshly updated data from millions of previously treated patients

tor our patients during treatment and in long-term follow-up,” said Karen E. Hoffman, MD, MHSc, MPH, Assistant Professor of Radiation Oncology, MD Anderson Cancer Center, and co-chair of the 2015 Big Data Workshop. Held at the National Institutes

There is a great opportunity to integrate structured data collection into the clinical workflow and to generate comprehensive data, which improves the lifesaving radiation therapy we provide to more than one million cancer patients each year —Karen E. Hoffman, MD, MHSc, MPH

with cancer. To hasten that day, radiation oncologists and physicists speaking at the 2015 Big Data Workshop called for increased collaboration between medical societies, electronic medical record system vendors, and federal agencies to develop common standards and interoperable systems to enable databases to combine information.

“Radiation oncology is well positioned to harness big data to assess quality, facilitate research, and enhance patient care, because our treatment planning and delivery systems collect digital, structured information about our patients, and we routinely moni-

of Health (NIH), the workshop was sponsored by the American Society for Radiation Oncology (ASTRO), the National Cancer Institute (NCI), and the American Association of Physicists in Medicine (AAPM).

Radiation Oncology Registries Despite their potential, existing registries and safety reporting systems specific to radiation oncology are few, limited, and incapable of exchanging data easily, workshop speakers noted.

A closer look at several related projects discussed at the workshop follows: • The ASTRO-sponsored National Ra-

diation Oncology Registry (NROR) recently completed a 1-year pilot project using prostate cancer as the initial disease site. Although 30 pilot centers were selected to participate, 11 pulled out due to legal or administrative concerns, and 5 sites did not participate because of data transfer issues, said Jason A. Efstathiou, MD, DPhil, Associate Professor and Director, Genitourinary Division, Department of Radiation Oncology, Massachusetts General Hospital, Boston. The 14 participating sites provided complete data for 430 patients, but it required significant manual data entry.

“ASTRO is continuing to monitor the field and considering the best options for future registry efforts, including collaboration with other specialty societies,” Dr. Efstathiou said. ASTRO is currently working with the American Association of Neurological Surgeons on a stereotactic radiosurgery registry and considering a possible collaboration with ASCO’s CancerLinQ™.

• The Radiation Oncology Incident Learning System, launched in June 2014 by ASTRO and AAPM, is an online portal that allows radiation oncology centers to provide nonpatient-specific data about safety incidents at their facility in a secure, nonpunitive environment. More than 100 facilities are reporting safety events into this system, Dr. Hoffman

For Big Data Projects, Bigger Is Better

I

n an interview with The ASCO Post, Robert S. Miller, MD, FACP, Senior Director, Quality and Guidelines, ASCO, and Medical Director, CancerLinQ™, described how the system could work with data specific to radiation oncology.

“The system is in the rapid build phase now, what we are calling the minimal viable product, or beta launch, with 15 vanguard practices.

We’re bringing them in one or two at a time. We’re learning lessons from each one on how to map the data in their electronic health record system into our cloud.

“Some radiation oncology information will be in the medical oncology record as a note, or increasingly in the electronic health

record, a structured note. We’re putting the information into what we’re calling interaction types— broad clinical categories like laboratories and demographic information. Radiation oncology–specific information could be mapped to those categories.

“One of the challenges—and this is a technical one that involves working with the vendors—is plugging in the machines. The linear accelerators speak to [the radiation oncology] electronic health record. We potentially could create a connection with those machines someday.

“The take-home message for me is that this has to be a multidisciplinary approach. Big data analysis and how it might benefit the care of

Robert S. Miller, MD, FACP

patients with cancer and improve quality has to be a bunch of people working together. The other lesson I got out of this conference [2015 Big Data Workshop] is the bigger, the better. The greater the size of the database, the more insights you can gain from the data.” n Disclosure: Dr. Miller reported no potential conflicts of interest.

said in an interview. “There is a great opportunity to integrate structured data collection into the clinical workflow and to generate comprehensive data, which improves the lifesaving radiation therapy we provide to more than one million cancer patients each year,” she said.

• The Cancer Imaging Archive, a project funded by NCI’s Cancer Imaging Program, collects and curates radiation therapy information that can be combined across trials to produce larger research cohorts. The curation process improves data integrity and optimizes the potential for data reuse.

The original goal of the project was to collect images from clinical trials to support research reproducibility, said principal investigator Fred W. Prior, PhD, Director, Electronic Radiology Laboratory, Mallinckrodt Institute of Radiology, Washington University, St. Louis.

Potential ASTRO-ASCO Collaboration Ronald C. Chen, MD, MPH, Associate Professor of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, who moderated a breakout session on the potential for big data in clinical decision-making and personalized medicine, said he favored the creation of a large cancer registry that would contain treatment details and quality measures for surgery, radiotherapy, and systemic therapy.

“ASTRO’s experience with NROR led to a recognition that each society developing its own registry was not an efficient use of resources. Collaboration makes much more sense,” said Dr. Chen.

A big data system for radiation oncology should capture the anatomic area treated, the radiation technique used, and the dose delivered, Dr. Chen added. Also, ASTRO’s guidelines and quality measures could be included in a comprehensive oncology registry, he said.

ASCO and ASTRO have discussed collaboration, according to Robert S. Miller, MD, FACP, Senior Director, Quality and Guidelines, ASCO, and Medical Director, CancerLinQ (see sidebar). “We are certainly very open to that possibility,” Dr. Miller said. “ASTRO is a very logical partner for ASCO in this effort.” continued on page 28

The ASCO Post | SEPTEMBER 25, 2015

PAGE 28

World Conference on Lung Cancer Thoracic Oncology

Bevacizumab Plus Standard Chemotherapy Improves Survival in Mesothelioma

By Caroline Helwick

T

he standard of care for malignant pleural mesothelioma may be poised for change, judging by results from a study by the French Cooperative Thoracic Intergroup. The addition of bevacizumab (Avastin) in the first-line setting to the current standard of care, pemetrexed (Alimta)/cisplatin, improved overall survival by almost 3 months in the phase III MAPS trial,1 according to a presentation at the 16th World Conference on Lung Cancer. The findings were reported by Arnaud Scherpereel, MD, Head, Pulmonary and Thoracic Oncology Department and Professor, University Hospital, Lille, France.

ment has been achieved in this disease in more than a decade,” he noted. According to Dr. Scherpereel, the scenario has changed with the results of MAPS, which could herald “a new treatment paradigm” for patients with mesothelioma who are eligible for bevacizumab and are not candidates for potentially curative surgery.

Study Details MAPS is a phase II/III open-label, 73-center study conducted between 2008 and 2014. It enrolled 448 patients with mesothelioma who were not amenable to curative treatment, randomizing them to standard che-

Adding bevacizumab to pemetrexed/cisplatin doublet significantly increased both progression-free survival (by 2 months) and overall survival (by 2.75 months), with only a slight, manageable increase of toxicity.

—Arnaud Scherpereel, MD

“Adding bevacizumab to pemetrexed/cisplatin doublet significantly increased both progression-free survival (by 2 months) and overall survival (by 2.75 months), with only a slight, manageable increase of toxicity,” Dr. Scherpereel said.

Mesothelioma is a very aggressive tumor with no validated curative treatment. Maximum overall survival hovers around 13 months, and “no improve-

motherapy with pemetrexed/cisplatin or the same regimen plus bevacizumab (15 mg/kg). After six cycles, patients on the experimental arm continued to receive bevacizumab alone until disease progression.

Efficacy, Safety of the Triplet After a median follow-up of 39.4 months, the primary endpoint, median overall survival, was significantly higher

Bevacizumab Triplet in Mesothelioma ■■ In unresectable malignant pleural mesothelioma, adding bevacizumab (15 mg/kg) to pemetrexed/cisplatin significantly improved overall survival and progression-free survival, according to the results of the MAPS trial.

■■ Median overall survival was 18.8 vs 16.1 months (hazard ratio = 0.76; P = .0126). Median progression-free survival was 9.6 vs 7.5 months (hazard ratio = 0.61; P < .0001).

■■ The triplet might become the new standard of care in mesothelioma.

Big Data Workshop continued from page 27

CancerLinQ has begun working with the first of 15 oncology practices selected for the system’s beta launch.

Some of the practices include radiation oncology components, said Dr. Miller, who spoke at the workshop about CancerLinQ. “We are not neces-

sarily set up from an informatics standpoint to map detailed radiation oncology treatment planning information just yet, but there’s nothing that would stop us from doing that,” he explained.

“Most of our early focus with CancerLinQ are aspects of clinical care that are applicable to either specialty,” Dr. Miller added. “The system is

EXPERT POINT OF VIEW

J

ames Jett, MD, of National Jewish Health in Denver, moderated the press briefing where the study results were presented and called MAPS a “landmark study” that could change the standard of care in this malignancy. Martin J. ­Edelman, MD, Professor of MediMartin J. Edelman, MD

James Jett, MD

cine at the University of Maryland, Baltimore, agreed with Dr. Jett’s comments during his discussion of MAPS at the 16th World Conference on Lung Cancer.

Dr. Edelman noted that mesothein the experimental arm receiving triplet therapy (18.8 vs 16.1 months; hazard ratio [HR] = 0.76; P = .015). Median progression-free survival was also significantly longer with the triplet (9.6 vs 7.5 months; HR = 0.61; P < .0001).

The median overall survival of the control arm was longer than has been observed in historical series or previous trials, perhaps because study subjects were unusually fit, Dr. Scherpereel said.

Grade 3/4 toxicities were observed in 71% of the bevacizumab arm and 62% of the control arm. Hematologic toxicities were not increased with bevacizumab, but nonhematologic adverse events were greater with triplet therapy, including a higher incidence not tuned to one particular mode of practice or specialty. We can bring in anything from anywhere. It’s all about getting as many charts as possible into CancerLinQ. The more data you aggregate, the better.”

ASTRO is planning a a Precision Medicine Workshop scheduled for June 16–17, 2016, on the NIH campus

lioma is a highly aggressive and lethal disease that is occasionally resectable and responds only modestly to chemotherapy. The MAPS findings suggest that the triplet of pemetrexed/ cisplatin/bevacizumab will become a new standard of care, he said.

“How these findings will be integrated with other novel therapies for mesothelioma will be the subject of future studies,” Dr. Edelman said.

“Nevertheless, it’s nice to have a positive trial in mesothelioma.” n Disclosure: Drs. Edelman and Jett reported no potential conflicts of interest.

of creatinine elevations (39% vs 28%), hypertension (56% vs 1%), arterial and venous thromboembolic events (7% vs 1%), and low-grade hemorrhage (41% vs 7%).

There was no significant difference between the arms in terms of percent of drug delivered or proportion of patients receiving second-line treatment.

Therefore, these factors do not explain bevacizumab’s benefits, he said. n

Disclosure: Dr. Scherpereel reported that Roche provided bevacizumab for the trial and his research lab received a grant in 2012–2015.

Reference 1. Scherpereel A, Mazières J, Margery J, et al: 16th World Conference on Lung Cancer.

Abstract 2142. Presented September 7, 2015.

in Bethesda, Maryland. n Disclosure: Drs. Hoffman, Efstathiou, Chen, Prior, and Miller reported no potential conflicts of interest.

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 29

Announcements

James P. Allison, PhD, Wins Clinical Medical Research Lasker-DeBakey Award

J

ames P. Allison, PhD, Chair of Immunology at The University of Texas MD Anderson Cancer Center, has been named the 2015 winner of the Lasker-DeBakey Clinical Medical Research Award from the Albert and Mary Lasker Foundation. The Lasker awards, in their 70th year, honor major achievements in basic science, clinical research, and public service around the world. Dr. Allison’s research is responsible for the development of immune checkpoint blockers, most notably ipilimumab (Yervoy), which remarkably extends the long-term survival of latestage melanoma.

MD. “As we explore the full potential of immunotherapy, countless cancer patients already have experienced renewed promise and health thanks to this groundbreaking advance, and we remain hopeful for so much more.”

Founded in 1942, the Albert and Mary Lasker Foundation seeks to improve health by accelerating support for medical research through recognition of scientific excellence, public education, and advocacy. Mary Lasker was

a prominent activist for public investment in medical research and is widely credited with motivating Congress and various presidents to expand federal funding, particularly through the National Institutes of Health. n

When one didn’t exist, When one didn’t exist, Dana-Farber Dana-Farber created a pathway created a pathway tototreat children with treat children with rare brain cancers. rare brain cancers.

James P. Allison, PhD

“I’m honored and grateful to receive the Lasker award. As a basic scientist, I was pleasantly surprised, really kind of stunned, to receive the clinical award,” Dr. Allison said. “This award is also important recognition of the early success of cancer immunotherapy and its great potential to extend survival of cancer patients for decades and, ultimately, to cure some types of cancer.”

“Dr. Allison found a way to remove the brakes that stop T cells from fighting tumor cells—a discovery that opens brand new and very effective ways to treat cancer,” said Joseph Goldstein, MD, Nobel Laureate, Chair of the Lasker Medical Research Awards Jury, and Chair of Molecular Genetics at The University of Texas Southwestern Medical Center in Dallas.

“The Lasker award highlights Dr. Allison’s genius, creativity, and passion to make an impact, all of which contributed to one of the most important therapeutic advances in a generation that continues to change the practice of oncology around the world,” said MD Anderson President Ronald A. ­DePinho,

Visit The ASCO Post website at ASCOPost.com

Researchers at Dana-Farber have been studying some of the rarest and most dangerous childhood brain cancers, hoping to develop new, more effective approaches treatment.

Ourofwork with cancers likedangerous DIPG, a brain stem glioma that affects Researchers at Dana-Farber have beentostudying some the rarest and most childhood brain cancers, hoping onlyto200 children each year and AT/RT, a lethaltobrain tumor that 100cancers annually, creating a better develop new, more effective approaches treatment.

Our affects work with likeisDIPG, a brain stemunderstanding glioma that affects of how attack theseeach diseases.

Taking on rare childhood cancers helped open new pathwaysa in the study of onlyto200 children year and AT/RT, a lethal brain tumor thathas affects 100usannually, is creating better understanding manyof adult cancers well,diseases. includingTaking ovarian, colon and possibly While the biology of study cancerof how to attackas these onbreast, rare childhood cancers haspancreatic helped uscancer. open new pathways in the remains we believe even small steps can breast, lead to colon giant leaps forwardpancreatic toward a brighter children, manycomplex, adult cancers as well, including ovarian, and possibly cancer. future While for theour biology of cancer and remains for everyone. complex, we believe even small steps can lead to giant leaps forward toward a brighter future for our children, and for everyone.

See videos, whitepapers and more at DiscoverCareBelieve.org/DIPG. See videos, whitepapers and more at DiscoverCareBelieve.org/DIPG.

© 2015 Dana-Farber Cancer Institute

© 2015 Dana-Farber Cancer Institute

The ASCO Post | SEPTEMBER 25, 2015

PAGE 30

Expert’s Corner Palliative Care in Oncology

One Doctor’s Road to Palliative Care Services in the Inner City A Conversation With Steven Reichert, MD

By Ronald Piana ulty position at Mount Sinai Hospital in New York. I was in general medicine, and since there was no hospitalist profession then, I did both inpatient and outpatient care.

Growing Interest in Palliative Care

Steven Reichert, MD

S

t. Barnabas Hospital is located in the heart of Bronx, New York, and as such, it has a culturally diverse, largely poor, patient population. The backbone of successful palliative care services is the doctor-patient communication bonding process. However, many of the patients with late-stage cancer at St. Barnabas present cultural and language barrier challenges for oncologic and palliative care services. To shed light on these issues, The ASCO Post recently spoke with Steven Reichert, MD, Director of Palliative Care Services at St. Barnabas Hospital.

Early Years Please tell the readers a bit about your background.

I was born and reared in Ohio and went to undergraduate school at the University of Michigan. I studied literature but always wanted to become a doctor.

I received my MD degree from the University of Cincinnati College of Medicine and did my residency training in internal medicine and primary care at Baystate Medical Center in Springfield, Massachusetts. Then I worked for a year at a hospital emergency department and another year in private primary care practice.

After that, I ended up taking a fac-

What circumstances led you from primary care into palliative care?

During my first year at Mount Sinai Hospital, I was an attending on a geriatric ward with Dr. Sean Morrison who, along with Dr. Diane Meier, was considered one of the early founders of palliative care. It was 1995, and at that time, most people did not understand the underlying principles behind palliative care. That experience began to pique my interest in the field.

tor at New York Hospital Queens, running the program for about 9 years.

During my tenure at New York Hospital Queens, I was also appointed the head of the quality assurance program.

So whenever there was a challenging patient, they called me. And it became readily apparent at our hospital, which was handling 300 to 400 internal medicine patients at a time along with 60 to 80 chronic bed patients and a lot of Medicare end-of-life care, that we needed palliative care services. So I began lobbying the administration for the go-ahead to create a palliative care program. Finally, the administration sent me and three other doctors to Minneapolis to take an intense course on how to begin such a program.

When we returned, we knew the ba-

I’ve learned that in my patient population, connecting on a spiritual level is tantamount to best practices.

—Steven Reichert, MD

During my time at Mount Sinai, I really enjoyed working with residents, so I decided to remain in academic medicine. Eventually, I became Associate Program Director at the Englewood Hospital and Medical Center in New Jersey, where I was involved in training and teaching medical students. Everything was primary care-based. While there, I took what was called EPEC training, which was an intense 3-day course in end-of-life care for physicians.

The person leading the course was a palliative care doctor named Cynthia Pan. I spent 6 years at the Englewood Hospital, and from there, I went on to be an internal medicine program direc-

sics of setting up a program but did not have the hands-on knowledge to run a palliative services department. So once again, we lobbied the administration, and they reached out and hired my previous EPEC instructor, Dr. Pan, as Director of Palliative Care Services. Meanwhile, I’d been working in palliative care by default because there was no one else to do it.

When Dr. Pan arrived, I became interested in making a career shift and asked her if I could work with her. She said yes, and since I was a program director, I thought I would just take an exam in palliative care, pass, and become a palliative care specialist. Wrong.

I did not expect the avalanche of learn-

ing that followed, from communication skills to pain management.

I also quickly found out that up until then, I had been doing many things wrong. For one, I wasn’t patient-centered; I wasn’t assessing my patients’ emotional and spiritual needs. Taking full advantage of Dr. Pan’s teaching and feedback, I began to grow as a palliative care doctor. In 2012, I took and passed my boards. So, that’s the story of my journey to palliative care.

Fledgling Program What led to your position at St. Barnabas Hospital?

My work situation at New York Hospital Queens changed, and I began to reach out for new opportunities in palliative care. Ironically, my best friend from high school was the Chief Medical Officer at St. Barnabas Hospital. He had inquired about my joining the St. Barnabas team in the past. So I called him, explained that I wanted to do palliative care, and asked what kind of program he had. Their program consisted of one nurse practitioner.

With that, he asked if I would like to head a palliative care service at St. Barnabas, and I became director of the hospital’s palliative care services 2 years ago.

Please tell the readers about the experience of running a palliative care unit in the inner city.

Because of the information I’d received from the course I took in Minneapolis, I expected a slow start to a fledgling palliative care program, about 50 consults the first year and an incremental growth in volume. Well, in my first 6 months at St. Barnabas, I did about 200 consults. Last year, I saw more than 700 patients, and the volume and demands continue to grow. The program is receiving accolades from patients, their

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ASCOPost.com | SEPTEMBER 25, 2015

PAGE 31

Expert’s Corner

families, and the hospital administration, which is very gratifying, especially since this is still a young program.

A Population in Need Please describe the patient population and the clinical challenges you and your staff face.

We are located in the heart of the Bronx, and our patient population is predominantly low-income Hispanics and African-Americans. About half of our services need to be conducted in Spanish, which I am fluent in. These are some of the poorest people in the country. Moreover, most of our patients are deeply religious,

which presents challenges for me. Studies show that very poor and undereducated religious individuals tend to have extremely high expectations at the end of life.

Quite honestly, there’s also a lack of trust in the system that many of these patients have, especially when a white doctor is treating them. There is a cul-

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.]

K-Ras Mutation-negative, EGFr-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information] • in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, 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, 5, and 6 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 6, 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, 5, and 6. 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: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 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.

tural barrier that needs to be addressed, and I’ve found the best way to do that is to connect on a spiritual level.

I’ll never forget an experience during my second month running the program. I was at the bedside of a very sick AfricanAmerican patient with cancer, and his continued on page 32

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.

K-Ras testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information].

Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.

Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux.

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 in Erbitux clinical trials (incidence ≥25%) include 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, 5, and 6, 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 SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) 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 reactions 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 reactions (≥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 38 1 24 1 Aspartate Transaminase, highc Alkaline Phosphatase, highc 33 <1 24 0 respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd 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 reactions, 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.

The ASCO Post | SEPTEMBER 25, 2015

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Expert’s Corner Steven Reichert, MD continued from page 31

daughter was across from me. I mentioned God, and his head perked up. His daughter asked me if I believed in God, and when I said, yes I do, she said, ‘You’re our man.’

I was able to work closely with her as her father made a peaceful transition to hospice care. I’ve learned that in my patient

population, connecting on a spiritual level is tantamount to best practices.

Another challenge is to get the rest of my staff to fully understand the needs of our patients and their families. It’s easy to be impatient with people who do not understand why their loved one is unresponsive. Our job is to work through those barriers in a respectful and thoughtful manner.

Closing Thoughts Do you have any last thoughts on the future of palliative care?

I think the next area of growth needs to be centered on the palliative care outpatient setting. This will be part of a newer movement toward thinking of the health-care system not in silo models, but in a shared responsibility between

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 (cetuximab) 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 reactions 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). table 2:

incidence of Selected Adverse reactions (≥10%) in Patients with recurrent Locoregional Disease or Metastatic SCCHN Eu-Approved Cetuximab Platinum-based plus Platinum-based therapy with therapy with 5-Fu 5-Fu Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona infections and infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.

Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab.

U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. 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 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). table 3:

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFr-expressing, Metastatic Colorectal Cancera Eu-Approved Cetuximab plus FOLFiri FOLFiri Alone (n=317) (n=350) Grades Grades Grades body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients blood and Lymphatic System Disorders Neutropenia 49 31 42 24 Eye Disorders Conjunctivitis 18 <1 3 0 Gastrointestinal Disorders Diarrhea 66 16 60 10 Stomatitis 31 3 19 1 Dyspepsia 16 0 9 0 General Disorders and Administration Site Conditions 14 2 <1 0 Infusion-related Reactionc Pyrexia 26 1 14 1 infections and infestations Paronychia 20 4 <1 0 investigations Weight Decreased 15 1 9 1 Metabolism and Nutrition Disorders Anorexia 30 3 23 2 (Continued)

Erb0813PBS_693US13PBS02201_7x9wip3.indd 2

providers and patients. A central goal of palliative care is to work with oncologists to prevent emergency room visits. Also, it is important to get the primary care doctor involved early in the care of a patient with cancer. A well-coordinated system ultimately creates better outcomes. n Disclosure: Dr. Reichert reported no potential conflicts of interest.

table 3: (Continued)

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFr-expressing, Metastatic Colorectal Cancera Eu-Approved Cetuximab plus FOLFiri FOLFiri Alone (n=317) (n=350) Grades Grades Grades body System Grades b 1–4 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”.

Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. 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 17 infusions (range 1–51). table 4:

incidence of Selected Adverse reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFr-expressing, Metastatic Colorectal Cancer treated with Erbitux Monotherapya Erbitux plus bSC bSC alone (n=118) (n=124) Grades Grades Grades body System Grades b 3 and 4 1–4 3 and 4 Preferred Term 1–4 % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related.

Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). 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 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.

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Announcements

Tari King, MD, Named Chief of Breast Surgical Services at Dana-Farber/Brigham and Women’s Cancer Center

T

ari King, MD, has been appointed Chief of Breast Surgery at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC). Dr. King will hold appointments at Brigham and

Women’s Hospital, Faulkner Hospital, and Dana-Farber Cancer Institute.

Dr. King will oversee breast surgery in the DF/BWCC, which includes breast surgical activities in the Susan F. Smith Center

for Women’s Cancers at Dana-Farber. As head of breast surgery, she will work collaboratively with medical oncology, radiation oncology, breast imaging, and pathology to continue to build DF/BWCC’s integrated

Tari King, MD The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis • Mucosal inflammation DruG iNtErACtiONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. uSE iN SPECiFiC POPuLAtiONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, 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 be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49.

No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric use: The safety and effectiveness of Erbitux in pediatric patients have not been established.

The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients.

The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 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 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.

OvErDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLiNiCAL tOxiCOLOGY 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 Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys.

It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument.

At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PAtiENt COuNSELiNG iNFOrMAtiON Advise patients: • 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 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.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

multidisciplinary clinical model for treating breast cancer.

“Dr. King brings extraordinary expertise in breast surgery and a track record of leadership in an academic medical center,” said Eric Winer, MD, Director of Breast Oncology Program and Thompson Chair of Breast Cancer Research at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Eric Winer, MD

Copyright © 2004–2013 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886B3

Rev August 2013 693US13PBS02201

“Dr. King comes with a national and international reputation as an outstanding surgeon, a thoughtful educator, a respected researcher, and an effective leader,” said Michael J. Zinner, MD, Chairman of the Department of Surgery at Brigham and Women’s Hospital.

Michael J. Zinner, MD

Prior to joining DF/BWCC, Dr. King held a number of positions at Memorial Sloan Kettering Cancer Center, most recently as Deputy Chief and Director of Research, Breast Service. She was also an Associate Professor of Surgery at Weill Medical College at Cornell University.

Dr. King received her medical degree from University of Colorado Health Sciences Center. n Erb0813PBS_693US13PBS02201_7x9wip3.indd 3

8/19/13 2:01 PM

The ASCO Post | SEPTEMBER 25, 2015

PAGE 34

Announcements Radiation Oncology

2015 ASTRO Gold Medal Recipients Announced

T

he American Society for Radiation Oncology (ASTRO) has chosen three radiation oncology physicians and researchers to receive the 2015 A ­ STRO Gold Medal: Carl R. B ­ ogardus, Jr, MD, FASTRO; Carl M. Mansfield, MD, ScD (Hon), FASTRO; and James B. Mitchell, PhD, FASTRO. Drs. Bogardus, Mansfield, and Mitchell will be recognized with the ASTRO Gold Medal during ASTRO’s 57th Annual Meeting, October 18–21, 2015, at the Henry B. González Convention Center in San Antonio, Texas.

The ASTRO Gold Medal is the honor received by members of ASTRO who have achieved outstanding lifetime contributions in the field of radiation oncology, including in research, clinical care, and teaching, as well as through their dedicated service to ASTRO. First awarded in 1977, the ASTRO Gold Medal has been conferred on 78 of ­ASTRO’s more than 10,000 members, including the three 2015 awardees.

“It is with great appreciation, admiration, and respect that I congratulate my esteemed colleagues, Drs. Bogardus, Mansfield, and Mitchell,” said ASTRO Chair Bruce G. Haffty, MD, FASTRO. “The impact of their work, collectively and individually, provided the firm foundation for radiation oncology’s integral role in the triad of cancer care. The clinical, biologic, and technologic advances we have achieved as a specialty are due in large part to their impressive and important work.”

Carl R. Bogardus, Jr, MD, FASTRO

Carl R. Bogardus, Jr, MD, FASTRO Dr. Bogardus is Professor, Clinical Director, and Vice Chairman of the Department of Radiation Oncology at the University of Oklahoma Health Sciences Center in Oklahoma City. He is the only person to have served as both President of ASTRO (1989–1990) and the American College of Radiology (1991–1992).

Dr. Bogardus has been an instrumental member of numerous ASTRO committees including the Medical Economics Committee and the Committee on Practice Regulation, as a representative on

apy; this method of treatment excised the tumor without removing the entire breast. He has also written a book on breast cancer and was editor of two radiation therapy textbooks.

Dr. Mansfield earned his medical degree from Howard University and an Honorary Doctor of Science degree from Lincoln University. In addition to his postdoctoral fellowship at Middlesex Hospital, he was the Chernicoff Fellow in Pediatric Radiation Therapy at Jefferson Medical College Hospital from 1964 to 1966 and served another year at the Meyerstein Institute of Radiotherapy at Middlesex Hospital Medical School from 1972 to 1973. the CPT Advisory Panel, and he served as Treasurer of the Board of Directors prior to his term as President.

His concepts of care and reimbursement, as detailed in his “User’s Guide for Radiation Oncology,” provided the stepping stones that have created the documentation for many of the technical and scientific advances in the field.

Dr. Bogardus was recognized as a Fellow of ASTRO in 2006.

Dr. Bogardus’ commitment to radiation oncology’s process of care includes his efforts as the inventor and senior developer of the ONCOCHART electronic medical record (EMR), a first-ofits-kind, full-featured EMR that documents the cognitive and procedural work for appropriate billing of radiation oncology services and also provides decision support and interoperability with other electronic systems.

He joined the University of Oklahoma Health Sciences Center as Assistant Professor of Radiology and Associate Radiation Therapist in 1964. During his more than 50-year tenure at the University, Dr. Bogardus served in numerous roles. Most notably, he was the founding Director of the University’s originally 3-year Resident Training Program in the Department of Radiological Sciences from 1964 to 1995 and again as the Director from 2007 to 2008 when the program grew to become a 4-year residency program within the newly created Department of Radiation Oncology.

Dr. Bogardus earned his medical degree at the University of Louisville School of Medicine. He served his residency in therapeutic radiology at Penrose Cancer Hospital in Colorado Springs, Colorado. His fellowship in radiation therapy and radiation physics was at the Mallinckrodt Institute of

Radiology at Washington University School of Medicine, St. Louis.

James B. Mitchell, PhD, FASTRO Carl M. Mansfield, MD, ScD (Hon), FASTRO

Carl M. Mansfield, MD, ScD (Hon), FASTRO Dr. Mansfield retired from a nearly 50-year medical career in 2002. He was Associate Director of the Greenebaum Cancer Center and Chairman of the Department of Radiation Oncology at the University of Maryland. His career included the positions of Professor and Chairman of the Department of Radiation Oncology at the University of Kansas Medical Center; Professor and Chairman of the Department of Radiation Oncology and Nuclear Medicine at Thomas Jefferson University Hospital; and Associate Director of the Division of Cancer Treatment, Diagnosis and Treatment Centers Radiation Research Program at the National Cancer Institute (NCI).

Dr. Mansfield is considered a pioneer in intraoperative radiation therapy for early-stage breast cancer. He produced a seminal 1983 report comparing perioperative and intraoperative (iridium-192) breast implants, which laid the groundwork for much of the continuing research in this field today. His work also led to advances in the conservative management of breast cancer through breast irradiation and local brachyther-

James B. Mitchell, PhD, FASTRO Dr. Mitchell is currently Branch Chief of the Radiation Biology Branch of the NCI at the National Institutes of Health (NIH). Dr. Mitchell was recognized as a Fellow of ASTRO in 2009 and served as the Vice-Chair of the Radiation Biology Committee and on ASTRO’s Scientific Committee, among numerous other roles. His more than 40-year career as a preeminent radiobiologist includes work in the Department of Radiation Oncology at Vanderbilt University Hospital, the Department of Radiology and Radiation Biology at Colorado State University, and the NCI at NIH. Dr. Mitchell’s achievements include his role as a teacher and leader in the field of tumor biology, and the development of novel radiation protectors and sensitizers. He also assisted in the development of photodynamic therapy for clinical cancer treatment at the NCI. Together with his colleague Murali Krishna, PhD, he has worked toward the development and testing of novel in vivo imaging platforms for the noninvasive determination of tissue hypoxia and metabolism.

Dr. Mitchell earned his PhD in cellular radiation biology from Colorado State University. n

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 35

Announcements

Texas Center for Proton Therapy Names Chang Chang, PhD, Director of Physics

C

hang Chang, PhD, a leader in proton therapy medical physics, has been named Director of Physics at Texas Center for Proton Therapy.

Previously, as Senior Medical Physicist at ProCure Proton Therapy Center in Somerset, New Jersey, Dr. Chang was

involved in the commissioning of new proton technology (including pencilbeam scanning treatment) and the RayStation treatment planning system for both passive and pencil-beam scanning proton treatments.

Pencil-beam scanning in conjuncGAZYVA® (obinutuzumab)

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information.

WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive.

Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations.

Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

tion with on-board cone-beam computed tomography gives clinicians a three-dimensional view of a patient’s anatomy for more precise treatment.

Pencil-beam scanning uses precise ultra-fine proton beams across each layer of the tumor. n

Chang Chang, PhD

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction.

Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) Adverse Reactions (MedDRAa) System Organ Class

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion.

Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Injury, poisoning, and procedural complications Infusion 69 21 0 0 reactions

11

8

4

Anemia

12

5

10

4

Leukopenia

7

5

0

0

Infections and infestations Urinary tract 6 2 infection

3

<1

Musculoskeletal and connective tissue disorder Back pain 5 <1 2 0

Table 4 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Adverse Reactions (MedDRAa) System Organ Class

5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary.

Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

Injury, poisoning and procedural complications Infusion 66 20 38 4 reactions Blood and lymphatic system disordersb Neutropenia 38 33 32

28

Thrombocytopenia 14

10

7

3

Leukopenia

4

2

<1

6

General disorders and administration site conditions Pyrexia 9 <1 7 <1

5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

6.1 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.

16

Thrombocytopenia 15

Respiratory, thoracic, and mediastinal disorders Cough 10 0 7 <1

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

Blood and lymphatic system disordersb Neutropenia 41 35 18

General disorders and administration site conditions Pyrexia 10 <1 7 0

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy.

Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection.

Patients with a history of recurring or chronic infections may be at increased risk of infection.

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

GAZYVA + Chlorambucil n = 241

Gastrointestinal disorders Diarrhea 10 2

8

<1

Constipation

5

0

8

0

Infections and infestations Nasopharyngitis 6 <1 Urinary tract infection

5

1

3

0

2

<1

a

MedDRA coded adverse reactions as reported by investigators.

b

Adverse events reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

The ASCO Post | SEPTEMBER 25, 2015

PAGE 36

Announcements

Carl H. June, MD, Awarded the 2015 Watanabe Prize

C

arl H. June, MD, an internationally recognized leader in the growing field of immunotherapy, was awarded the Watanabe Prize at the 7th Annual Meeting of the Indiana Clinical and Translational Sciences Institute (CTSI) on September 11 on the campus

of Indiana University–Purdue University Indianapolis.

Dr. June, Richard W. Vague Professor in Immunotherapy and Director of the Center for Cellular Immunotherapies in the Perelman School of Medicine at the University of Pennsylvania,

has led the development and testing of novel forms of immunotherapy in cancer and chronic infections, making groundbreaking contributions in determining mechanisms by which the body’s immune system can be activated to attack such diseases.

Carl H. June, MD

Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) GAZYVA + Chlorambucil n = 241

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

78

48

53

27

Lymphopenia

80

40

9

3

Leukopenia

84

37

12

<1

Chemistry Hypocalcemia

38

3

33

2

Hyperkalemia

33

5

18

3

Hyponatremia

30

8

12

3

AST (SGOT increased)

29

1

16

0

Creatinine increased

30

<1

20

2

ALT (SGPT increased)

27

2

16

0

Hypoalbuminemia

23

<1

15

<1

Alkaline phosphatase 18 increased

0

11

0

Hypokalemia

1

5

<1

15

Table 6 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Investigations

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia

76

46

69

41

Lymphopenia

80

39

50

16

Leukopenia

16

84

35

62

Thrombocytopenia 48

13

40

8

Anemia

39

10

37

10

Chemistry Hypocalcemia

37

3

32

<1

Hyperkalemia

14

1

10

<1

Hyponatremia

26

7

18

2

AST 27 (SGOT increased)

2

21

<1

ALT 28 (SGPT increased)

2

21

1

Hypoalbuminemia 23

<1

16

<1

Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

(7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion).

The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).

Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.

6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial Experience Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers.

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

8.5 Geriatric Use Of 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

The August M. Watanabe Prize in Translational Research, presented by the Indiana CTSI and the Indiana University School of Medicine, recognizes a member of the scientific or medical community who has achieved outstanding accomplishments in translational research. As the recipient, Dr. June spent several days in Indiana sharing his knowledge with audiences at the Indiana University School of Medicine and partner institutions.

The Indiana CTSI Annual Meeting also highlighted two outstanding young investigators named Watanabe Translational Scholars. Announced at the meeting (after we went to press), these prize winners were scheduled to present brief overviews of their research during the event, and will be mentored

by Dr. June over the next 2 years.

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)].

• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)].

• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA® [obinutuzumab]

Initial US Approval: 2013

Manufactured by: Genentech, Inc.

Code Revision Date: December 2014

A Member of the Roche Group South San Francisco, CA 94080-4990

GAZYVA is a registered trademark of Genentech, Inc.

U.S. License No: 1048

GAZ/011615/0009 1/15 © 2015 Genentech, Inc.

Anantha Shekhar, MD, PhD

Established in 2008, The Indiana CTSI, directed by Anantha Shekhar, MD, PhD, is a statewide collaboration of Indiana University, Purdue University, and the University of Notre Dame, along with many public and private corporate partnerships, to facilitate the translation of scientific discoveries in the laboratory into new patient treatments. For more information, visit indianactsi.org. n

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 37

Announcements

ASTRO Awards Seven Physician-Researchers $675,000 in Grants for Radiation Oncology Research

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he American Society for Radiation Oncology (ASTRO) has selected seven leading physician-researchers to receive a total of $675,000 in awards and grants to advance radiation oncology research. Together, the grants will support studies in cancer biology, radiation physics, translational research, outcomes/health services research, and comparative effectiveness research within radiation oncology. Recipients will be recognized at ASTRO’s 57th Annual Meeting, October 18–21, 2015, in San Antonio, Texas.

Kent William Mouw, MD, PhD

Kent William Mouw, MD, PhD, Dana-Farber Cancer Institute. Dr. Mouw will be investigating the genomic determinants of chemoradiotherapy responses in anal carcinoma. His focus is to map the genetic landscape of a large number of anal tumors to understand their biology, which could help identify appropriate therapeutic targets.

Bruce G. Haffty, MD, FASTRO

“ASTRO proudly supports these seven exceptional researchers in their efforts to help us continue to advance radiation oncology care,” said ASTRO Chair Bruce G. Haffty, MD, FASTRO. “ASTRO is committed to engaging and funding recent medical graduates in their critical research efforts that will strengthen their radiation oncology careers, and the specialty as a whole.”

Junior Faculty Career Research Training Award The ASTRO Junior Faculty Career Research Training Award provides $100,000 annually for 2 years to two winners to support the careers of promising junior faculty, offering them the opportunity for dedicated time to work on research projects in radiation oncology, biology, physics, or outcomes/ health services. Recipients are boardeligible physicians, physicists in radiation oncology, or radiobiologists who are within the first 3 years of their junior faculty appointment.

The two 2015 recipients are:

Robert Mutter, MD

Robert Mutter, MD, Mayo Clinic.

Dr. Mutter will study comprehensively characterized chemoresistant triple-negative breast cancer xenograft models established from patients with high-risk breast cancer in a preoperative chemotherapy clinical trial. He will investigate if chemoresistance predicts radioresistance, and test new DNA-repair strategies aimed at overcoming resistance.

Residents/Fellows in Radiation Oncology Research Seed Grant The ASTRO Residents/Fellows in Radiation Oncology Research Seed Grant awards $25,000 for 1-year projects to residents and fellows who are planning to pursue careers focusing on basic science or clinical research in radiation oncology services.

The three 2015 grant recipients are:

Ariel Marciscano, MD

David Mayhew, MD, PhD

Ariel Marciscano, MD, Johns Hopkins University. Dr. Marciscano will be researching “immuno-PET” as a non­ invasive biomarker to characterize the tumor microenvironment and the implications for combining stereotactic radiotherapy with immune checkpoint blockades.

David Mayhew, MD, PhD, University of Alabama. Dr. Mayhew will evaluate the role of a noncanonical form of mRNA translation, termed internal ribosome entry site (IRES) translation, in the cellular stress response of tumors and its subsequent impact on treatment resistance in multiple breast cancer cell lines in vitro, as well as tumor xenograft in vivo.

Jennifer Shah, MD, Stanford University. Dr. Shah will investigate the feasibility of performing serial perfusion computed tomography scans in patients undergoing lung tumor stereotactic ablation body radiation therapy, with the goal of characterizing the postradiation vascular changes and how they correlate to tumor response.

Comparative Effectiveness Research Award The ASTRO/Radiation Oncology Institute (ROI) Comparative Effectiveness Research Award provides $50,000 annually for 2 years to two researchers who will conduct comparative effectiveness research examining radiation oncology treatment. Awardees are board-certified or board-eligible physicians in radiation oncology at the time the award begins, focused on academic radiation oncology.

Jennifer Shah, MD

The two 2015 recipients are: Timothy Zagar, MD, University of North Carolina, Chapel Hill. Dr. Zagar will be researching the comparative effectiveness of endocrine therapy and radiation therapy regimens for elderly women (> 70 years of age) with early stage, estrogen receptor–positive breast cancer.

Timothy Zagar, MD

Mark Mishra, MD, University of Maryland Medical Center. Dr. Mishra will compare patient-reported outcomes to determine if the use of intensity-modulated radiation therapy compared to three-dimensional cathode ray tube can result in a reduction in patient-relevant side effects after prostate irradiation.

Mark Mishra, MD

For more information about ­ STRO-supported grants and awards, A visit www.astro.org/grants. n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 25, 2015

PAGE 38

FDA Update

FDA Approves Rolapitant for Prevention of Chemotherapy-Induced Nausea and Vomiting

T

he U.S. Food and Drug Administration (FDA) approved rolapitant (Varubi) to prevent delayed-phase chemotherapy-induced nausea and vomiting. Rolapitant is approved in adults in combination with other antiemetic agents that prevent nausea and vomiting associated with initial and repeat courses of emetogenic and highly emetogenic cancer chemotherapy.

and vomiting during the delayed phase compared with the control group.

Rolapitant inhibits the CYP2D6 enzyme, which is responsible for metabolizing certain drugs, and

is contraindicated with the use of thioridazine, a drug metabolized by the CYP2D6 enzyme. Use of the two drugs together may increase the amount of thioridazine in the blood

and cause an abnormal heart rhythm.

The most common side effects of rolapitant include neutropenia, hiccups, decreased appetite, and dizziness. (See page 24 for more on rolapitant). n

‘Major Issue’ for Quality of Life Nausea and vomiting are common side effects experienced by cancer patients undergoing chemotherapy.

Symptoms can persist for days after the chemotherapy drugs are administered.

Nausea and vomiting that occurs from 24 hours to up to 120 hours after the start of chemotherapy is referred to as delayed-phase nausea and vomiting and can result in serious health complications. Prolonged nausea and vomiting can lead to weight loss, dehydration, and malnutrition leading to hospitalization in cancer patients.

“Chemotherapy-induced nausea and vomiting remains a major issue that can disrupt patients’ lives and sometimes their therapy,” said Amy Egan, MD, MPH, Deputy Director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Today’s approval provides cancer patients with another treatment option for the prevention of the delayed phase of nausea and vomiting caused by chemotherapy.”

Rolapitant is a substance P/neurokinin-1 (NK-1) receptor antagonist. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by certain cancer chemotherapies, particularly in the delayed phase. The new agent is provided to patients in tablet form.

Clinical Trial Data The safety and efficacy of rolapitant were established in three randomized, double-blind, controlled clinical trials where rolapitant in combination with granisetron and dexamethasone was compared with a control therapy (placebo, granisetron, and dexamethasone) in 2,800 patients receiving a chemotherapy regimen that included highly emetogenic (such as cisplatin and the combination of anthracycline and cyclophosphamide) and moderately emetogenic chemotherapy drugs.

Those patients treated with rolapitant had a greater reduction in vomiting and use of rescue medication for nausea

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ASCOPost.com | SEPTEMBER 25, 2015

PAGE 39

Announcements

Barbara Pro, MD, Joins the Lurie Cancer Center

T

he Robert H. Lurie Comprehensive Cancer Center of Northwestern University announced the addition of medical oncologist Barbara Pro, MD. A leader in the research and treatment of lymphomas, Dr. Pro joined the Lurie Cancer Center in September 2015. She

Barbara Pro, MD

has been appointed Professor of Medicine in the Division of Hematology/ Oncology at Northwestern University Feinberg School of Medicine. She will also serve as Director of Northwestern Medicine Developmental Therapeutics Institute’s Fellowship Program.

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Dr. Pro comes to the Lurie Cancer Center from Thomas Jefferson University and Hospitals in Philadelphia, where she was Professor of Medical Oncology, as well as Chief of the Lymphoma Section and Director of the Multidisciplinary Cutaneous Lymphoma Clinic. n

The ASCO Post | SEPTEMBER 25, 2015

PAGE 40

Announcements

Lurie Cancer Center Receives $11.7 Million NCI Grant to Improve Treatment Using Nanotechnology

N

orthwestern University has received a 5-year, $11.7 million grant from the National Cancer Institute (NCI) to use nanotechnology to develop next-generation cancer treatments.

With NCI support, the new Northwestern University Center for Cancer Nanotechnology Excellence (Northwestern CCNE) will use nucleic acid– based nanoconstructs called spherical

nucleic acids to gain access to intracellular environments, discover new aspects of cancer biology, and create effective cancer treatment options.

Spherical nucleic acids are nontoxic to

humans, making them a versatile tool in medicine. They were invented at Northwestern in 1996 and have been used for therapeutic purposes since 2010.

Under the direction of principal in-

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ASCOPost.com | SEPTEMBER 25, 2015

PAGE 41

Announcements

vestigators Chad A. Mirkin, PhD, and Leonidas C. Platanias, MD, PhD, the Northwestern CCNE will unite scientists, engineers, and clinicians from diverse fields, such as nanoscience, cancer biology, chemistry, materials science, physics, engineering, and medicine. They will work toward the common goal of developing spherical nucleic acid nano-

Chad A. Mirkin, PhD

Leonidas C. Platanias, MD, PhD

structures poised to enter the clinic as revolutionary, cancer-killing agents to improve and save the lives of patients suffering from glioblastoma multiforme and prostate cancer.

The CCNE will feature three projects (one discov-

ery-based and two translational) and one core facility. The center also will have for-profit partners united to provide novel nanotechnology-based solutions to daunting and complex issues in cancer research and treatment.

“The support from the National Cancer Institute will enable researchers to continue to make significant cancer-relevant discoveries that ultimately can be transferred to the clinic and profoundly impact the way cancers are studied and treated,” Dr. Platanias said. n

Don’t Miss These Important Reports in This Issue of The ASCO Post

Kathleen I. Pritchard, MD, FRCPC, on Menopausal Hormone Therapy and Breast Cancer see page 57

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Angelo E. Volandes, MD, on His Recently Published Book on End-of-Life Care see page 74

The ASCO Post’s Tribute to Gianni Bonadonna, MD see page 77

For more on prostate cancer, visit ASCOPost.com

The ASCO Post | SEPTEMBER 25, 2015

PAGE 42

Direct From ASCO

ASCO University® Releases 2015 Curricula for Advanced Practice Providers (ACAPP™)

A

SCO University has released an updated version of ASCO’s Curricula for Advanced Practice Providers (ACAPP ™). This popular series assists with the orientation of advanced practice providers (APPs) into oncology practices—a growing need as increasing numbers of APPs are hired to meet the demand for team-based care.

Practices can choose to purchase either a general curriculum or individual, tumor-focused curricula. The general curriculum, which contains basic and premium levels of content, is designed for newly graduated APPs or those beginning oncology practice, whereas the tumor-specific curricula provide indepth digital education on specific tu-

Volume 7, Issue 3

May 2011

Journal of oncology Practice

mor types for APPs with more clinical oncology experience.

“ACAPP, which is vetted through the ASCO University Editorial Board, has been a dynamic program since its inception in 2013,” said Heather M. Hylton, MS, PA-C, Lead Physician Assistant at Memorial Sloan Kettering Cancer Center, member of the ASCO University Editorial Board and primary collaborator on the 2015 ACAPP. “Program content is updated each year, and now the program will be taken to the next level: ASCO is collaborating with the Association of Physician Assistants in Oncology, the Advanced Practitioner Society for Hematology and Oncology, and the Hematology/Oncology Phar-

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

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

What’s Hot in

JOP

macy Association to build a curricular framework upon which future content for ACAPP will be created.”

This year’s updated program contains new courses in the general curriculum, such as hematopoietic growth factors, radiation oncology primer, and infectious disease/use of antibiotics.

The updated tumor-focused packages include the cancer genetics and the tumor genomics programs, two of ASCO University’s largest and most popular resources. Table 1 includes a complete list of currently available ACAPP courses, as well as courses that will be released throughout the year.

ASCO University will collaborate with other organizations representing APPs to enhance the curricular backbone of the ACAPP program and address unmet areas of education.

“ASCO has been a leader in its efforts to collaborate with APPs, and this is an exciting opportunity for APPs to

work with ASCO on further expansion of this program,” Ms. Hylton said.

Oncology practices may purchase packages for their employees, or individual APPs may purchase the curricula. A post-assessment is included in all packages to help gauge comprehension. In addition, all courses offer a certificate of participation, which is accepted toward recertification by the American Nurses Credentialing Center, California Board of Registered Nursing, American Academy of Physician Assistants, and the Medical Group Management Association.

For more information about the 2015 ACAPP Curricula, visit university.asco.org/acapp. n Originally printed in ASCO Daily News. © American Society of Clinical Oncology. “ASCO University® Releases 2015 Curricula for Advanced Practice Providers (ACAPP™)” am.asco.org 1 June 2015. All rights reserved.

Table 1. Current and Upcoming ACAPP™ Courses 2015 Curricula for Advanced Practice Providers General Curriculum—Basic Package Communicating Prognosis (2014 Update)

Cardiac Complications of Cancer Therapy

Cancer Care for Older Patients (2014 Update)

Use of Social Media

Cancer Care for Adolescents and Young Adults

Triage: Emergency or not?

Chemotherapy Administration and Pharmacology

Radiation Oncology Primer

American Society of Clinical Oncology Quality Training Program

Grading of Tumors

Symptom Management after Radiation Therapy

by Arif H. Kamal, et al

Staging of Tumors

Infectious Disease and Use of Antibiotics

Overview of Anti-cancer Therapies

Cancer-Associated Fatigue

Health-Related Quality of Life of Food-Insecure Ethnic Minority

Hematopoietic Growth Factors

Team-Based Care in Oncology Practice*

Patients With Cancer

Chemotherapy Safety Standards (2015 Update)

What It Costs to Deliver Care*

FUF: Breast as a Second Malignancy (2015 Update)

ASCO Flashcards: Oncology Terms and Abbreviations*

Impact of the National Cancer Institute Community Cancer

Pain Management

ASCO Flashcards: Symptom Management*

Centers Program on Clinical Trial and Related Activities at a

Survivorship (2015 Update)

ASCO Flashcards: Billing and Coding Basics*

New Drugs in Oncology 2015

ASCO Flashcards: Drug Toxicities*

New Drugs in Oncology 2014

ASCO Flashcards: Palliative Care*

Cultural Competence for Oncology Practice

ASCO Flashcards: Chemotherapy Acronyms*

Nutritional Interventions

EPEC-O (Available on iTunes University)*

JOP.ascopubs.org Feasibility and Effectiveness of a Pilot Program to Facilitate Quality Improvement Learning in Oncology: Experience of the

by Francesca Gany, et al

Community Cancer Center in Rural Nebraska

by Mehmet Sitki Copur, et al

Are Patients With Cancer Less Willing to Share Their Health Information? Privacy, Sensitivity, and Social Purpose

by David Grande, et al

General Curriculum—Premium Option ASCO-SEP 4th Edition (includes eBook, Online Question Bank, and ASCO Flashcards: ASCO-SEP) Tumor-Focused Curricula Packages

Complications Associated With Use of Long-Term Central Venous Catheters Among Commercially Insured Women With Breast Cancer

by Allison Lipitz-Snyderman, et al

Breast Cancer

Lung Cancer

Gastrointestinal Cancers

Hematologic Malignancies

Genitourinary Cancers *Courses that are not CME accredited.

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 43

Direct From ASCO

DEEPER RESPONSES? LONGER DURATION OF THERAPY? It’s time to take a deeper look at the critical debates in multiple myeloma today.

SEE WHAT YOUR PEERS SAY AND SHARE YOUR OPINION AT DEBATINGMYELOMA.COM

Takeda Oncology and are registered trademarks of Takeda Pharmaceutical Company Limited.

Other trademarks are the property of their respective owners.

Copyright © 2015, Millennium Pharmaceuticals, Inc.

All rights reserved.

Printed in the USA

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4/15

The ASCO Post | SEPTEMBER 25, 2015

PAGE 44

Direct From ASCO

Conquer Cancer Foundation Donor Spotlight: Fibrolamellar Cancer Foundation

W

hen Tucker Davis was diagnosed with fibrolamellar hepatocellular carcinoma (FL-HCC) in 2008, there was very little information about this very rare cancer and, as Tucker would soon discover, even fewer treatment options available. An annoying cough and sharp pain radiating down his back leg

Tucker Davis

eventually prompted him to see his physician. After a few tests, he was shocked to learn that he had this very rare form of liver cancer that is only correctly diagnosed in an estimated 200 people each year worldwide. After discovering the lack of information available about FL-HCC and nonexistent patient com-

Annual Fibrolamellar Cancer Foundation Patient & Family Gathering held at the Lake Mansfield Trout Club, Stowe, VT.

munity, Tucker, along with his girlfriend and two friends, started the Fibrolamellar Cancer Foundation (FCF).

Tucker passed away in 2010 at only 28 years old. According to Mar-

Be a Voice in The Campaign to Conquer Cancer

W

e’ll provide the resources. You provide the voice. The Campaign to Conquer Cancer is raising $150 million to support a world free from the fear of cancer. Our potential to raise money increases with every new person who learns about our work. We need the most trusted leaders in the oncology community to share the message about our critical movement—that’s you. Most people outside the oncology community are unaware that in just 15 years, the Conquer Cancer Foundation (CCF) has granted more than $150

million to fund patient and caregiver education, boost the careers of young oncologists, and support clinical research around the world. Let the people who turn to you for advice on medicine and health know CCF resources are at the core of cancer treatment and discoveries. To learn more, sign up at conquer. org/asco, and we’ll share some ways you can help us connect others to The Campaign to Conquer Cancer. n © 2015. American Society of Clinical Oncology. All rights reserved.

na Davis, Tucker’s mother and President of FCF, “The last 18 months of his life were his finest hour. We saw courage in him that we had never seen before. He was funny, sweet, kind, goofy, never got depressed, and just had an attitude to live.” Tucker once said, “Mom, I know there is a cure out there and I hope we find it in my lifetime, but if we don’t, you have to find it.” Tucker’s legacy lives on in the foundation he founded and established to help other patients and families affected by FL-HCC.

The Goals of FCF The mission of FCF is three-fold: find a cure and treatment options; raise awareness of this disease; and connect and support the fibrolamellar community of patients and their families. According to John Hopper, Executive Director of FCF, one major challenge is that very little government research is being funded in this area since there are such low incidence rates of the disease.

FCF has addressed this by supporting the creation of the Fibrolamellar-Hepatocellular Carcinoma Consortium, which brings together multiple academic medical centers and universities to cooperate and share information about FL-HCC. FCF is aggressively supporting research in this area and has funded the Tucker Davis Fibrolamellar Research Facility, the first tissue bank for fibrolamellar samples, which is maintained at the Rockefeller University.

It is also funding efforts to create mouse models to replicate tumors so physicians and scientists can investigate different therapies.

In 2016, FCF is generously supporting a Conquer Cancer Foundation of ASCO Young Investigator Award (YIA) in FL-HCC. “To encourage someone early in his/ her career to learn about FL-HCC, focus on it, and give him or her opportunity to collaborate with a senior researcher at that organization is a great starting point,” said Mr. Hopper. He urges young investigators to take a “deep look” at FL-HCC and hopes that young minds coming out of medical and fellowship programs may see this as a way to make a difference in people’s lives. FCF is especially pleased to be working with the Conquer Cancer Foundation and ASCO to generate additional awareness about this disease through the YIA program, which reaches a very large global population.

“While fibrolamellar hepatocellular carcinoma is rare, it is relatively simple with few mutations noted, occurring in apparently healthy young people with a continued on page 46

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 45

Direct From ASCO

ASCO Urges Expansion of Cancer Research to Include Older Adults

A

SCO issued landmark recommendations in the Journal of Clinical Oncology calling for federal agencies and the cancer research community to broaden clinical trials to include older adults (age 65 and older) and to redefine trial eligibility.

More than 60% of cancers in the United States occur in older adults,

a population that will grow exponentially over the coming years. Yet the evidence base for treating older adults is sparse because they are underrepresented in clinical trials, and trials designed specifically for them are rare.

ASCO’s recommendations include asking regulatory agencies,

Food Safety for Patients With Cancer

C

ancer.Net and the United States Department of Agriculture’s Food Safety and Inspection Service have collaborated on an infographic of food safety tips for people with cancer. This infographic is an excellent way to help your patients under-

stand which foods are safe to eat, which foods to avoid, safe internal temperatures of meats, symptoms of food poisoning, and questions to ask the doctor. Direct your patients to www.Cancer.Net/blog to view this new infographic as well as additional resources on food safety. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO Continues to Support 21st Century Cures

T

he U.S. House of Representatives passed monumental legislation that will accelerate the discovery, development, and delivery of promising new cancer treatments.

The 21st Century Cures Act advances big data and precision medicine and strengthens the National Institutes of Health and Food and Drug Administration.

ASCO has weighed in heavily throughout the development of this legislation and will continue to work closely with lawmakers on its advancement.

ASCO encourages the passage of this

legislation in the U.S. Senate this fall.

The 21st Century Cures legislation will help foster big data advancements, like ASCO’s CancerLinQ™, a cuttingedge health information technology platform that will revolutionize how we care for people with cancer, and the Targeted Agent and Profiling Utilization Registry (TAPUR) Study, ­A SCO’s first-ever clinical trial, designed to learn from the real-world practice of precision medicine. n © 2015. American Society of Clinical Oncology. All rights reserved.

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

Write to The ASCO Post at editor@ASCOPost.com

research funders, and researchers to consider whether the evidence supports eligibility criteria based on age, performance status, or comorbid conditions—three primary reasons older adults are excluded from clinical trials. Researchers should also adopt innovative trial designs that would fill knowledge gaps in

the treatment of older adults with cancer.

ASCO plans to organize a public meeting to advance the issues raised in its position statement in the fall of 2016. n © 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | SEPTEMBER 25, 2015

PAGE 46

Direct From ASCO CCF Donor Spotlight continued from page 44

generally predictable natural history, so many of the typical confounders are not present,” said Alan Venook, MD, Professor of Medical Oncology and Translational Research at the University of California, San Francisco, ASCO member, and FCF Scientific Advisory Board member. “The bonus is that it is not unlikely that a discovery in a rare cancer may open up other areas of exploration in common cancers,” he said.

derstanding of the disease all gathered to learn from one another and engage in collaborative efforts.

the country who have been affected by FL-HCC. There is no agenda, program, or scheduled sessions during this re-

All the pieces are out there.

Energetic minds want to research this.

Passionate oncologists want a cure for this.

—John Hopper

Creating a Community FCF is focused on motivating research and encouraging collaboration in the scientific community. In 2014, FCF convened its first scientific conference in Greenwich, Connecticut, where approximately 30 American and international physicians and scientists who are studying FL-HCC, treating patients with FL-HCC, or expanding their un-

Creating a community for patients and their families was of unparalleled importance to Tucker Davis. FCF maintains an active dialogue with its stakeholders through social media and on its website. Since 2012, FCF has hosted a yearly gathering in Stowe, Vermont, for over 100 people from all over

treat. It is simply a wonderful opportunity for patients, families, and caregivers to meet others who have also been affected by this awful disease and to create connections and promote bonding among this community.

With obvious passion and conviction, Mr. Hopper explains that FL‑HCC

is the most interesting puzzle he has faced in his approximately 35 years in the business world. “All the pieces are out there. Energetic minds want to research this. Passionate oncologists want a cure for this. What we have needed is someone to be able to put these pieces together and see the big picture. Strategic collaboration will allow us to extend people’s lives and, hopefully, find a cure for this disease,” he said.

To learn more about the Fibrolamellar Cancer Foundation, please visit www.fibrofoundation.org. To learn more about the Conquer Cancer Foundation, please visit www.

ConquerCancerFoundation.org. n Originally printed in ASCO Connection. © American Society of Clinical Oncology.

“Conquer Cancer Foundation Donor Spotlight: Fibrolamellar Cancer” connection.asco.org 21 August 2015. All rights reserved.

Chief Executive Officer The American Society of Clinical Oncology (ASCO) is seeking an accomplished leader in clinical oncology to serve as their next Chief Executive Officer (CEO). ASCO is a professional society committed to conquering cancer through research, education, prevention, and delivery of high quality patient care.

Founded in 1964, ASCO today counts more than 36,000 members worldwide and has an annual budget of $100M. The CEO works with a distinguished Board of Directors, a talented professional staff of more than 350 individuals, and hundreds of dedicated volunteers to envision and implement a strategic plan that engages and serves all physicians as they work to fight cancer. The CEO provides leadership and vision on the execution of strategic plans and oversees the fiscal health of the organization while building and supporting a highly committed and capable management team. The CEO must ensure that ASCO’s current major initiatives are successful and also guide a conversation about new opportunities for ASCO to support the field in a dynamic healthcare environment. All of these efforts will be sustained by responsible management of internal resources and diligent philanthropic efforts.

The successful candidate for this prestigious position will have experience as a leader in clinical oncology with a deep passion for, commitment to, and track record of accomplishments in cancer clinical medicine. The candidate should have working knowledge of and some experience in the many areas in which ASCO plays an important role in improving cancer care, including clinical and translational research, physician and public education and communication, cancer care delivery, governmental affairs and policy, and global health. A prior leadership role with ASCO in a volunteer or board capacity is strongly desired as is an in-depth understanding of the current trends and issues affecting oncology clinical practice and clinical research today.

A medical degree is required. The ideal candidate must have a demonstrated track record of managing and leading a large and complex organization with a comparably sized budget and a highly educated, high intellect professionals. The CEO also serves as CEO of the affiliated Conquer Cancer Foundation, and experience with philanthropy is beneficial.

This position is based at ASCO headquarters in Alexandria, Virginia. Candidates from all oncology disciplines and sub-specialties, domestic and international, are encouraged to apply. ASCO is proud to be an Equal Opportunity Employer (EOE).

Isaacson, Miller has been retained for this important recruitment and all nominations, inquiries, and applications should be directed in confidence to: www.imsearch.com/5499.

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 47

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The ASCO Post | SEPTEMBER 25, 2015

PAGE 48

Issues in Oncology S. Vincent Rajkumar, MD continued from page 1

on investment or whether it is based on what prices the market can bear.”

According to the article, over the past 15 years, the average price of cancer drugs in the United States has increased 5- to 10-fold, reaching more than $100,000 per year in 2012. The combination of escalating drug prices and requirements by insurance companies for patients to share more and more of those costs is resulting in about 10% to 20% of patients with cancer not taking the prescribed treatment or compromising it, wrote the oncologists. To stem the rise in drug prices, the oncologists proffered this seven-step plan: Create a review mechanism—activated after U.S. Food and Drug Administration (FDA) drug approval—to propose a fair price for new treatments based on the value to patients and health care.

• Allow Medicare to negotiate drug prices.

• Allow the Patient-Centered Outcomes Research Institute to evaluate the benefits of new treatments; enable similar organizations to include drug prices in their assessments of the treatment value.

• Allow importation of cancer drugs across borders for personal use.

• Pass legislation to prevent drug companies from delaying access to generic drugs.

• Reform the patent system to make it more difficult to prolong product exclusivity unnecessarily.

• Encourage organizations that represent cancer specialists and patients, such as ASCO, the American Society of Hematology (ASH), Ameri-

can Association for Cancer Research (AACR), American Cancer Society (ACS), and National Comprehensive Cancer Network (NCCN), to consider the overall value of drugs and treatments in formulating treatment guidelines. (See “ASCO Releases Details of Its Conceptual Framework for Assessing Value in Cancer Care” in the June 25, 2015, issue of The ASCO Post.)

get too many experts to sign on because there really is no personal benefit for us and we could be putting ourselves at risk with the drug companies we are criticizing. We depend on these companies for access to their drugs for clinical studies and support for research as well as for consulting and speaking opportunities.

Of course, the authors of this paper are unique. They are not just a collection of experts in oncology, but, in my opinion, they are the very best experts and true giants in the field. I am simply honored to be part of this group.

Seven Solutions

Hagop Kantarjian, MD

Origins of the Commentary How did the group of 118 oncologists come together to develop the seven-step plan advocated for improving the situation caused by the high cost of cancer drugs?

The background of how this article developed is that many of us have been working separately on this issue and arguing for change for a long time.

I wrote a paper about the high cost of cancer drugs in 2012,2 and Hagop ­Kantarjian, MD [Edward W. and Betty Knight Scripps Professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center], and 118 other experts in chronic myeloid leukemia wrote about the unsustainable prices of cancer drugs in 2013,3 but we had limited impact.

When I first started pursuing this issue, I wasn’t very hopeful that we would

How did you arrive at the seven solutions for reducing drug costs proposed in your article?

They reflect a process of studying the problem, asking questions, and determining steps that we think would be effective. The fact that most of us are involved in clinical trials and know what it takes to bring a drug to market helped. We understand the costs involved; we know how many dollars it takes to develop a drug, the clinical trials needed to approve a drug, and how indications of the approved drug expand over time.

We take care of patients, so we know the financial consequences of these high-priced drugs. For some well-insured patients with low prescription drug copays, the personal financial burden of cancer is not great. But most patients can’t afford the high copays on drugs that cost tens of thousands of dollars and aren’t a cure for their cancer.

We considered all these issues and thought about solutions, and many of us arrived at the same list of solutions,

which are all commonsense steps. For example, consider the recommendation to allow Medicare to negotiate drug prices. Here you have a situation where the largest buyer of the most expensive drugs on the market can’t negotiate with a pharmaceutical company on the price of a drug—and most importantly, on drugs that only work for a few weeks—and can’t ask the question, “Why are you charging $100,000 or $200,000 for this drug?”

We are all full-time researchers in our respective specialties. My research is in multiple myeloma. We are not economists or politicians, but we know why drug prices are so high, and we know what needs to be done to have a real impact in lowering prices, such as making it a free-market situation where the buyer and the seller can negotiate price.

Impact of Targeted Therapies Will molecularly designed clinical trials, which may enable more drugs to be winners in the treatment of cancers with specific mutations, help reduce the cost of drug research and development and, therefore, reduce the market price of a new drug?

Absolutely not; they will have the opposite effect, because pricing will depend on what competing companies are charging for their drugs and the size of the patient population utilizing the drug. One example is panobinostat (Farydak) in the treatment of multiple myeloma. The FDA approved the drug earlier this year, but it offers no significant improvement in overall survival or patient-reported quality-of-life outcomes—yet each pill costs more than $1,000.

If targeted therapies are approved

News and Views from the World of Clinical Oncology and Hematology

Visit The ASCO Post website at

www.ASCOPost.com

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 49

Issues in Oncology

without price controls, they will be priced very, very high because there will be few patients with that specific target, and the patent on such drugs will last for many years. On the other hand, everything changes if such a drug is curative.

Imported Drugs One of your solutions is to allow the importation of cancer drugs across borders.

What are the safety implications of doing that, and who would be the watchdog to ensure the drugs are not counterfeit?

If you are instituting this kind of program as public policy, you need to have safeguards. We are not proposing that the FDA buy cheaper drugs from other countries and sell them here. We are saying that if private citizens want to take on the responsibility of assessing the risks and benefits of buying cancer drugs from other countries, they should be allowed.

You always have to look at what the alternative might be if patients are forced to go without treatment because they can’t afford it and die of their disease.

Pharmaceutical companies say they have patient assistance programs to help people afford treatment, but you have to be

really poor and have limited personal assets to qualify for those programs.

Early Response to Proposal What has been the reaction to your proposal from the oncology community, including patient groups and the pharmaceutical and insurance industries?

The response so far has been mostly very positive. We did have some pushback from some oncology and pharmaceutical groups who point out that the cost of cancer drugs make up only 9% of Medicare’s budget and claim that negotiating drug prices won’t make a big difference in our overall health-care spending or fix all the inefficiencies in the health-care system.

We agree that there are many reasons our health-care costs are so exorbitant, but that doesn’t mean we should do nothing. Let’s fix one problem at a time. For example, let Medicare negotiate drug prices with the pharmaceutical companies.

We are highlighting one issue that we think is a major concern and that is unjust. Our primary allegiance is to the patients we treat and to our research, so we can find new treatments and im-

prove patient outcomes. It would not be wise for us to take our eyes off the work we need to do. It is the responsibility of those involved in legislating public policy to address the other inefficiencies in the health-care system.

We do have to ask ourselves, why are we in the oncology community supporting these marginally effective, high-priced drugs? If we ignored them, perhaps the prices would drop. I don’t propose to have the magic bullet solution, but at least our proposal starts a dialogue to address the problem.

Next Steps What are your next steps?

I would like nothing more than to concentrate on myeloma research and not have to worry about the high cost of cancer drugs. It is too stressful to do both. But it is important to keep up the pressure and keep writing, speaking up, and increasing the visibility of the issue. We are working with our professional organizations such as ASCO, ASH, and AACR, as well as engaging with leaders in our own institutions to develop solutions.

We are also giving our full sup-

port and voice to patient-based grassroots movements advocating against the high price of cancer drugs, such as the Change.org petition (http://chn. ge/1DCWT1M). Patients are the ones most affected by these costs, and they need to speak up.

We also need to realize that oftentimes the patients most affected by high health-care costs are the ones who are uninsured or underinsured and have no voice. We need to be their voice. n

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

References 1. Tefferi A, Kantarjian H, Rajkumar SV, et al: In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc 90:996-1000, 2015.

2. Siddiqui M, Rajkumar SV: The high cost of cancer drugs and what we can do about it. Mayo Clin Proc 87:935-943, 2012.

3. Experts in Chronic Myeloid Leukemia: The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: From the perspective of a large group of CML experts. Blood 121:4439-4442, 2013.

FDA Update

FDA Grants Regular Approval to Brentuximab Vedotin in High-Risk Classical Hodgkin Lymphoma

T

he U.S. Food and Drug Administration has approved brentuximab vedotin (Adcetris) as post–autologous hematopoietic stem cell transplantation consolidation treatment for patients with classical Hodgkin lymphoma at high risk of relapse or progression, Seattle Genetics has announced.

The approval is based on the phase III AETHERA trial that was designed to compare up to 16 cycles (approximately 1 year) of brentuximab vedotin therapy administered every 3 weeks following autologous hematopoietic stem cell transplantation to placebo. The primary endpoint was met with a significant improvement in median progression-free survival of 42.9 months (95% confidence interval [CI] = 30.4–42.9) for patients who received brentuximab vedotin vs 24.1 months (95% CI = 11.5–not estimable) for patients who received placebo, an improvement of 18.8 months (hazard ratio [HR] = 0.57;

95% CI = 0.40–0.81, P = .001).

In addition, data from the AETHERA trial converted the U.S. accelerated approval of the relapsed classical Hodgkin lymphoma indication to regular approval.

Brentuximab vedotin is an antibodydrug conjugate directed to CD30, which is expressed in classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma, as well as other lymphoma subtypes. This is the third indication for brentuximab vedotin, which was granted accelerated FDA approval in August 2011 for two other indications: (1) treatment of Hodgkin lymphoma patients for whom autologous transplant or at least two prior multiagent chemotherapy regimens have failed, and who are not autologous transplant candidates; and (2) treatment of systemic anaplastic large cell lymphoma patients for whom at least one one prior multiagent chemotherapy regimen has failed. n

FDA Accepts for Priority Review the Biologics License Application for Elotuzumab for the Treatment of Relapsed Multiple Myeloma

B

ristol-Myers Squibb and AbbVie recently announced that the U.S. Food and Drug Administration has accepted for priority review the Biologics License Application for elotuzumab, an investigational signaling lymphocyte activation molecule

(SLAMF7)-directed immunostimulatory antibody, for the treatment of multiple myeloma as combination therapy in patients who have received one or more prior therapies.

Elotuzumab was previously granted Breakthrough Therapy designation, which is intended to expedite the development and review of drugs for serious

or life-threatening conditions.

The filing acceptance is primarily supported by data from the phase III ELOQUENT-2 trial, a randomized, open-label study, which evaluated elotuzumab in combination with lenalidomide (Revlimid) and dexamethasone vs lenalidomide and dexamethasone alone. The results of this trial were reported by Lonial et al in The New England Journal of Medicine.

Additionally, the filing was supported by data from study CA204-009, a phase II, randomized, open-label study that evaluated elotuzumab with bortezomib (Velcade) and dexamethasone vs bortezomib and dexamethasone alone. These phase II results were presented in an oral session at the 20th Congress of the European Hematology Association. n

The ASCO Post | SEPTEMBER 25, 2015

PAGE 50

Announcements

NCI Awards Huntsman Cancer Institute, University of New Mexico Cancer Center Comprehensive Cancer Center Designations

T

he National Cancer Institute (NCI) recently awarded Huntsman Cancer Institute (HCI) at the University of Utah and The UNM Cancer Center (UNMCC) at the University of New Mexico Comprehensive Cancer Center status.

An NCI-Designated Comprehensive Cancer Center must demonstrate depth and breadth of cancer research, as well as substantial transdisciplinary research that bridges these scientific areas and changes cancer care. In addition, a comprehensive cancer center must demonstrate professional and public education and outreach capabilities, including the distribution of clinical and public health advances in the communities it serves. The evaluations were done by a team of national cancer experts and included a rigorous scientific review, a competitive grant process, and a site visit.

Jon M. Huntsman, Sr

Huntsman Cancer Institute HCI is the only cancer center to be designated by the NCI in the five-state Intermountain West region, which includes Utah, Wyoming, Montana, Idaho, and Nevada.

The comprehensive cancer center designation recognizes not only cancer research, training, and public outreach programs that have long been conducted at HCI, but acknowledges the depth and breadth of HCI research in each of the three major cancer research areas: laboratory, clinical, and population-based research. The designation also recognizes HCI for the impact of its research findings on national cancer care guidelines and improved patient outcomes.

“This designation is the result of professionalism and exceptional expertise of our physicians, scientists, and administrative staff at Huntsman Cancer Institute,” said Jon M. ­Huntsman, Sr, Huntsman Cancer Institute’s Founder and Chief Benefactor. “Only a small percentage of the nation’s cancer programs have the excellence necessary to receive comprehensive cancer center

status. What a difference this will make to the cancer patients in our state, in the region, and in the world.”

NCI evaluates each of its designated cancer centers every 5 years. Since the

previous evaluation in 2009, when HCI applied and obtained renewal of its cancer center status, it has recruited 33 new program members and garnered 20% more NCI funding of its studies. HCI

opened more than 60 new collaborative grants and doubled enrollment in clinical trials of cancer treatments in the 5-year project period. In addition, building expansion completed in 2011

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ASCOPost.com | SEPTEMBER 25, 2015

PAGE 51

Announcements

doubled the size of the cancer hospital, and construction is underway that will double the size of HCI’s research facilities upon its completion in 2017.

“Huntsman Cancer Institute stands as an exceptional model of the best that health care and cancer care can be,” said Vivian Lee, MD, PhD, MBA, Senior Vice President of

University of Utah Health Sciences.

“The Cancer Center has developed a top-notch system that integrates researchers and clinicians to work closely together to advance cutting edge care and marry science with compassion.”

HCI’s research excellence has been made possible by generous

support of the Huntsman family and the Huntsman Cancer Foundation, which supports HCI’s research mission through philanthropic contributions. A 10-member External Advisory Board provides planning and evaluation direction to HCI; it includes such outstanding scientists as Edward Benz Jr, MD, President

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of Dana-Farber Cancer Institute; Nobel Laureate Elizabeth Blackburn, PhD, of the University of California at San Francisco; and Brian Druker, MD, Director of the Oregon Health Sciences University Knight Cancer Center.

HCI’s research strategy is to transcontinued on page 52

The ASCO Post | SEPTEMBER 25, 2015

PAGE 52

Announcements NCI-Designated Centers continued from page 55

late genetic understanding of cancer into individualized risk assessment, diagnosis, and treatment. HCI and its researchers have earned international recognition for their work in identifying gene mutations for hereditary colon cancer, breast and ovarian can-

cers, melanoma, neurofibromatosis, and paraganglioma.

University of New Mexico Cancer Center UNMCC’s designation makes it the only such cancer center in New Mexico.

“15 years ago we made a promise—to be of service to the people of

New Mexico and to overcome New Mexico’s cancer burden—and we committed ourselves to building New Mexico’s finest, most comprehensive cancer treatment program,” said Cheryl Willman, MD, Director and CEO of UNMCC. Following submission of the 1,486-page application in September

Cheryl Willman, MD

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Announcements

of 2014, UNMCC underwent a second stage review with 32 site visitors who evaluated the Center onsite for a 2-day period in February 2015. A detailed report and evaluation was generated which was then reviewed by the National Cancer Advisory Board in June 2015.

At UNMCC, 116 doctors in every

cancer specialty work with over 500 health care professionals to provide care to more than 10,000 cancer patients each year in more than 135,000 clinic visits. These patients come from every county in New Mexico, as well as from out of state. In addition, UNMCC partners with Memorial Medical Center (MMC) in Las

Cruces, where UNM physicians work in concert with MMC physicians and staff to provide treatment to an additional 600-700 Southern New Mexicans each year.

UNMCC, working with community health systems across the state, built the New Mexico Cancer Care Alliance, a statewide clinical trials network that

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provides access to new cancer drugs and treatments in more than 160 studies each year.

UNMCC has also joined a partnership with other NCI Cancer Centers to build the Total Cancer Care/ORIEN project, in which all UNM cancer patients will have the opportunity to have their cancer tissues undergo advanced genome sequencing, matching them to the best targeted treatments for their disease.

Supported by more than $72 million annually in research funds, UNMCC scientists work with partners at Los Alamos and Sandia National Laboratories, Lovelace Respiratory Research Institute, and New Mexico State University to develop more effective cancer diagnostics and treatments.

The Center’s team of 132 cancer scientists has developed new diagnostics and drugs for leukemia, melanoma, and cancer of the breast, ovary, prostate, liver, pancreas, and brain. Since 2010, they have been awarded 33 new patents and have started 13 new biotechnology companies.

The UNMCC education and training programs were particularly noted, with more than 50% of students representimg minority and underserved groups. Since 2010, the Center has trained over 250 cancer scientists and over 168 cancer physicians and healthcare professionals. n

The ASCO Post

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The ASCO Post | SEPTEMBER 25, 2015

PAGE 54

JCO Spotlight Thoracic Oncology

Immune Checkpoint Inhibitor Nivolumab Is Active in Patients With Heavily Pretreated Advanced Non–Small Cell Lung Cancer

By Matthew Stenger

I

n a phase I cohort expansion trial reported in the Journal of Clinical Oncology, Scott N. Gettinger, MD, of Yale Cancer Center, New Haven, Connecticut, and colleagues found that monotherapy with the anti–programmed cell death protein 1 (PD1) checkpoint inhibitor antibody nivolumab (Opdivo) produced durable responses and promising survival rates in patients with heavily pretreated non–small cell lung cancer (NSCLC).1 Nivolumab is being evaluated in phase III trials in NSCLC.

Nivolumab in NSCLC ■■ Objective response occurred in 17.1% of nivolumab-treated patients, including 24.3% of those receiving 3 mg/kg; median duration of response was 17.0 months in all responders and in those receiving 3 mg/kg.

■■ Overall survival at 1, 2, and 3 years was 42%, 24%, and 18% among all patients and 56%, 42%, and 27% in those receiving 3 mg/kg.

Study Details In the study, 129 patients with advanced NSCLC enrolled from 12 U.S. sites between November 2008 and January 2012 received nivolumab at 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed (RECIST version 1.0) after each cycle. Eligibility requirements included one to five prior systemic treatments for advanced NSCLC, disease progression on at least a platinum- or taxane-based regimen, and at least one measurable lesion.

Patients had a median age of 65 years (range = 38–85 years), 61% were male, and 98% had Eastern Cooperative On-

cology Group performance status of 0 or 1. Histology was nonsquamous in 58% and squamous in 42%.

The number of prior systemic treatments was one or two in 46% and a minimum of three in 54%. Prior treatment included platinum-based therapy in 99%; tyrosine kinase inhibitors in 28%; surgery in 66%; radiotherapy in 58%; and hormonal, immunologic, or biologic therapy in 12%.

EGFR mutation status was mutant in 9%, wild-type in 43%, and unknown in 47%. KRAS mutation status was mutant in 16%, wild-type in 28%, and unknown in 56%.

Response Rates Median follow-up was 39 months.

Across all nivolumab dose levels, the objective response rate was 17.1% among all patients, including response rates of 16.7% in patients with squamous histology and 17.6% in those with nonsquamous histology. Response rates in patients receiving the 3-mg/kg dose selected for further development were 24.3% among all patients, including 22.2% in those with squamous histology and 26.3% in those with nonsquamous histology.

Median duration of response among all responders was 17.0 months (range = 1.4+ to 36.8+ months), including median duration not reached in patients with squamous NSCLC, 14.2 months in those with nonsquamous histology, and 17.0 months in those receiving 3 mg/kg.

Eleven (50%) of the 22 responses were documented at the first 8-week tumor assessment. Median progression-free survival in responders was 20.6 months (range = 4.7+ to 40.3+ months). Response was ongoing in 41% of responders at the time of ­analysis.

Among 18 responders who discontinued nivolumab for reasons other

Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. —Scott N. Gettinger, MD, and colleagues

than disease progression, 9 (50%) had responses longer than 9 months after the end of treatment. Stable disease of at least 24 weeks was observed in an additional 10% of patients.

Overall Survival Median overall survival across all doses was 9.9 months, with 1-, 2-, and 3-year rates of 42%, 24%, and 18%.

Among patients with squamous and nonsquamous histology, median overall survival was 9.2 months and 10.1 months, with 1-, 2-, and 3-year rates of 41%, 24%, and 19% and 42%, 27%, and 16%. Among 37 patients receiving 3 mg/kg, 1-, 2-, and 3-year survival rates were 56%, 42%, and 27%.

Immune-Pattern Responses Unconventional immune-pattern responses—ie, persistent reduction in target lesions in the presence of new lesions or regression of target lesions after initial growth—were observed in an additional six patients (5%).

Overall survival in these patients was 7.3, 11.2, 16.7, 26.7, 34.5+ , and 54.3+ months at the time of analysis.

Toxicity The most common treatment-related adverse events of any grade were fatigue (24%), decreased appetite (12%), and diarrhea (10%). Treatment-related grade 3 or 4 adverse events occurred in 14% of patients, with fatigue (3%) being

most common. Any-grade treatmentrelated adverse events of special interest included skin events in 15% of patients, gastrointestinal events in 12%, and pulmonary events in 7%. Grade ≥ 3 pneumonitis occurred in four patients (3%).

Death considered related to treatment occurred in three patients (2%), in association with pneumonitis in each patient.

The investigators concluded: “Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.”

Ongoing phase III trials include comparisons of nivolumab vs docetaxel in previously treated advanced squamous and advanced nonsquamous NSCLC and a comparison vs platinumbased therapy in previously untreated advanced PD ligand 1 (PD-L1)-positive disease. n

Disclosure: The study was supported by Bristol-Myers Squibb and Ono Pharmaceutical.

For full disclosures of the study authors visit jco. ascopubs.org.

Reference 1. Gettinger SN, Horn L, Gandhi L, et al: Overall survival and long-term safety of nivolumab (anti–programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non–small-cell lung cancer. J Clin Oncol 33:2004-2012, 2015.

Visit The ASCO Post website at ASCOPost.com

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PAGE 56

Journal Spotlight Breast Cancer

Differing Patterns of Breast Cancer Risk After Hormone Therapy With Estrogen Plus Progestin or Estrogen Alone

By Matthew Stenger

I

n an analysis of Women’s Health Initiative trials reported in JAMA Oncology, Rowan T. Chlebowski, MD, PhD, of Harbor-UCLA Medical Center, and colleagues found differing patterns of breast cancer risk among women receiving menopausal hormone therapy with estrogen plus progestin or estrogen alone.1 Women receiving estrogen plus progestin had reduced early risk, with risk subsequently increasing throughout treatment and during postintervention follow-up. Women receiving estrogen alone had reduced risk during intervention, which persisted through early postintervention.

Study Details The study included data from 27,347 postmenopausal women aged 50 to 79 years who were enrolled in two Women’s Health Initiative trials at 40 U.S. centers from 1993 to 1998 and followed for a median of 13 years through September 2010. In one trial,2 16,608

intervention duration of 7.2 years.3 Annual mammography was protocol mandated and breast cancers were confirmed by medical record review.

Risk in Estrogen/Progestin Trial In the estrogen-plus-progestin trial, risk of invasive breast cancer was reduced during the first 2 years of intervention (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.47–1.08) due to interference with mammographic detection, but risk increased during the subsequent two 2-year intervals during intervention (HR = 1.36, 95% CI = 0.95–1.94, and HR = 1.65, 95% CI = 1.17–2.32), resulting in a significantly increased risk for the entire intervention period (HR = 1.24, 95% CI = 1.01–1.53) while participants were receiving the combined hormone therapy.

When the therapy was discontinued, the hazard ratio decreased during the early postintervention period. For

The ongoing influences on breast cancer [risk] after stopping hormone therapy in the WHI trials require recalibration of breast cancer risk and benefit calculation for both regimens…

—Rowan T. Chlebowski, MD, PhD, and colleagues

women with a uterus were randomly assigned to estrogen plus progestin (n = 8,506) or placebo (n = 8,102), with a median intervention duration of 5.6 years. In the other, 10,739 women with prior hysterectomy were randomly assigned to estrogen alone (n = 5,310) or placebo (n = 5,429) with a median

the entire postintervention period of follow-up, breast cancer risk persisted and was significantly increased (HR = 1.32, 95% CI = 1.08–1.61).

Risk in Estrogen-Alone Trial In the estrogen-alone trial, risk of invasive breast cancer risk was lower

Posttreatment Breast Cancer Risk ■■ Among patients receiving estrogen plus progestin, risk was reduced early during intervention and early postintervention, but increased later in intervention and in the later postintervention period.

■■ Among patients receiving estrogen alone, risk was reduced during intervention and the early postintervention period but increased thereafter.

than 1 throughout the intervention period (HR = 0.79, 95% CI = 0.61–1.02).

Risk was significantly reduced during the early postintervention period (HR = 0.55, 95% CI = 0.34–0.89) but the effect was attenuated during the late postintervention period (HR = 1.17, 95% CI = 0.73–1.87).

Postintervention Comparisons In exploratory analyses, characteristics of breast cancers diagnosed during the early vs late ­postintervention periods differed in both trials, perhaps reflecting the sudden change in estrogen and/or progestin levels. In both trials, however, no differences in patient cancer characteristics were seen comparing intervention to the entire post intervention period.

The investigators concluded: “In the [estrogen-plus-progestin] trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early post-intervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.”

They noted: “With longer follow-up of the two Women’s Health Initiative hormone therapy trials, a complex pat-

tern of changing year-to-year influences on breast cancer [risk] was observed.

The ongoing influences on breast cancer [risk] after stopping hormone therapy in the Women’s Health Initiative trials require recalibration of breast cancer risk and benefit calculation for both regimens, with greater adverse influence for estrogen and progestin use and somewhat greater benefit for use of estrogen alone.” n Disclosure: The Women’s Health Initiative program is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health. For full disclosures of the study authors, visit oncology.jamanetwork.com.

References 1. Chlebowski RT, Rohan TE, Manson JE, et al: Breast cancer after use of estrogen plus progestin and estrogen alone: Analyses of data from two Women’s Health Initiative randomized clinical trials. JAMA Oncol 1:296-305, 2015.

2. Chlebowski RT, Anderson GL, Gass M, et al, WHI Investigators: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.

JAMA 304:1684-1692, 2010.

3. Anderson GL, Chlebowski RT, Aragaki A, et al: Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women’s Health Initiative randomized placebocontrolled trial. Lancet Oncol 13:476-486, 2012.

Updated Analysis of Menopausal Hormone Therapy and Breast Cancer Risk See page 57 for Kathleen Pritchard’s perspective on the report by Chlebowski et al.

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 57

Perspective

Updated Analysis of Menopausal Hormone Therapy and Breast Cancer Risk

By Kathleen I. Pritchard, MD, FRCPC

A

s reviewed in this issue of The ASCO Post, Chlebowski and colleagues1 reported differing patterns of breast cancer risk during or after hormonal therapy with estrogen plus progestin2 or estrogen alone,3 in an analysis of two Women’s Health Initiative (WHI) trials. This recent update on risk provides complex and somewhat puzzling results.

Women receiving estrogen plus progestin had a reduced early risk during the first 2 years of estrogen plus progestin administration, but their risk subsequently increased while still receiving estrogen plus progestin during years 3 and 4 and during postintervention follow-up.

Conversely, women who received estrogen (because they had previously had a hysterectomy) had a reduced risk of breast cancer during the administration of estrogen up to 2 years and during the early time period post intervention up to 4.5 years; their risk increased thereafter.

Furthermore, estrogen plus progestin was associated with more large progesterone receptor–negative and triple-negative tumors during the early vs late postintervention period, whereas estrogen was associated with more HER2-positive and fewer moderately differentiated tumors during early vs late postintervention.

would or would not turn into an increased risk in the postintervention period. However, overall, one might conclude that in terms of the risk of

Dr. Pritchard is Senior Scientist, Odette Cancer Research Program, Sunnybrook Research Institute and the University of Toronto, Canada.

pears to continue to reduce the risk of breast cancer during the intervention period and into the early postintercontinued on page 58

ASCO Meetings gucasym.org

Genitourinary Cancers Symposium January 7-9, 2016 | San Francisco, California Cosponsored with: American Society for Radiation Oncology and Society of Urologic Oncology

Cancer Survivorship Symposium: Advancing Care and Research A Primary Care and Oncology Collaboration

survivorsym.org

January 15-16, 2016 | San Francisco, California Cosponsored with: American Academy of Family Physicians and American College of Physicians, Inc.

Gastrointestinal Cancers Symposium

gicasym.org

January 21-23, 2016 | San Francisco, California Cosponsored with: American Gastroenterological Association Institute, American Society for Radiation Oncology, and Society of Surgical Oncology

Celebrating Ten Years

ASCO Quality Care Symposium

quality.asco.org

February 26-27, 2016 | Phoenix, Arizona

Markers in Cancer Diagnostic Development Tutorial May 2-3, 2016 | Bethesda, Maryland In collaboration with European Organisation for Research and Treatment of Cancer and National Cancer Institute

Bottom Line Summary A simple bottom line summary of the large and complex WHI estrogen plus progestin trial could be that women with an intact uterus can take estrogen plus progestin for 2 years but then must stop, as the risk of breast cancer will increase during the subsequent 2-year period, resulting in a significantly increased risk for the entire 4-year intervention period. Furthermore, the postintervention period would carry an increased risk out to a median of 5.5 years. In fact, we do not know whether by stopping at the end of 2 years, the reduced risk seen during the first 2 years of this trial

breast cancer, estrogen plus progestin is to be avoided.

On the contrary, for women who have had a hysterectomy, estrogen ap-

Annual Meeting

markersincancer.org

am.asco.org

June 3-7, 2016 | Chicago, Illinois

Celebrating Ten Years

Best of ASCO®

boa.asco.org

Chicago June 24-25, 2016 | Chicago, Illinois Washington, DC July 15-16, 2016 | Washington, DC Los Angeles July 22-23, 2016 | Los Angeles, California

Palliative Care in Oncology Symposium September 9-10, 2016 | San Francisco, California Cosponsored with: American Academy of Hospice and Palliative Medicine, American Society for Radiation Oncology, and Multinational Association of Supportive Care in Cancer

pallonc.org

The ASCO Post | SEPTEMBER 25, 2015

PAGE 58

Perspective

Kathleen I. Pritchard, MD, FRCPC Conflicting Data on continued from page 61

Estrogen Alone

vention period, up to about 4.5 years post intervention. Thus, a woman who has had a hysterectomy might take estrogen for the benefits it offers in bone preservation and vasomotor relief without incurring much of an increased risk of breast cancer during the intervention and in the early postintervention period.

The results of observational studies generally support those of the WHI regarding the use of estrogen plus progestin. However, for estrogen alone, the randomized WHI study does not completely correlate with the results

The combination of estrogen plus progestin is associated with an increased incidence of breast cancer. However, estrogen alone may safely be given for periods of time to women who have had a hysterectomy without fear of an increased risk of breast cancer.

Complex Pattern of Endocrine Influences These data do not yield completely to a simple explanation, however.

There is a complex pattern of endocrine influences on breast cancer risk.

These influences include a mixing of the masking effect of combined hormone therapy (estrogen plus progestin) on mammographic diagnostic performance, leading to delayed breast cancer diagnosis early on and hence more advanced-stage cancers and larger tumors later, as is reported in this study.

Furthermore, the drop in increased rates following discontinuation of both estrogen plus progestin and estrogen alone undoubtedly relates, at least in part, to regression of tumors that are already present but subdetectable and may—or may not—reemerge later on.

However, in the WHI trial, there was no statistically significant interaction between time from menopause and influence on breast cancer risk. A lower breast cancer risk with estrogen alone has received support from some other randomized trials, in particular the ESPRIT trial.4 This remains a

—Kathleen I. Pritchard, MD, FRCPC

of observational studies, in which estrogen has generally been associated with an increased risk of breast cancer.

The reasons for these conflicting data are not entirely clear. Time from menopause to hormone therapy initiation (gap time) could reconcile some of these differences, because there is less evidence of estrogen use in influencing breast cancer risk when therapy is started closer to menopause.

complex area, and further follow-up of WHI and other observational and randomized studies will hopefully prove elucidating.

Thus, the WHI studies continue to produce complex and surprising results.

In the meantime, one can conclude as a working hypothesis that the combination of estrogen plus progestin is associated with an increased incidence of breast cancer. However, since data

from a randomized trial such as WHI will generally trump observational data, estrogen alone may safely be given for periods of time to women who have had a hysterectomy without fear of an increased risk of breast cancer. n Disclosure: Dr. Pritchard reported no potential conflicts of interest.

References 1. Chlebowski RT, Rohan TE, Manson JE, et al: Breast cancer after use of estrogen plus progestin and estrogen alone: Analyses of data from 2 Women’s Health Initiative randomized clinical trials.

JAMA Oncol 1:296-305, 2015.

2. Chlebowski RT, Anderson GL, Gass M, et al, WHI Investigators: Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.

JAMA 304:1684-1692, 2010.

3. Anderson GL, Chlebowski RT, Aragaki A, et al: Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 13:476-486, 2012.

4. Cherry N, McNamee R, Heagerty A, et al: Long-term safety of unopposed estrogen used by women surviving myocardial infarction: 14-year follow-up of the ESPRIT randomized controlled trial.

BJOG 121:700-705, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Ronald A. DePinho, MD, on Cancer Prevention as a Childcare Issue see page 1

Naiyer Rizvi, MD, on First-Line Nivolumab/Ipilimumab in Non-Small Cell Lung Cancer see page 1

S. Vincent Rajkumar, MD, on 118 Oncologists Speaking Out on Drug Costs see page 1

Jonathon B. Cohen, MD, on Double-Hit Lymphoma see page 4

Jennifer A. Ligibel, MD, on Obesity Clinical Trials in Cancer Survivors see page 6

Amelia Langston, MD, on Autologous Stem Cell Transplantation in Mantle Cell Lymphoma see page 9

Jonathan Beitler, MD, on the Omission of Chemotherapy in Some HPV-Positive Head and Neck Cancers see page 18

William J. Hogan, MB, BCh, on High-Risk Patients With Febrile Neutropenia see page 26

Karen E. Hoffman, MD, MHSc, MPH, on Big Data in Radiation Oncology see page 27

Visit The ASCO Post online at ASCOPost.com

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Take a deeper look at our reliability and quality visit biotechnologybyamgen.com Download the LAYAR app on your smartphone and scan this page. Š2014 Amgen Inc. All rights reserved. 80012-R2-V1

Our Roots Go Deep

The ASCO Post | SEPTEMBER 25, 2015

PAGE 60

Journal Spotlight Genitourinary Oncology

Statin Use at Start of Androgen-Deprivation Therapy Increases Time to Progression During Treatment of Prostate Cancer

By Matthew Stenger

S

tatin use has been associated with improved outcomes in prostate cancer. In a study reported in JAMA Oncology, Lauren C. Harshman, MD, of Dana-Farber Cancer Institute, Boston, and colleagues found that statin use at the time of the initiation of androgendeprivation therapy was associated with prolonged time to prostate-specific antigen (PSA) progression during androgen-deprivation therapy in men with hormone-sensitive prostate cancer.1 The mechanism of this effect may be the statin’s competitive inhibition of dehydroepiandrosterone sulfate uptake.

Impact of Statins on Prostate Cancer Therapy ■■ Statin use at the start of androgen-deprivation therapy was associated with significantly longer time to progression during androgendeprivation therapy.

■■ The effect of statins may be related to competitive inhibition of dehydroepiandrosterone sulfate uptake.

Potential Mechanism DHEAS is a precursor of testosterone that stimulates prostate cancer cell proliferation and a substrate for the organic anionic transporter SLCO2B1, which is also used by statins to enter cells. In studies in vitro in the 22RV1 (which has a relatively high level of SLCO2B1 expression) and LNCaP (which has a relatively low level of ­SLCO2B1 expression) prostate cancer cell lines, Xiaodong Wang, PhD, of the Kantoff Laboratory, found that statins blocked dehydroepiandrosterone sulfate uptake by competitively binding to SLCO2B1. The degree of uptake inhibition differed among statins within and between cell lines.

In cell proliferation studies, dehydroepiandrosterone sulfate significantly increased proliferation of LNCaP and 22RV1 cell lines that were maintained in androgen-depleted medium. Dehy-

droepiandrosterone sulfate-induced proliferation was inhibited by statin treatment and prevented by SLCO2B1 knockdown, with statin treatment producing no significant inhibition of SLCO2B1 knocked-down cell proliferation. The findings indicate that statin treatment can inhibit SLCO2B1-mediated dehydroepiandrosterone sulfate uptake and dehydroepiandrosterone sulfate–induced cell growth in androgen-dependent prostate cancer cell lines.

Our in vitro finding that statins competitively reduce dehydroepiandrosterone sulfate uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged [time to progression] in statin users.

—Lauren C. Harshman, MD, and colleagues

Study Details The retrospective analysis included 926 patients who had received androgen-deprivation therapy for biochemical or metastatic recurrence or new metastatic disease between January 1996 and November 2013 at DanaFarber Cancer Institute. Of them, 283 (31%) were taking statins at the start of androgen-deprivation therapy (“statin users”). Progression was defined as at least two increases in PSA level, with the date of progression defined as the date of first increase in PSA level (nadir plus ≥ 0.02 ng/mL).

In total, 93% of statin users continued statin use at the time of progression or at last follow-up. Among the 643 nonusers at the time of initiation of androgen-deprivation therapy, 72 started statin therapy while receiving androgen-deprivation therapy, with a median time of 24 months from androgen-deprivation therapy start to statin use.

Statin users had a lower median PSA level at diagnosis (9.1 vs 11.8 ng/mL) and at androgen-deprivation therapy initiation (10.3 vs 12.5 ng/mL) and a longer median duration from diagnosis to androgen-deprivation therapy initiation (3.85 vs 2.33 years). Moreover, statin users were more likely to have lower-stage disease (56% vs 44% T1 disease, P = .005), less likely to have de novo metastases (11% vs 18%, P = .01) or nodal involvement (5% vs 10%, P = .03) at diagnosis, more likely to have undergone local therapy (82% vs 68%, P < .001) or to have received androgen-

deprivation therapy as part of local therapy (33% vs 26%, P = .02), and less likely to have metastases at androgendeprivation therapy initiation (53% vs 63%, P = .005).

Prolonged Time to Progression After a median follow-up of 5.8 years, 644 patients (70%) had disease progression while receiving androgendeprivation therapy, with median time to progression during androgen-deprivation therapy being 20.3 months.

Median time to progression was 27.5 months (95% confidence interval [CI] = 21.1–37.7 months) in statin users vs 17.4 months (95% CI = 14.9–21.1 months) in nonusers (P < .001).

After adjusting for predefined prognostic factors including biopsy Gleason score, type of primary therapy, use of prior androgen-deprivation therapy along with localized therapy, metastatic status, and PSA level at initiation of androgen-deprivation therapy, statin use remained a significant predictor of reduced risk of progression (adjusted hazard ratio [HR] = 0.83, P = .04). The results were similar in analysis stratified by year of androgen-deprivation therapy initiation using 5-year increments (adjusted HR = 0.83, 95% CI = 0.69–0.99) and when the 72 patients who started using a statin during androgen-deprivation therapy were excluded from the nonuser group (adjusted HR = 0.71, 95% CI = 0.59–0.85).

A benefit of statin use was observed irrespective of whether patients had radiographic evidence of metastatic disease compared with biochemical relapse only at androgen-deprivation therapy initiation, with adjusted hazard ratios of 0.79 (95% CI = 0.58–1.07) for M0 disease and 0.84 (95% CI = 0.67–1.06) for M1 disease (P = .72 for interaction).

The investigators concluded: Statin use at the time of androgen-deprivation therapy initiation was associated with a significantly longer time to progression during androgen-deprivation therapy even after adjustment for known prognostic factors. Our in vitro finding that statins competitively reduce dehydroepiandrosterone sulfate uptake, thus effectively decreasing the available intratumoral androgen pool, affords a plausible mechanism to support the clinical observation of prolonged time to progression in statin users. n Disclosure: The study was supported by the Dana-Farber Prostate Cancer SPORE and Department of Defense. Dr. Harshman’s research is also supported by a Prostate Cancer Research Foundation Young Investigator Award.

For full disclosures of the study authors, visit oncology.jamanetwork.com.

Reference 1. Harshman LC, Wang X, Nakabayashi M, et al: Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormonesensitive prostate cancer. JAMA Oncol.

May 7, 2015 (early release online).

September is Prostate Cancer Awareness Month.

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 61

Announcements

MD Anderson Names Valerae O. Lewis, MD, Chair of Orthopaedic Oncology

V

alerae O. Lewis, MD, has been named Chair of Orthopaedic Oncology at The University of Texas MD Anderson Cancer Center. Dr. Lewis has been a faculty member at MD Anderson for 15 years, serving in a variety of roles. The unit she will lead, the Department of Orthopaedic Oncology, is a new department at MD Anderson, created within the Division of Surgery in 2014. She is the first woman to chair an orthopaedic department at a freestanding cancer center and in The University of Texas System.

Her efforts also have helped improve efficiency and increased access to MD Anderson’s orthopaedic clinical services. She has also played a major role in educational efforts at MD Anderson and within her field. Since 2002, she has served as Director of MD Anderson’s

Musculoskeletal Oncology Fellowship Program.

Dr. Lewis worked with colleagues in the Musculoskeletal Tumor Society to establish the educational standards for musculoskeletal oncology fellowships. Through the American

NOW ENROLLING

REFLECTIONS–

a clinical trial program created by Pfizer to investigate the potential biosimilarity of several products trastuzumab

rituximab

infliximab

adalimumab

CLINICAL TRIALS

METASTATIC BREAST CANCER Patients with HER2+ mBC who have not received prior therapy in the first-line setting with the exception of endocrine therapy

PF-05280014 + paclitaxel vs Herceptin® (trastuzumab) + paclitaxel in the first-line treatment of patients with HER2+ metastatic breast cancer (mBC)

Dr. Lewis is best recognized for her expertise in the complex surgical management of pelvic sarcomatrastuzumab and limb salvage for the pediatric patient.

Her past research has investigated the gene functions tied to osteosarcoma and the development of medications that might interrupt this process.

Service to MD Anderson Dr. Lewis joined MD Anderson in 2000. She has led MD Anderson’s orthopaedic oncology efforts since 2006, first as Section Chief ad interim and then as Section Chief adalimumab since rituximab infliximab 2008. She has served as Department Chair ad interim since September 2014. For more than 10 years, she also has served on the orthopaedic faculty at UTHealth and the Baylor College of Medicine. Dr. Lewis was named holder of the Dr. John Murray Professorship in Orthopaedic Oncology in 2010.

MD Anderson’s orthopaedic oncology group is the largest in the United States, made possible through Dr. Lewis’ successful recruitment efforts, which expanded the department from two to six faculty members. The department is renowned for its expertise in saving limbs impacted by cancer, the treatment of metastatic diseases, and the management of pelvic and spinal sarcoma patients.

In addition to Dr. Lewis’ clinical efforts, she has focused on enhancing safety and improving patient outcomes.

bevacizumab

STUDY DESIGN

B327-02

Valerae O. Lewis, MD

Academy of Orthopaedic Surgeons, she has helped shape educational opportunities for orthopaedic surgeons in the United States. Dr. Lewis has served a pivotal role in developing a curriculum to facilitate culturally competent care. n

Target enrollment: 690 patients

A global, phase 3, comparative clinical trial evaluating the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-05280014, an investigational compound being studied as a potential biosimilar to Herceptin.

• Primary endpoint: objective response rate (ORR) • NCT01989676

rituximab

infliximab

1:1 randomization double-blind

adalimumab

bevacizumab PF-05280014 + paclitaxel

B328-06

trastuzumab + paclitaxel

FOLLICULAR LYMPHOMA

PF-05280586 vs Rituxan®/MabThera (rituximab) for the first-line treatment of patients with CD20-positive, low tumor burden follicular lymphoma (LTB-FL)

Patients with LTB-FL who have not received prior therapy in the first-line setting Target enrollment: 394 patients

A global, phase 3, comparative clinical trial evaluating the efficacy, safety, PK, and immunogenicity of PF-05280586, an investigational compound being studied as a potential biosimilar to Rituxan/MabThera.

1:1 randomization double-blind

• Primary endpoint: ORR • NCT02213263

PF-05280586

bevacizumab

rituximab

ADVANCED NON-SQUAMOUS NSCLC

B73910-03

Eligible patients with advanced non-squamous NSCLC who have not received prior therapy in the first-line treatment setting and who are eligible to receive carboplatin/paclitaxel/bevacizumab

PF-06439535 + paclitaxel and carboplatin vs Avastin® (bevacizumab) + paclitaxel and carboplatin in the firstline treatment of patients with advanced non-squamous NSCLC

Target enrollment: 798 patients

A global, phase 3, comparative clinical trial evaluating the efficacy, safety, PK, and immunogenicity of PF-06439535, an investigational compound being studied as a potential biosimilar to Avastin.

1:1 randomization double-blind

• Primary endpoint: ORR • NCT02364999

PF-06439535 + paclitaxel and carboplatin

bevacizumab + paclitaxel and carboplatin

PF-05280014, PF-05280586, and PF-06439535 are investigational compounds.

For more information about these trials, including secondary endpoints and eligibility criteria, please visit: www.pfizercancertrials.com and www.clinicaltrials.gov or call the Pfizer clinical trial call center at 1-800-718-1021.

BIO752800-01

© 2015 Pfizer Inc.

This information is current as of April 2015.

HER2=human epidermal growth factor receptor 2; NSCLC=non-small cell lung cancer.

Herceptin® is a registered US trademark of Genentech Inc. Rituxan® is a registered US trademark of Biogen Idec Inc. MabThera is a trademark of F. Hoffmann-La Roche AG. Avastin® is a registered US trademark of Genentech, Inc.

All rights reserved.

April 2015

The ASCO Post | SEPTEMBER 25, 2015

PAGE 62

Geriatrics for the Oncologist

ASCO 2015: Geriatric Oncology Highlights

By Amy MacKenzie, MD, and Andrew Chapman, DO, FACP

T

he theme of the 2015 ASCO Annual Meeting, Illumination and Innovation, is especially appropriate as we consider the field of geriatric oncology.

For too long, the elderly cancer patient has remained in the dark regarding treatment planning, clinical trial enrollment, and shared decision-making.

Our nation is aging; with that will come

awareness of the unique needs of this population and the efforts to expose all oncologists to the critically relevant aspects of geriatric oncology. In addition to presentations devoted to geriatric oncology, sessions were designed to highlight these critical issues to enable providers and researchers to better understand and identify geriatric needs at

Given the projected ‘silver oncologic tsunami,’ it is crucial that the most relevant aspects of senior adult oncology reach as wide an audience as possible.

—Amy MacKenzie, MD, and Andrew Chapman, DO, FACP

sessions addressed the issues of surgery in the older ovarian cancer patient and the older breast cancer patient.

Older women with ovarian cancer have a higher percentage of late-stage and aggressive disease. Although this may simply be a factor of biologic age, elderly women are less likely to be seen by a gynecologic oncologist.2 Thus, the opportunity for a clinically meaningful surgery in a nonemergent setting often is not made available to the older woman.

The question of whether or not poor prognosis is a result of age bias is an important one. Assessment of functional reserve, in addition to recognition of age, is an essential preoperative step in older women. PACE, the preoperative assessment in elderly cancer patients, uses a comprehensive geriatric assessment plus a brief fatigue inventory to assess fitness for surgery and to identify potential postoperative needs.

Chemotherapy Tolerance

a greater number of senior adult oncology patients in need of individualized care plans and a specialized approach to treatment. The gap exists across all cancer types that affect the older patient, and, as such, every oncologist needs to be familiar with the needs of the geriatric patient.

This year’s annual meeting demonstrated ASCO’s increasing Dr. MacKenzie is Assistant Professor and Dr. Chapman is Clinical Professor, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

all points on the cancer continuum. Given the projected “silver oncologic tsunami,” it is crucial that the most relevant aspects of senior adult oncology reach as wide an audience as possible.

Fitness for Surgery Fitness for surgery in the older patient is a topic that has been covered in the literature over the past several years.1 Older patients are often not taken to elective surgery based on chronologic age alone, potentially leaving fit patients without a surgical option. Two important

Addressing a patient’s ability to tolerate chemotherapy is a vital skill for all oncologists but particularly when treating older patients, given the greater potential for adverse reactions with a narrower margin for error. An oncologist’s ability to predict toxicity to chemotherapy is frequently based on the assessment of performance status; however, this does not always capture information that might be relevant to chemotherapy tolerance.

Chemotherapy administration in the older patient with a solid tumor was addressed in several sessions at the Annual Meeting. The key message delivered is that oncologists are in need of tools to better assess elderly patients prior to chemotherapy.

A number of chemotherapy toxicity scores that can add to the oncologist’s ability to formulate an individualized

GUEST EDITOR

Stuart M. Lichtman, MD

G

eriatrics for the Oncologist is guest edited by Stuart M. ­Lichtman, MD, and developed in collaboration with the International Society of Geriatric Oncology (SIOG). Dr. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of SIOG. Visit www.siog.org for more on geriatric oncology. treatment plan are available for use.

William Tew, MD, of Memorial Sloan Kettering Cancer Center, New York, discussed the CARG (Cancer and Aging Research Group) toxicity score3 in his talk on clinical trials in the elderly. Martine Extermann, MD, of Moffitt Cancer Center, Tampa, Florida, discussed both the CARG score and the score developed by her and her colleagues: the CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score.4 Both of these tools are available online [mycarg.org] and can help to predict potential toxicity risk from the use of chemotherapy in a patient with cancer.

For more information, visit http://www.siog.org

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 63

Geriatrics for the Oncologist ‘Staging the Aging’ The perspective of the geriatrician is a key component in care of the elderly patient with cancer. Miriam Rodin, MD, PhD, geriatrician at St. Louis University, posed five key questions on “staging the aging” that are vital for all oncologists to incorporate in decision-making: 1) What is the impact of functional status on remaining life expectancy?

2) What is the impact of comorbidity on remaining life expectancy?

3) What is the likely outcome of treating this cancer?

4) Would successful treatment lead to increased overall survival, or does the risk of treatment decrease the quality of life for the remaining life expectancy?

5) How does the patient value the length vs the quality of life?

Keeping these points in the patientprovider discussion is essential when making decisions that value the patientcentered model of care. Our current models of care do not routinely take these issues into account when considering treatment. We, as providers, must begin to incorporate these questions into our conversations with senior adult oncology patients if we are going to provide patient-centered care that is meaningful to each individual patient.

‘Geriatricizing’ Clinical Trials The future improvement of geriatric oncology–based care relies heavily on the development of clinical trials specifically for older patients with cancer as well as the enrollment of senior patients on existing clinical trials. All trials need to address questions relevant to this subset of patients, as their preferences and needs may differ markedly from those of their younger counterparts.

The role of geriatric oncology in clinical trials was addressed at the Annual Meeting by Stuart M. Lichtman, MD. Elderly patients have often been excluded from trials, leaving few to no data for patients over the age of 80. Studies are urgently needed to study differences both within the elderly population and between the elderly and younger patients.

Innovative trial design and endpoints relevant to the geriatric population are critical issues that need to be incorporated into clinical trials going forward. There is an urgent need to expand datasets that reflect the patient population with the disease at hand—the senior adult. In short, clinical trials need to be “geriatricized” to better meet the needs of the growing elderly cancer population.

All oncologists have the potential to improve the care of the geriatric patient with cancer. This can be accomplished

with better education for the growing oncologic workforce in the specific needs of the geriatric patient, as well as through team-based cancer care delivery. ASCO has recognized the value of providing excellent, individualized care to our senior adult oncology patients. The oncologic silver tsunami is spotlighting the need to bring this specialized treatment planning

and care to all elderly cancer patients. n

Disclosure: Drs. MacKenzie and Chapman reported no potential conflicts of interest.

References 1. Audisio RA, et al: Shall we operate?

Preoperative assessment in elderly cancer patients (PACE) can help. Crit Rev Oncol Hematol 65:156-163, 2008.

2. Alphs HH, et al: Predictors of surgical

outcome and survival among elderly women diagnosed with ovarian and primary peritoneal cancer. Gynecol Oncol 103:1048-1053, 2006.

3. Hurria A, et al: Predicting chemotherapy toxicity in older adults with cancer. J Clin Oncol 29:3457-3465, 2011.

4. Extermann M, et al: Predicting the risk of chemotherapy toxicity in older patients.

Cancer 118:3377-3386, 2012.

In EGFRm+ advanced NSCLC,

NEARLY 2 OUT OF 3 CASES OF PROGRESSION WITH FIRSTGENERATION EGFR TKIs ARE RELATED TO THE T790M MUTATION1,2 Lung cancer is the leading cause of cancer-related deaths both in the US and worldwide.3,4 For NSCLC EGFRm+ patients, the recommended frst-line treatment is EGFR tyrosine kinase inhibitors (TKIs).5

The majority of tumors will acquire EGFR TKI–resistance mutations Despite initial high response rates with frst-generation EGFR TKIs, many tumors will develop new mutations and become resistant.6,7 A major barrier to disease control is resistance to treatment. Resistance to frst-generation therapy will develop in most patients with EGFRm+ advanced NSCLC on a currently approved EGFR TKI.7 After disease progression, clinical guidelines recommend subsequent treatments including either continuing with an EGFR TKI therapy or beginning platinum-based chemotherapy.5

Nearly 2 out of 3 cases of progression with first-generation EGFR TKIs are related to the T790M mutation In patients with NSCLC who are EGFRm+, T790M is an acquired mutation and has been identifed as the most common mechanism of acquired resistance in nearly 2 out of 3 patients.1,2 Development of T790M mutation may confer resistance through several potential mechanisms, which may include8,9: - Steric hindrance, which reduces receptor binding of reversible EGFR TKIs - Increased binding affnity of EGFR for ATP, resulting in reduced TKI potency

T790M Is the Most Common Mechanism of Acquired Resistance to First-Generation EGFR TKI Therapy1

63%

T790M (98/155)

CI, (9555 –70 ) %

%

MET amplifcation (4/75)

5% (95% CI, 1%–13%)

HER2 amplifcation (3/24)

NEARLY 2 OUT OF 3

%

13% (95% CI, 3%–32%)

0%

10% 20% 30% 40% 50% 60% 70%

Study of 155 patients with radiographic progression following a response or durable stable disease with frst-generation EGFR TKI therapy.

CASES ARE RELATED TO T790M

Other rare mechanisms of acquired resistance may include BRAF, FGFR, and PIK3CA mutations, and transformation to small-cell histology.10,11

Discovering the cause of resistance Patients should be monitored for radiologic or clinical progression. Tumors can also be assessed for molecular progression to uncover additional acquired mutations.1,12-16 When patients with EGFRm+ status progress, prior to changing therapy, a biopsy is reasonable to identify mechanisms of acquired resistance, as stated in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).5

AstraZeneca is a leader in lung cancer research AstraZeneca is conducting ongoing research to understand the science of the T790M mutation as a driver of resistance.

Find out more at EGFRevolution.com.

References: 1. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 2. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 3. American Cancer Society.

Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed March 17, 2015. 4. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.7.2015. ©National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed June 12, 2015. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Mok TS, Wu YL, Thongprasert S, et al. Geftinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 7. Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334. 8. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to geftinib. N Engl J Med. 2005;352:786-792. 9. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affnity for ATP. Proc Natl Acad Sci U S A. 2008;105:2070-2075. 10. Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369. 11. Ware KE, Marshall ME, Heasley LY, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One. 2010;5:e14117. doi:10.1371/journal.pone.0014117.12. Johnson KR, Ringland C, Stokes BJ, et al. Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet. 2006;7:741-746. 13. Lussier YA, Khodarev NN, Regan K, et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specifc microRNAs. PLoS One. 2012;7:e50141. doi:10.1371/journal.pone.0050141. 14. Jackman DM, Miller VA, Cioffredi, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non–small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res. 2009;15:5267-5273. 15. Noronha V, Joshi A, Gokarn A, et al. The importance of brain metastasis in EGFR mutation positive NSCLC patients. Chemother Res Pract. doi:10.1155/2014/856156. 16. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. ©2015 AstraZeneca. All rights reserved. 3140404 6/15

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Physiatry in Oncology Why It Is Important to Have a Physiatrist on a Cancer Care Team

By Sean Smith, MD

P

hysical medicine and rehabilitation in oncology care explores the benefits of cancer rehabilitation in oncology clinical practice to screen survivors for physical and cognitive impairments along the care continuum to minimize survivors’ disability and maximize their quality of life.

According to a report from the American Cancer Society,1 studies show that multidisciplinary cancer rehabilitation—which often involves a team of rehabilitation professionals that includes physiatrists, physical therapists, occupational therapists, speech-language pathologists, and rehabilitation nurses—improves pain control, physical and cognitive function, and overall quality of life in cancer survivors. Yet, despite the proven benefits of cancer rehabilitation, the discipline is often underutilized in oncology care or is recommended after there is decline in a patient’s physical or mental function.

earlier intervention and less symptom burden. As experts in musculoskeletal and neurologic conditions, physiatrists are able to assess pain, weakness, restrictions, and more to determine both a diagnostic workup and a treatment plan. This is an asset that should be incorporated into the multidisciplinary care of oncology patients.

When to Use Imaging and Other Tests for Cancer Pain Physiatrists receive extensive training in the assessment of the musculoskeletal system, and during a patient’s physical exam, they can pick up impairment subtleties an oncology provider might miss. Musculoskeletal dysfunction, including pain, occurs frequently in patients with cancer and can cause both the patient and the provider to worry that the cancer has returned or spread, possibly leading to unnecessary tests and procedures. In fact, many of the aches and pains patients experience

Physiatrists receive extensive training in the assessment of the musculoskeletal system, and during a patient’s physical exam, they can pick up impairment subtleties an oncology provider might miss.

—Sean Smith, MD

Physical medicine and rehabilitation physiatrists specialize in the prevention, diagnosis, and treatment of disorders related to the nerves, muscles, bones, and brain that may lead to temporary or permanent impairment and should be utilized to diagnose conditions as they arise, which could lead to Dr. Smith is Director of the Cancer Rehabilitation Program at the University of Michigan Department of Physical Medicine & Rehabilitation in Ann Arbor, Michigan.

are not directly related to malignancy and can be managed as they would in a person without a history of cancer.

Physiatric evaluation may obviate the need for extensive testing or lead to more precise tests being ordered, saving time, reducing costs, and potentially resulting in fewer invasive diagnostic procedures that often carry risks of complications.

The need for imaging and other diagnostic tests continues to be evaluated, but evidence suggests that musculoskel-

Physiatric Evaluation in Cancer Care ■■ Physiatrists should be utilized for patients with musculoskeletal and neurologic diagnostic challenges.

■■ Ultrasonography can be used in the clinic to diagnose and help manage musculosketetal impairments in real time.

■■ EMG can be used for diagnosis and to guide management decisions, and many physiatrists are board-certified in electrodiagnostic medicine.

■■ Physiatrist evaluation of symptoms such as pain, weakness, and joint restriction can lead to prompt diagnosis and early intervention and improve the quality of life for cancer survivors.

etal issues lead to some level of unnecessary testing.2,3 Certainly, surveillance scans are essential in the continuum of patient care, but in-clinic symptoms can be assessed by a physiatrist, which may lead to quicker and more effective treatment as well as reassurance for both patients and oncologists.

Here is how physiatric evaluation of the musculoskeletal and neurologic systems may reduce the need for extensive testing.

Musculoskeletal Expertise Using their extensive experience in treating musculoskeletal disorders, physiatrists consider a patient’s cancer diagnosis and treatment to determine the etiology of a specific impairment.

For example, a patient who maintains a sedentary lifestyle while receiving chemotherapy will likely develop muscle atrophy and possibly hip pain. A physiatrist can discern whether this pain is consistent with bursitis/tendinopathy, osteoarthritis (or avascular necrosis in the setting of high-dose glucocorticoid administration), pelvic dysfunction, or a labral tear and whether the patient’s symptoms require further testing. A provider unfamiliar with hip joint pathology may order expensive and unnecessary tests in this setting, when, in fact, a diagnosis can be made clinically.

In addition to conducting a thorough musculoskeletal physical exam to evaluate problems, physiatrists will frequently use musculoskeletal ultrasound for diagnostic and therapeutic purposes, which can result in earlier intervention, increased patient satisfaction, and elimination of the need for more costly imaging studies. Besides providing information to help physiatrists assess a patient for bursitis or tendinopathy, for example, the test can be used to guide an intra-articular hip joint injection.

Ultrasonography will also reveal any intramuscular metastatic lesions, which would require additional studies to fully assess and would be coordinated with members of the oncology team to implement.

Physiatrists are also expert in evaluating spine pain, which is prevalent in patients with cancer and may be related to the cancer or caused by other factors.

Differentiating among radiculopathy, peripheral mononeuropathy, and myelopathy pain can be challenging, but accurately evaluating the problem can help determine whether additional

GUEST EDITOR

Sean Smith, MD

P

hysiatry in Oncology explores the benefits of cancer rehabilitation in oncology clinical practice to screen survivors for physical and cognitive impairments along the care continuum to minimize survivors’ disability and maximize their quality of life. The column is guest edited and occasionally written by Sean Smith, MD, Director of the Cancer Rehabilitation Program at the University of Michigan Department of Physical Medicine and Rehabilitation in Ann Arbor. studies are needed to guide treatment.

Physiatrists can also assess spinal stability in the setting of metastatic disease and may recommend treatment or surgical referral.

Electrodiagnostic Medicine Many physiatrists are Board certified in both Physical Medicine and Rehabilitation and Electrodiagnostic Medicine and can diagnose neuromuscular disorders through electromyography (EMG). Examples of the utility of EMG in patients with cancer include determining whether limb pain is related to radiculopathy, confirming a diagnosis of chemotherapy-induced peripheral neuropathy, monitoring chemotherapy toxicity, and even assessing the severity of routine disorders like carpal tunnel syndrome to guide treatment. Repeating studies can monitor a patient’s recovery or decline, and whether an EMG shows a pattern not expected in a typical recovery, a physiatrist may investigate the problem with different modalities.

Electromyography is an extension of a physiatrist’s physical examination and can determine whether there is neuromuscular damage, where the lesion or lesions are located, how chronic the problem is, and whether further test-

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 65

Physiatry in Oncology ing may assist in the diagnostic process.

Electromyography can also be used to monitor side effects from chemotherapy and may lead to treatment adjustment, improving patients’ quality of life.

Reducing Symptom Burden A protocol known as the Prospective Surveillance Model evaluates patients prior to treatment, during chemotherapy administration, and as symptoms develop, with the goal of reducing symptom burden through early intervention.4 Electrodiagnostic evaluation can predict the development of neuropathy with different chemotherapeutic agents,5-7 and coordination between the medical oncology team and a physiatrist can help limit toxicity and symptom burden.

Even if chemotherapy dosing is not titrated downward based on electrodiagnostic studies, interventions such as proactively increasing neuropathic pain medication, providing durable medical equipment for safe ambulation, engaging in a balance and strengthening program, and patient education can be initiated.

Electromyography can also diagnose myriad other processes, including myopathies, paraneoplastic syndromes, or neuropathic processes unrelated to chemotherapy. Once these disease processes are diagnosed, interventions can be used to minimize functional decline. n References 1. Silver JK, Baima J, Mayer RS: Impairment-driven cancer rehabilitation: An essential component of quality care and survivorship. CA Cancer J Clin 63:295-317, 2013.

2. Miller BJ, Avedian RS, Rajani R, et al: What is the use of imaging before referral to an orthopaedic oncologist? A prospective, multicenter investigation. Clin Orthop Relat Res 473:868-874, 2015.

3. Lavery HJ, Brajtbord JS, Levinson AW, et al: Unnecessary imaging for the staging of low-risk prostate cancer is common.

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

Urology 77:274-278, 2011.

4. Stubblefield MD, McNeely ML, Alfano CM, Mayer DK: A prospective surveillance model for physical rehabilitation of women with breast cancer: Chemotherapy-induced peripheral neuropathy. Cancer 118(8 suppl):2250-2260, 2012.

5. Velasco R, Bruna J, Briani C, et al: Early predictors of oxaliplatin-induced cu-

mulative neuropathy in colorectal cancer patients. J Neurol Neurosurg Psychiatry 85:392-398 2014.

6. Argyriou AA, Polychronopoulos P, Iconomou G, et al: Paclitaxel plus carboplatin-induced peripheral neuropathy: A prospective clinical and electrophysiological study in patients suffering from solid malignanciesstu. J Neurol 252:1459-1464, 2005.

7. Stubblefield MD, Slovin S, MacGregor-Cortelli B, et al: An electrodiagnostic evaluation of the effect of pre-existing peripheral nervous system disorders in patients treated with the novel proteasome inhibitor bortezomib. Clin Oncol (R Coll Radiol) 18:410-418, 2006.

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

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Cancer Stem Cells and Their Role in Recurrence and Metastasis Despite current advances in cancer therapy, tumor recurrence and metastasis remain a clinical challenge.1 Cancer stem cells are a subset of the total cancer cell population that is highly tumorigenic.2,3 Chemotherapy and radiation have been shown to affect the primary tumor, but not the cancer stem cell.4 Many patients with cancer, even though diagnosed early, succumb to the disease because of recurrence and metastasis.5,6 Cancer stem cells are thought to contribute to this recurrence and metastasis.7

Boston Biomedical is developing the next generation of cancer therapeutics with drugs designed to inhibit cancer stem cell pathways. Clinical trials are underway with the goal of reducing recurrence and metastasis.

Another characteristic of cancer stem cells is that they possess stemness. Stemness distinguishes cancer stem cells by their ability to continually self-renew, differentiate into cancer cells, migrate, and regrow the tumor.7,8 Most chemotherapeutic strategies target actively proliferating cancer cells, resulting in bulk tumor shrinkage. Cancer stem cells, however, are highly resistant to these therapies and may not be eradicated during treatment, resulting in recurrence and metastasis.4,7 Moreover, chemotherapy and radiation have the potential to induce stemness properties in non-stem cancer cells.2,9 Several signaling pathways are involved in the induction and maintenance of stemness in cancer stem cells, including JAK/ STAT, Wnt/β-catenin, Hedgehog, Notch, and Nanog.10-12 Targeting these aberrant signaling pathways may result in cancer stem cell apoptosis, while reducing the toxicity to normal tissues that is associated with chemotherapy.4

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Learn more at www.bostonbiomedical.com References: 1. Li Y, Rogoff HA, Keates S, et al. Supression of cancer relapse and metastasis by inhibiting cancer stemness.

Proc Natl Acad Sci. 2015;112(6):1839-1844. 2. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer stemness by chemotherapy.

Cell Cycle. 2012;11(14):2691-2698. 3. Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant. 2005:11(2 suppl 2):14-16. 4. Boman BM, Huang E. Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol.

2008;26(17):2828-2838. 5. Ahmad A. Pathways for breast cancer recurrence. ISRN Oncol. 2013;2013:290568. doi: 10.1155/2013/290568.

6. Hung JH, Wu YC. Stage I non-small cell lung cancer: recurrence patterns, prognostic factors and survival. In: Cardoso P, ed. Topics in Thoracic Surgery. Shanghai, China: InTech; 2012:285-292. http:// www.intechopen.com/books/topics-in-thoracic-surgery/stage-inon-smallcell-lung-cancer-recurrence-patterns-prognostic-factorsand-survival. Accessed May 8, 2015. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261.

8. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 9. Ghisolfi L, Keates AC, Hu X, Lee D, Li CJ. Ionizing radiation induces stemness in cancer cells.

PLOS ONE. 2012;7(8):1-11. 10. Hoffmeyer K, Raggioli A, Rudloff S, et al. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-1554. 11. Bourguignon LYW, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149160. 12. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. Notch signaling: targeting cancer stem cells and epithelial-tomesenchymal transition. Onco Targets Ther. 2013;6:1249-1259.

The ASCO Post | SEPTEMBER 25, 2015

PAGE 66

Book Review

Microbes by the Trillions

By Ronald Piana

“A

s I walked back through the forest that night in the summer of 2005, with twenty bats in cotton bags hanging around my neck and all manner of insect life dashing for the light of my torch, I realized my ankles were itching.” How can a reader resist a book with such an arresting opening? One can’t, and the good news is that it gets better all the way to the last page.

The book is called 10% Human: How Your Body’s Microbes Hold the Key to Health and Happiness and is ostensibly about the 100 trillion or so microbes that make up the other 90% of us. But it is much more than a book about microbes. It’s about us, the human beings they occupy for better or for worse.

rounds collecting bats. But something had got through the barrier of fabric and chemicals protecting my skin.

Something itchy.”

Returning to base camp, Ms. Collen pealed back the layers of clothing to reveal 50 or so ticks that were embedded in her skin. She cocooned herself in a sleeping bag and by lamplight wrenched the ticks out with tweezers: one tough woman. Months later, back in London, the tropical infection introduced by the ticks took hold, bringing her to the brink of death. Weird symptoms came and went, her body would suddenly seize up, her feet would swell, and she had bouts of debilitating fatigue and pain.

When she was finally diagnosed years

I was given a dose of antibiotics long and intense enough to cure a herd of cattle. I learnt just how much I needed the 100 trillion friendly little creatures who had, until recently, called my body their home.

—Alanna Collen

The author, biologist Alanna Collen, draws on the latest scientific research to show how our personal colony of microbes influences our weight, our immune system, our mental health, and even the partner we choose. That’s a pretty big bite of ideas and information to chew and swallow, but this skilled author makes it work.

A Life-Changing Experience The idea for 10% Human, in part, was planted by the author’s life-changing experience. During work for her biology degree, Ms. Collen became fascinated with bats and grabbed an opportunity to study bats in a Malaysian wildlife preserve. She was soon to learn that the trials of life in a tropical rain forest could live far beyond the experience itself.

She writes, “The humidity and drenching sweats, the muddy trails, my fear of tigers, and the mosquitos were enough to contend with as I made my

later, she writes, “I was given a dose of antibiotics long and intense enough to cure a herd of cattle.” The antibiotics cured Ms. Collen, but they also stripped her body not only of the bad bacteria, but also of those that belonged in her.

“My skin was raw and I was prone to picking up every infection going. I felt I’d become inhospitable to microbes, and I learnt just how much I needed the 100 trillion friendly little creatures who had, until recently, called my body their home,” writes Ms. Collen.

Make no mistake, 10% Human is serious science writing and covers important public health issues. In fact, Ms. Collen argues quite persuasively that many of our modern diseases have their root in our failure to cherish our most fundamental and enduring relationship: that with our personal colony of microbes. Moreover, according to Ms. Collen, this relatively new line of inquiry elucidates many of the questions

about modern diseases left unanswered by the Human Genome Project.

Satisfying on Every Level A central challenge for science writers is to deal with heady scientific subjects in a way that is accessible and fun to read. People who read this kind of science book want to come away better informed and intellectually challenged by the content, but they don’t want to slog through run-on sentences full of scientific jargon.

Ms. Collen’s book satisfies on every level. And one reason is her devotion to the attention-grabbing opening, as evidenced by the start of chapter one, titled Twenty-First Century Sickness. “In September 1978, Janet Parker became the last person on Earth to die of smallpox.” Bang!

She then treats the reader to a firstrate trip back in time, when there were “wards crammed full of sick and dying, wounds left open and rotting, and doctor’s coats covered in blood and gore after surgeries.”

After a fascinating history of the days when nasty microbes ran amok, the author discusses a theme that she threads throughout the book: the relationship of the gut and the immune system in the etiology of a variety of chronic diseases.

She also makes a solid case for the rise of environmentally driven conditions such as asthma.

The ASCO Post readers may take issue with Ms. Collen’s downplaying the role of genetics in a host of autoimmune diseases, but she lays her therapies without sounding pedantic. Ms. Collen puts a lot of stock in what we put in our bodies and how we nurture or antagonize our microbes. She writes, “Despite all the hype, our human genome did not quite live up to our visions of becoming a blueprint for life and a philosophy for living…. For the first time, Darwin’s theory of evolution and our other 90 microbial percent are showing us the way to live.”

Moreover, she never stops at simply reporting the outcome of a given experiment or data set. For example, instead of jumping to the logical conclusion

Bookmark Title: 10% Human: How Your Body’s Microbes Hold the Key to Health and Happiness Author: Alanna Collen Publisher: Harper Collins Publication date: April 27, 2015 Price: $39.99; hardcover, 400 pages that higher worldwide fat and sugar consumption has led directly to the obesity crisis, she steps outside the box and asks whether the trouble is what we’re eating or what we’re not eating.

If fat and sugar calories have displaced microbe-friendly foods like high-fiber vegetables, she notes, the body’s biome has likely also changed.

Ms. Collen’s book about microbes and public health issues moves around the globe, never lacking for interesting topics to highlight her theses. For example, in a chapter titled From the Very First Breath, she begins in Australia, where a koala joey is transitioning from feeding solely on mother’s milk to a diet of eucalyptus leaves.

The problem is that the mammalian

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 67

Book Review

genome is not equipped to produce enzymes necessary to produce anything of worth from eucalyptus leaves: Microbes and mother koala to the rescue.

Via her saliva, the mother koala delivers a secretion of a predigested eucalyptus leaf to her offspring; once taken in his gut, the joey has its own army of microbes to make eucalyptus edible. This

is one of her strongest chapters and the most science-heavy, dealing with oligosaccharides, live bacteria, hormones, and gut microbiota, all woven into a convincing argument for natural birthing practices and early health practices.

Ending Messages The ending messages of the book at

times run to preachy, a minor flaw in such an accomplished and well-written book. Ms. Collen speaks with the authority of a person who nearly died of an infection and then had her body realtered into a walking infection magnet due to the massive doses of microbekilling antibiotics needed to save her.

This is a valuable book, because it deals

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with large-scale public health issues in a charmingly written format.

Ms. Collen leaves with an important message: “Antibiotics gave me back a quality of life I feared I’d lost, but along the way, they took me places I’d never experienced and I wouldn’t hesitate to take them if my life were in danger, but if I had the option to wait and see if my immune system might deal with it on its own, I would.”

10% Human is a page-turner that will leave science-loving readers wishing for more. It is strongly recommended for The ASCO Post reader. n

Don’t Miss These Important Reports in This Issue of The ASCO Post

To receive your complimentary print copy of THE ASCO POST, go to www.ascopost.com/subscribe or call the Circulation Department at (631) 935-7651 to see if you qualify.

Get up-to-date information on: n

Highly validated coverage of cancer research & policy news

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Patient care & clinical practice issues

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Evidence-based research from peer-reviewed clinical journals

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Reports on major oncology meetings worldwide

n

News from the National Institutes of Health, the National Cancer Institute, the US Food & Drug Administration and the US Congress

Christopher Flowers, MD, MS, on Autologous Stem Cell Transplantation in Mantle Cell Lymphoma see page 9

Nabil Saba, MD, on the Omission of Chemotherapy in Some HPV-Positive Head and Neck Cancers see page 18

For more on prostate cancer, visit ASCOPost.com

The ASCO Post | SEPTEMBER 25, 2015

PAGE 68

2015

2015 Oncology Meetings October

Advances in Cancer ImmunotherapyTM October 2 • Nashville, Tennessee For more information: www.sitcancer.org/sitc-meetings/ aci2015/tn Institute for Clinical ImmunoOncology (ICLIO) 1st Annual National Conference October 2 • Philadelphia, Pennsylvania For more information: http://accc-iclio.org/events/iclio-1stannual-national-conference/ 5th International Breast Cancer Prevention Symposium October 2-3 • Le Gosier, Guadeloupe, French West Indies For more information: www.purdue.edu/breastcancer/ CAP ’15-The Pathologists’ MeetingTM (College of American Pathologists) October 4-7 • Nashville, Tennessee For more information: www.thepathologistsmeeting.org American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/meetings_events/ future_congress/future

http://cmeregistration.hms.harvard. edu/events/30th-anniversaryannual-critical-issues-in-tumormicroenvironment-angiogenesismetastasis-and-immuno/ event-summary-567a0dd5664947b09 6f8a5fd33946e52.aspx 20th World Congress on Advances in Oncology and 18th International Symposium on Molecular Medicine October 8-10 • Athens, Greece For more information: www.spandidos-publications.com/ pages/conference Congress of the International Society of Pediatric Oncology October 8-11 • Cape Town, South Africa For more information: http://siop2015.kenes.com Palliative Care in Oncology Symposium October 9-10 • Boston, MA For more information: http://pallonc.org Genetics and Genomics of Gynecologic Cancers October 15-16 • New York, New York For more information: https://www.mskcc.org/event/ genetics-and-genomics-gynecologic National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies™ October 16-17 • San Francisco, California For more information: www.nccn.org/professionals/ meetings/hematological/default. aspx

5th Annual Brain Tumor Symposium October 5 • Philadelphia, Pennsylvania For more information: https://cme.jefferson.edu/ content/5th-annual-brain-tumorsymposium 30th Anniversary Annual Critical Issues in Tumor Microenvironment: Angiogenesis, Metastasis, and Immunology October 5-8 • Cambridge, Massachusetts For more information:

ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org/Meetings-andEvents/2015-Annual-Meeting/Index. aspx

2015 International Cancer Education Conference October 21-23 • Tucson, Arizona For more information: http://2015.attendicec.org ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp

AACI/CCAF Annual Meeting October 25-27 • Washington, DC For more information: http://www. aaci-cancer.org/annual_meeting/ Modern Management of Urologic Cancers: A Multidisciplinary Approach (Memorial Sloan Kettering) October 29-31 • New York, New York For more information: http://www. themerzgroup.com/mskcc/mskccurologic-conference/ Lynn Sage Breast Cancer Symposium October 29-November 1 • Chicago, Illinois For more information: www.lynnsagebreastcancer.org

Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies October 22-24 • New York, New York For more information: http://www.imedex.com/lymphomamyeloma-conference/index.asp Cutaneous Oncology Symposium 2015 October 23-24 • Fernandina Beach, Florida For more information: https:// ce.mayo.edu/hematology-andoncology/node/3306

Caring for the Caregivers X October 30 • Waltham, MA For more information: http://www.massmed.org Continuing-Education-and-Events/ Event-Information/?code=CFC2015

November NRCI Cancer Conference November 1-4 • Liverpool, United Kingdom For more information: http://conference.ncri.org.uk

4th Annual New Therapeutics in Oncology: The Road to Personalized Medicine October 23-25 • Los Angeles, CA For more information: https:// www.regonline.com/builder/ site/?eventid=1727722 13th Annual West Coast Colorectal Cancer Symposium October 23 • Seattle, Washington For more information: http:// www.swedish.org/for-healthprofessionals/cme/conferences/ colorectal-cancer-symposium

3rd International Conference on Hematology & Blood Disorders November 2-4 • Atlanta, Georgia For more information: http:// hematology.conferenceseries.com

53rd Annual Meeting of the Japan Society of Clinical Oncology (JSCO) October 24-26 • Kyoto, Japan For more information: www.jsco. or.jp/english/index/page/id/73

Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting November 4-8 • National Harbor, Maryland For more information: www.sitcancer.org/2015

ESGO 2015-International Meeting of the European Society of Gynaecological Oncology October 24-27 • Nice, France For more information: http://esgo2015.esgo.org

33rd Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® November 4-6 • New York, New York For more information: http://www.chemotherapyfoundationsymposium.org/CMS/

continued on page 70

Atezolizumab (MPDL3280A): an investigational, engineered anti-PDL1 antibody

CURRENTLY ENROLLING Clinical trials in various tumor types for atezolizumab (MPDL3280A)* Trials for atezolizumab (MPDL3280A), an investigational anti-PDL1 antibody, are currently recruiting patients in various tumor types †: • Kidney

• Bladder — NCT02302807 (Ph III) — NCT02450331 (Ph III)

• Breast — NCT02425891 (Ph III)

• Colorectal — NCT02291289

• Hematologic malignancies — NCT02431208 — NCT02220842

• Melanoma — NCT01656642

— NCT02420821 (Ph III)

• Lung

• Solid tumors

— NCT02486718 (Ph III) — NCT02409355 (Ph III) — NCT02409342 (Ph III) — NCT02367794 (Ph III) — NCT02367781 (Ph III) — NCT02366143 (Ph III) — NCT02013219

— NCT02350673 — NCT02323191 — NCT02304393 — NCT01633970 — NCT02410512 — NCT02174172 — NCT01375842

For more information about the atezolizumab (MPDL3280A) clinical trial program Visit: Locate.AntiPDL1trials.com or ClinicalTrials.gov Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only) Email: global.rochegenentechtrials@roche.com

*Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trials and should not be construed as a recommendation for use of any product for unapproved purposes. †

All trials consistent with information on ClinicalTrials.gov as of July 6, 2015.

© 2015 Genentech USA, Inc. All rights reserved. PDL/031615/0020(1) Printed in USA.

The ASCO Post | SEPTEMBER 25, 2015

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2015

2015 Oncology Meetings continued from page 72

JADPRO Live at APSHO for Advanced Practitioners in ­Oncology November 5-8, 2015 • Phoenix, Arizona JW Marriott Desert Ridge For more information: jadprolive.com

ESMO Summit Americas 2015 Oncology Updates: From Evidence to Practice November 6-8 • Miami, Florida For more information: www.esmo.org/Conferences/ESMOSummit-Americas-2015

12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, Massachusetts For more information: www. integrativeonc.org/index.php/events

10th Annual New York Lung Cancer Symposium November 7 • New York, New York For more information: http://www.gotoper.com/ conferences/nyl/meetings/10thAnnual-New-York-Lung-CancerSymposium City of Hope Presents: Multidisciplinary Approaches to Cancer Symposium November 5-8 • Las Vegas, Nevada For more information: https://cme.cityofhope.org/ eventinfo_5980.html Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org

13th Annual School of Breast Oncology November 5-7 • Atlanta, Georgia For more information: http://www.gotoper.com/ conferences/sobo/meetings/13thAnnual-School-of-Breast-Oncology

17th Annual Brain Tumor Update and 6th Annual International Symposium on Long-Term Control of Metastases to the Brain and Spine November 7-8 • Las Vegas, Nevada For more information: http://www. clevelandclinicmeded.com/live/ courses/2015/brainmets15/.aspx?Ev entItemID=52&DetailItemID=196#.

VSZlr_msXpU Best of ASTRO November 13-14 • San Diego, CA For more information: www.astro.org/Meetings-andEvents/2015-Best-of-ASTRO/Index.aspx 2015 Oncologic Emergency Medicine Conference November 13-14 • Houston, Texas For more information: http://www.mdanderson.org/ education-and-research/educationand-training/schools-and-programs/ cme-conference-management/ conferences/d114243-2015oncologic-emergency-medicineconference.html

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics November 5-9 • Boston, Massachusetts For more information: http:// www.aacr.org/Meetings/Pages/ MeetingDetail

8th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved November 13-16 • Atlanta, Georgia For more information: http:// www.aacr.org/Meetings/ Pages/MeetingDetail. aspx?EventItemID=68#.Vba1EqTbJjq

14th International Kidney Cancer Symposium November 6-7 • Miami, Florida For more information: http://registeruo.niu.edu/ iebms/wbe/wbe_p1_main. aspx?oc=40&cc=WBE4014167

Society for Integrative Oncology 12th International Conference November 14-16 • Boston, Massachusetts For more information: http://www.integrativeonc.org/ conference

ESMO Symposium on Immuno-Oncology November 20-21 • Lausanne, Switzerland For more information: www.esmo.org/Conferences/ Immuno-Oncology-2015

December 9th European Colorectal Congress (ECC) December 1-4 • St. Gallen, Switzerland For more information: www.colorectalsurgery.eu 4th Cancer Epigenetics Conference November 16-17 • San Francisco, California For more information: https://www. gtcbio.com/conferences

Advances in Cancer ImmunotherapyTM December 4 • New Orleans, Louisiana For more information: www.sitcancer. org/sitc-meetings/aci2015/la

Advances in Cancer 10th Annual Practical Course in Dermoscopy & Update on Malignant Melanoma 2015 December 4-6 • Scottsdale, Arizona For more information: https://ce.mayo.edu/dermatology/ node/2463 ImmunotherapyTM November 18 • San Francisco, California For more information: www.sitcancer.org/sitc-meetings/ aci2015/casf 11th Annual Personalized Medicine Conference November 18-19 • Boston, Massachusetts For more information: http://personalizedmedicine. partners.org/Education/ Personalized-Medicine-Conference/ Program.aspx 12th International Congress of the Society for Melanoma Research November 18-21 • San Francisco, California For more information: http://www. melanomacongress.com/ 20th Annual Scientific Meeting of the Society for Neuro-Oncology November 19-22 • San Antonio, Texas For more information: www.soc-neuro-onc.org

57th Annual ASH Meeting & Exposition December 5-8 • Orlando, Florida For more information: www.hematology.org/ San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org

American Society for Cell Biology Annual Meeting December 12-16 • San Diego, CA For more information: http://ascb.org/2015meeting/ European Society for Medical Oncology Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ESMOAsia-2015-Congress

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 71

Book Review

An Unvarnished, Behind-the-Scenes Look at the Hospital Nurse

By Ronald Piana

F

lorence Nightingale, the most famous and influential figure in the development of modern nursing, began her career tending to the wounded in the Crimean War in 1853. Under her leadership, the role and education of nursing were defined. From war to natural disasters, nurses have played a heroic part in the history of medical care.

tals that stand within a 50-mile radius of a major American city. On the surface, they are very different. Pines Memorial Hospital is a pleasant-looking building with a 16-story tower and broad windows overlooking a tree-lined suburban avenue. Pines Memorial’s 190 beds serve a highly educated, wealthy population.

Several miles away, South General

The Nurses is a mixed bag of high-drama nursing and even some very good critique on our health-care system, from the inside out.

Over the decades, nursing has evolved into a multidisciplinary profession of highly educated and trained health-care providers. And perhaps no branch of nursing has a more clearly defined and essential role in patient care than the oncology nurse, regarded as the backbone of the cancer care delivery system.

Television and books have a long history of featuring the medical profession’s dramatic urgencies, most of them overreaching and distorting the reality of hospitals and clinics, creating a hyperfrenetic unspooling of dramatic doctor-patient encounters. Health-care professionals shrug this off: Blood, sex, and hyped up life-and-death events sell.

Best-selling author Alexandra Robbins has made a career of delving into the secret lives of sororities, overachievers, geeks, and so on, so why not nurses?

She does just that in her new book titled The Nurses: A Year of Secrets, Drama, and Miracles With the Heroes of the Hospital.

The Nurses is a mixed bag of high-drama nursing and even some very good critique on our health-care system, from the inside out. Moreover, one reason that books and television shows about hospitals are successful is because everyone can empathize with being sick, injured, scared, and helpless.

Four Real-Life Stories The Nurses is told through the real-life stories of four nurses at different hospi-

Hospital occupies a mostly poor neighborhood; it has 300 beds and a level I trauma center. South General’s ER sees 95,000 patients a year. Then, 45 minutes west, the 425-bed Academy Hospital treats a ritzy demographic of young and middle-aged residents in the nearby million-dollar homes and elite university.

Rounding off the foursome is Citycenter Medical, which has a level I trauma unit that treats most of the city’s gunshot victims, homeless, and drug-seeking addicts. As different as their patient populations are, all four hospitals have one common thread. “In each of these disparate institutions, pale blue curtains shroud pods of frightened people.”

From Silly to Serious Ms. Robbins organized her book into 10 well-designed chapters with catchy titles, such as “The Stepford Nurse,” “Burnt to a Crisp,” and “When Nurses Bully Nurses.” This serious beach-read format is her literary bailiwick, and it’s made her a steady presence on best-seller lists.

Although there is a good deal of serious and informative content in the book, at times—perhaps too often for readers of The ASCO Post—Ms. Robbins plays to what she feels is her built-in audience with overly chatty and silly scenes.

The Nurses is most compelling when it threads value into the narrative, such as in the chapter “Burnt to a Crisp.” Nursing

is a physically and mentally demanding career, and Ms. Robbins tackles subjects the oncology community has addressed: burnout and workforce shortage. “Experts estimate that approximately 30% of nurses are burnt out, which has been defined as a loss of caring. Burnout symptoms include irritability, difficulty concentrating, low energy, and sustained thoughts of quitting.”

Ms. Robbins illustrates burnout syndrome with serious anecdotal evidence correlating it with a dangerous uptick in preventable hospital errors. She then wades into the fiscal issue of budget cuts and consolidation, which results in understaffing. Policy is not her strongpoint, but she hits most of the difficult fiscal challenges with authority. To her credit, she gives a balanced overview of these critical issues and ends this well-researched chapter by looking at how hospital administrations across the country are dealing with nurse burnout and understaffing.

Throughout The Nurses, the author treats the reader to compelling nursehospital dramas, which not only entertain but also underscore the value that nurses bring to the health-care system.

As a value-added section, Ms. Robbins ends with a what you can do chapter, broken into short, subtitled narratives offering sound advice to all those in the business of running a hospital.

Advice for Nurses For nurses, she gives advice, such as becoming a mentor. When asked about their career choice, most oncologists stress the value of their mentors’ strong advice and guidance. Ms. Robbins offers a thoughtful section on the essential role mentors play in keeping the health-care system fully energized.

However, she seems to drop the ball on one of the most significant issues facing our system: hospital-acquired infections. The Centers for Disease Control and Prevention estimates that hospital-acquired infections kill upward of 100,000 citizens each year. Ms.

Bookmark Title: The Nurses: A Year of Secrets, Drama, and Miracles With the Heroes of the Hospital Author: Alexandra Robbins Publisher: Workman Publishing Company Publication date: April 14, 20155 Price: $17.53; hardcover, 368 pages Robbins’ advice to nurses is shockingly brief: “Bring hand sanitizer and antibacterial wipes. Use them.”

Ms. Robbins is adept at communicating serious issues with accessible and lively writing. People looking for a behind-the-scenes beach read with some serious information threaded into the juicy parts should enjoy The Nurses. Unfortunately, for some readers of The ASCO Post, much of this entertaining book may be considered decidedly lowbrow and filled with clichés and gossipy dialogue. n

IN APPROACHING HR+ ADVANCED BREAST CANCER

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Š 2015 Novartis

HAVE YOU LEFT YOUR PATIENTS VULNERABLE TO PI3K-mTOR SIGNALING? When overlooked, hyperactivation of the PI3K-mTOR pathway drives resistance to endocrine monotherapy and HR+ disease progression1,2 • PI3K-mTOR is the most common aberrantly activated pathway in breast cancer, with genetic defects occurring in >70% of cases2,3 • The PI3K-mTOR pathway is a major source of resistance and progression in HR+ advanced breast cancer1,2 • Novartis is committed to realizing the full therapeutic potential of targeting the PI3K-mTOR pathway for patients with HR+ advanced breast cancer

HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin.

References: 1. Miller T. Endocrine resistance: what do we know? Am Soc Clin Oncol Educ Book.

2013:e37-e42. 2. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224-235. 3. Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014;7:203-215.

The PI3K-mTOR pathway is an important component to consider in approaching HR+ advanced breast cancer. Find out more at TargetingPI3K-mTOR.com.

Printed in USA

4/15

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The ASCO Post | SEPTEMBER 25, 2015

PAGE 74

Book Review

In Search of a Good Ending for a Life Well Lived

By Ronald Piana

A

quick Google search on books about end-of-life care will yield pages of hits on the subject. The current leader of the pack on the issues surrounding life in the context of impending death is the acclaimed book Being Mortal by Atul Gawande, MD (see The ASCO Post, December 1, 2014). The shelves are full of books on the experience of dying and how we, as mortal creatures, make sense of our own terminal destiny.

So, how do authors who feel they have something to add to the subject elbow their way into that crowded space? Write something that moves the needle, even slightly. Write with power and conviction, but never sound preachy. Incorporate compelling anecdotal evidence and patient narratives. Give it a catchy title and a good cover, and there you go.

Of course, this is easier said than done. But a new book, The Conversation: A Revolutionary Plan for Endof-Life Care, does just that. The author, Angelo E. Volandes, MD, is a physician and researcher at Harvard Medical School and cofounder of Advanced Care Planning and Decisions.

He is also an accomplished writer who takes Strunk & White’s credo— “Omit needless words”—to heart.

Minus endnotes, The Conversation is a mere 240 pages, but it leaves the reader satisfied, not wanting more.

A Not-So-Simple Issue The Conversation explores the lives of seven seriously ill patients who experienced very different deaths, each hinging on whether or not a doctor had a discussion with the patient before he or she could no longer make a decision. “In the case of those people who did not have the benefit of discussing their options, the stories of their end-of-life care exhibit the neglect that deeply permeates the U.S. health care system. They offer a glimpse into the hidden hospital world that defines how many Americans die.”

In contrast, by exploring the lives of those patients whose deaths were

improved by discussing their preferences ahead of time, Dr. Volandes offers the reader a template; a way to make sure that the care delivered at the end of life is consistent with his or her wishes. It sounds simple, so why is this still an unresolved issue in the oncology community? The short answer is, it isn’t simple because it is so uncomfortable talking to people about their own mortality.

Dr. Volandes points out that in order for these tough, much-needed conversations to take place, medical schools need to bolster their end-oflife care curriculum, a message shared by many in the oncology community.

Dr. Volandes writes, “Talking to patients is given short shrift in medical training. The focus of medical education is on technology and treatments; medicine is about doing, not talking.” The good news is that much has changed since Dr. Volandes was in medical school, and leaders in the oncology community have been at the forefront of that much-needed

Bookmark Title: The Conversation: A Revolutionary Plan for End-of-life Care Author: Angelo E. Volandes, MD Publisher: Bloomsbury Publication date: January 13, 2015 Price: $26.00; hardcover, 240 pages

Conversation. We meet Prof. Thompson in Chapter 4, “Where for We Go From Here,” as she is about to embark on a semester-long journey exploring American poetry. A renowned scholar, she never read from notes, and she performed with an aplomb that most senior professors rarely achieve. As

In the case of those people who did not have the benefit of discussing their options, the stories of their end-of-life care exhibit the neglect that deeply permeates the U.S. health care system.

They offer a glimpse into the hidden hospital world that defines how many Americans die.

—Angelo E. Volandes, MD

call for awareness. For example, “At Mount Sinai, all medical students are required to spend a week on rotation with the school’s nationally recognized palliative care team, which is led by Dr. Diane Meier, arguably the country’s leader in the field.”

Heart-Wrenching Episode Readers may be especially drawn to Prof. Helen Thompson, one of the seven patients highlighted in The

she began reciting Walt Whitman’s most famous poem, Leaves of Grass— her 31st such recital—she suddenly went silent, staring ahead numbly at her anxious students.

Dr. Volandes met Prof. Thompson 9 months later. “When I admitted her to the hospital, Helen was fiftysix years old and had been diagnosed with aggressive glioblastoma multiforme; a six-centimeter tumor was crushing her brain.”

Dr. Volandes prescribed dexamethasone to decrease the swelling and inflammation. Then it was time to talk to Helen and her husband who were in the exam room clutching each other’s hands. By now, the tumor had overtaken much of her brain. Dr. Volandes asked how she was feeling, and she responded that she’d had quite an eventful day, adding, “When can I get back to my students?” Dr. Volandes was taken aback. He asked if she’d discussed the full impact of her brain cancer with her oncologist.

She replied, “No, we were focused on fighting the tumor.”

This is an important and heartwrenching chapter, and the author handles it with the care it deserves.

Prof. Thompson had inoperable glioblastoma multiforme, and after being hospitalized for a seizure, she’d still not had the tough conversation with her oncologist. She was living in that limbo of false hope that too many patients like her inhabit. At that point, Dr. Volandes very delicately interceded, guiding her along with compassion and honest conversation.

And she thanked him for that as she left the hospital and entered hospice care.

Each of the six other patient episodes illustrates, without redundancy, a lesson in how and when to initiate thoughtful conversations about

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 75

Book Review

clinical realities and how to plan for the next step, whatever that might be.

Dr. Volandes has developed a set of teaching videos called The Conversation that help practitioners learn how best to manage their patients facing a terminal illness. A tireless promoter of his approach to end-of-life care, giving lecture after lecture from coast to coast, he is a man on a mission, and readers of The ASCO Post with connections to the palliative care community will cheer him on.

these vital conversations,” writes Dr. Volandes.

The appendices give easy-to-read examples of how to initiate “the conversation” in a multitude of clinical scenarios. Here the reader will also find valuable information about health-care proxies and advance directives, plus a guide to online re-

sources. This is value-added content that every provider who deals with very sick patients should review and pass along to colleagues.

The Conversation is a highly recommended book for readers of The ASCO Post. Dr. Volandes has moved the needle in this genre—not an easy task. He admits there were times in

his early career when he didn’t stop in the clinic to have the conversation.

“I had started a cascading series of medical procedures without ever asking the patient what he or she wanted…. [M]y hope is that all people get the opportunity to live the way they wish, throughout all the chapters of their lives.” n

Strong Finish The afterword and the appendices, usually skipped or glanced over by readers, contain some of the strongest material in the book. Here, Dr. Volandes supports his arguments for The Conversation with empirical data and convincing anecdotal evidence.

One study he cites followed terminally ill patients for a year, and it showed that one-fifth of those patients who stated in a questionnaire that they did not want burdensome medical interventions received such nonetheless, which Dr. Volandes considers an egregious medical error. “These medical errors are entirely preventable if doctors, nurses, and social workers have done their due diligence and engaged patients in

Our commitment to cancer research

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Merck is passionate about improving health and is committed to helping people with cancer. Keynote is a series of investigational trials studying pembrolizumab (MK-3475)—a type of investigational immunotherapy that works by targeting the PD-1 pathway.

Merck has investigational clinical trials underway or planned in multiple cancer types.

Write to The ASCO Post at editor@ASCOPost.com Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

If you have patients who may be eligible for a trial, visit

www.keynoteclinicaltrials.com

for more information about this ongoing research.

The ASCO Post | SEPTEMBER 25, 2015

PAGE 76

JCO Spotlight Genetics/Genomics

ASCO Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility

By Matthew Stenger

A

s reported in the Journal of Clinical Oncology by Mark E. Robson, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, ASCO has issued a policy statement update on genetic and genomic testing for cancer susceptibility.1 The statement, commissioned by ASCO’s Cancer Prevention and Ethics Committees, seeks to address the impact of massively parallel (next-generation) sequencing in cancer susceptibility testing.

tumor-associated variants and should not be obligated to seek germline variants.

Oncology providers should communicate the potential for incidental and secondary germline information to patients before conducting somatic mutation profiling and should review the potential benefits, limitations, and risks before testing. Providers should carefully ascertain patient preferences regarding the receipt of germline information and allow patients to decline the receipt of

This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner.

—Mark E. Robson, MD, and colleagues

As stated by the authors: “This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice.”

The general recommendations are summarized below.

Germline Implications of Somatic Mutation Profiling ASCO supports the communication to patients of medically relevant incidental germline findings from somatic mutation profiling conducted in the clinical setting. Only laboratories equipped to provide analytically and clinically valid results should conduct secondary analyses to identify germline variants. Laboratories that are not resourced to provide clinically valid information from secondary analysis of the normal sample in tumor-normal subtractive analyses should only report

such information. This may require referral for additional counseling to help the patient clarify his or her preferences.

In the setting of tumor-normal sequencing, laboratories conducting secondary analyses should develop mechanisms to report only somatic results for patients who choose to decline receipt of germline findings. ASCO supports research to determine how best to deliver pretest education, support patient preferences, and understand outcomes of providing incidental and secondary germline information with somatic testing.

Multigene Panel Testing for Cancer Susceptibility ASCO recognizes that concurrent multigene testing (ie, panel testing) may be efficient in circumstances that

require evaluation of multiple highpenetrance genes of established clinical utility as possible explanations for a patient’s personal or family history of cancer. Depending on the specific genes included on the panel employed, panel testing may also identify mutations in genes associated with moderate or low cancer risks and mutations in high-penetrance genes that would not have been evaluated on the basis of the presenting personal or family history. Multigene panel testing will also identify variants of uncertain significance in a substantial proportion of patient cases, simply as a result of the multiplicity of genes tested.

It is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient’s personal and/or family history.

Because of the current uncertainties and knowledge gaps, providers with particular expertise in cancer risk assessment should be involved in the ordering and interpretation of multigene panels that include genes of uncertain clinical utility and genes not suggested by the patient’s personal and/or family history. Research is encouraged to delineate the optimal use of these tests, development of guidelines, and education of providers.

Quality Assurance in Genetic Testing ASCO recognizes the complexity of analysis and interpretation of genetic tests. ASCO supports high-quality standards to help providers and patients understand the accuracy, benefits, and limitation of genetic tests from individual laboratories. It is believed that current regulation of tests to detect inherited genetic variants is insufficient. Where tests are considered laboratory-developed or commercial tests, ASCO supports a riskbased approach to the U.S. Food and Drug Administration regulation.

High-risk tests used to identify patients who are at increased risk for

Keeping Up on Next-Generation Sequencing ■■ The purpose of the statement is “to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice.”

■■ Recommendations are made in the areas of germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services.

cancer should be subject to regulatory review. It is also recognized that regulation must be designed in a manner that does not compromise innovation or limit patient access to testing.

Education of Oncology Professionals ASCO affirms that the recognition and management of individuals at inherited risk for cancer are core elements of oncology practice. The skills required to provide cancer risk assessment services are not specific to a particular discipline but, rather, incorporate elements from oncology, medical genetics and genetic counseling, and other disciplines. Continued education of oncologists and other health-care professionals in the area of cancer risk assessment and management of individuals with an inherited predisposition to cancer is recommended.

It is also recommended that specific skills be integrated into oncology training and continuing education, including skills relevant to understanding hereditary predisposition to cancer, hereditary cancer risk assessment, genetic testing, recognition of major hereditary cancer syndromes, and management of individuals at increased hereditary cancer risk. Oncology training programs should develop a set of core skills for new trainees and ensure adequate time in training for achieving these skills.

Access to Cancer Genetic Services ASCO is committed to ensuring access to high-quality cancer genetic services and supports continued expansion of thirdparty reimbursement for evidence-based genetic and genomic tests and preventive care in keeping with the rapid pace of scientific advances. In addition, ASCO opposes any payment policies that have the potential to negatively affect the care of patients with cancer by serving as barriers to the appropriate use of genetic testing services. ASCO will continue to advocate for coverage policies that support access to cancer risk assessment and prevention services for individuals who are suspected to be at increased genetic risk. n

Disclosure: For full disclosures of the statement authors, visit jco.ascopubs.org.

Reference 1. Robson ME, et al: J Clin Oncol. August 31, 2015 (early release online).

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 77

In Memoriam

Internationally Acclaimed Cancer Researcher, Gianni Bonadonna, MD, Dies at 81

By Ronald Piana

Gianni Bonadonna, MD

G

ianni Bonadonna, MD, was considered the “Father of Italian Oncology,” but his scientific contributions to the field and his generous collegial spirit extended far beyond the shores of his native land. Dr. Bonadonna was at the forefront in the battle to convince the surgical establishment that adjuvant therapy could significantly improve clinical outcomes.

He was a scientist’s scientist. He was also a patient’s doctor, having this message for the younger generation of oncologists: “Don’t get too caught up in the deluge of data and statistics. It is time to reconnect with the patient.” Dr. Bonadonna died on September 7, 2015. He was 81.

Dr. Bonadonna was born in 1934 in Milan. An enthusiastic student bent on a career in medicine, he graduated with his medical degree from the University of Milan in 1959. He ventured to America in 1961 to pursue his growing interest in cancer, spending time at Memorial Sloan Kettering Cancer Center in New York. Following this time, he would return to Italy to join the Istituto Nazionale dei Tumori of Milan, where he became Director of the Division of Medical Oncology. It would prove a long-lasting and fruitful tenure.

Paradigm-Shifting Collaboration One of the most significant debates in oncology took place in the mid1960s, as the primacy of radical mastectomy was being challenged by pioneering oncologic researchers who resolved to demonstrate the benefits of chemotherapy in breast cancer outcomes. Dr. Bonadonna would play a major role in this lifesaving paradigm shift in breast cancer treatment.

At the National Cancer Institute (NCI), George P. Canellos, MD, and Vincent T. DeVita, Jr, MD, and other

investigators had tested various combinations of drugs to treat advanced breast cancer and developed a regimen they felt had great promise: CMF (cyclophosphamide, methotrexate, and fluorouracil).

One of their colleagues, Paul S. Carbone, MD, had tried to persuade major U.S. cancer centers to launch a trial of CMF, but it was deemed too risky and they were turned down. Undaunted, Dr. Carbone reached out to a forward-thinking surgeon at the Istituto Nazionale dei Tumori, Umberto Veronesi, MD, who, in turn, sent Dr. Bonadonna to the NCI to review the promising data on CMF. Dr. DeVita told The ASCO Post about Dr. Bonadonna’s elegant arrival at the NCI. “I met Gianni’s plane in the early

Dr. Bonadonna’s work ethic and intellect were renowned, as was his zest for life. Past ASCO President Gabriel N. Hortobagyi, MD, FACP, told The ASCO Post, “Dr. Gianni Bonadonna was one of the world’s most influential cancer researchers, and his work has improved the lives of countless people living with cancer. In addition to being a wonderful physician, clinical investigator, and clinical trialist, Gianni was an avid traveler, a well-known author, and a passionate oncologist, a pioneer with endless curiosity and willingness to take risks. I will always remember him as a warm and loyal friend, with whom I spent many hours of intense discussions about medicine, life, and philosophy. I will miss him dearly.”

Dr. Gianni Bonadonna was one of the world’s most influential cancer researchers, and his work has improved the lives of countless people living with cancer. In addition to being a wonderful physician, clinical investigator, and clinical trialist, Gianni was an avid traveler, a well-known author, and a passionate oncologist, a pioneer with endless curiosity and willingness to take risks.

—Gabriel N. Hortobagyi, MD, FACP

morning. He walked off in a maroon velour suit without a wrinkle in it and wore the nicest pair of shoes I had ever seen. I thought he must have slept standing up!

He spent a week going over the data and modifying CMF for Italian use, and we spent the week going out to dinner together, pleased to find a sort of kinship between us that grew as the years went on. On Gianni’s recommendation, the Istituto Tumori agreed to do the nowfamous CMF adjuvant trial published almost 40 years ago in The New England Journal of Medicine, and it vaulted Gianni to medical oncology fame.”

Dr. DeVita continued, “Gianni used the same resources for Hodgkin disease in close consultation with our group— and so began a collaborative arrangement that spun off many benefits to cancer patients everywhere.” Dr. Bonadonna designed and conducted the first clinical trials to explore the use of doxorubicin and developed the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) protocol, which remains the gold-standard treatment for Hodgkin lymphoma.

ASCO Award in His Honor In 2007, as a tribute to his contributions to the field of breast cancer research, ASCO instituted the Gianni Bonadonna Breast Cancer Award and Lecture, which is presented annually to a researcher of merit in this discipline. On the news of Dr. Bonadonna’s death, Jay R. Harris, MD, recipient of the award in 2008, remarked to The ASCO Post, “Dr. Bonadonna was a remarkable man and clinical investigator. Most investigators are pleased if they make a major impact in one field. Dr. Bonadonna was noteworthy for making a major impact in two fields: breast cancer and lymphoma. He broke ground in developing adjuvant systemic therapy for breast cancer, which has saved thousands of lives. The concept of using systemic therapy in the absence of disease was radical. He and his team also developed what became the standard therapy for Hodgkin lymphoma—ABVD—which has maintained its importance for decades. He was also a mentor and teacher to legions of oncologists. He leaves a remarkable legacy and will be greatly missed.”

Another awardee and former ASCO President, Nancy E. Davidson, MD, offered her thoughts: “I am saddened by the loss of Gianni Bonadonna. He was a true pioneer in the field of medical oncology. His team at the Istituto Nazionale dei Tumori made seminal contributions to the treatment of Hodgkin lymphoma and early-stage breast cancer, which have stood the test of time. Only someone like Gianni could publish 25- to 30-year follow-ups of clinically meaningful results from randomized clinical trials in these important areas.”

Dr. Davidson added, “I count myself fortunate to be among the recipients [of the Gianni Bonadonna Breast Cancer Award] because Gianni was one of the very best.

He set the bar for excellence in clinical and translational research, which has improved the lives of patients around the world.”

Ties That Bind Dr. Bonadonna authored more than 550 publications in the clinical oncology field, several books on medicine for lay people, and even one book on the Sepoy Rebellion in India. His awards for meritorious service in the field of oncology are too numerous to list. But it was not elegant words on paper or glowing rhetoric that defined Dr. Bonadonna’s legacy. It is the countless thousands of cancer patients whose lives were uplifted by his work and discoveries. And the colleagues he’s left behind.

Dr. DeVita told The ASCO Post that he and Dr. Bonadonna kept in touch over the years, especially after Dr. ­Bonadonna had a near-fatal stroke in 1995. The two famous oncologists exchanged Christmas greetings this past December. Dr. Bonadonna wrote: Dear Vince, The time around the New Year is always a time of memories not always pleasant except for our unbreakable friendship. I am fine, and every day I go to my office and keep on writing. As long as I can, I want to do as Sir Winston Churchill said: “We will never surrender!”

On a cold winter morning in 1975, Dr. Bonadonna flew to Brussels to present the results of his NCI-sponsored CMF trial. The trial’s success was so unexpected that it was greeted by stunned silence in the auditorium. Now, some 4 decades later, the oncology community offers a moment of silence in tribute to one of our finest: Dr. Gianni Bonadonna. n

When multiple myeloma relapses

INDICATION Kyprolis® (carfilzomib) for Injection is a proteasome inhibitor that is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

IMPORTANT SAFETY INFORMATION Cardiac Toxicities: New onset or worsening of pre-existing cardiac

failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/ risk assessment.

Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.

Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea: Dyspnea was reported in patients treated with Kyprolis.

Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension: Hypertension, including hypertensive crisis and

hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis: Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Acute Renal Failure: Cases of acute renal failure and renal

Infusion Reactions: Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Tumor Lysis Syndrome: Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis.

Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Thrombocytopenia: Kyprolis causes thrombocytopenia with

insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy.

This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS),

acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal.

In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH

recovery to baseline platelet count usually by the start of the next cycle.

Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure,

including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS): Cases of TTP/HUS including fatal outcome

have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected.

If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, KYPROLIS, and KYPROLIS logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2015 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA TROPIC-KYPR-103559 August 2015 Printed in USA

Ne w

RESPOND

In dic at

ion

with the power of significantly improved progression-free survival (PFS)

Posterior Reversible Encephalopathy Syndrome (PRES):

Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

The KYPROLIS regimen significantly improved PFS in patients with relapsed multiple myeloma1

Embryo-fetal Toxicity: Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.

In the ASPIRE study of KYPROLIS + lenalidomide + low-dose dexamethasone (KRd) vs lenalidomide + low-dose dexamethasone (Rd), the KYPROLIS regimen delivered improved efficacy with a safety profile comparable to Rd.1,2*

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

26.3 months median progression-free

ADVERSE REACTIONS The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

References: 1. KYPROLIS [prescribing information]. Thousand Oaks, CA: Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary; 2015. 2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

N Engl J Med. 2015;372(2):142-152.

Please see Brief Summary of full Prescribing Information on adjacent pages.

survival with the KYPROLIS regimen vs 17.6 months with Rd, a 49% improvement over Rd (P value [two-sided] 0.0001)1

Find out more at www.kyprolis.com/hcp *ASPIRE was a global, multicenter, open-label, randomized phase 3 pivotal trial evaluating KYPROLIS in patients with relapsed multiple myeloma. 792 patients were randomized in a 1:1 ratio (396 patients to KRd, 396 to Rd). Patients received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity.1,2 The primary endpoint was progression-free survival.

Secondary endpoints included overall survival, overall response rate (partial response or better), duration of response, and safety.2

The ASCO Post | SEPTEMBER 25, 2015

PAGE 80

Announcements

Jeffrey S. Weber, MD, PhD, Joins NYU Langone and Perlmutter Cancer Center

J

effrey S. Weber, MD, PhD, an expert in immunotherapy and melanoma, will join the senior faculty of NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center. Dr. ­Weber will serve as Deputy Director of the Perlmutter Cancer Center and Co-

Jeffrey S. Weber, MD, PhD

director of its Melanoma Program and will oversee its work in experimental therapeutics. He officially joins the NYU Langone faculty on November 2, 2015.

Dr. Weber’s research, which has been continuously funded by the National Cancer Institute (NCI)

for over 20 years, focuses on experimental therapeutics and drug development, particularly in the areasB:16.75” of immunotherapy and checkpointT:16.25” inhibitory antibody development inS:14.625” melanoma and other types of cancer.

Specifically, his laboratory moni-

(carfilzomib) forintravenous injection, foruse intravenous use Brief of Hepatic ToxicityFailure and Hepatic Failure KYPROLIS® KYPROLIS (carfilzomib)® for injection, for Brief Summary of Summary Hepatic Toxicity and Hepatic Prescribing Information.

Prescribing Information.

Cases of hepatic failure, fatal cases, have(< been (< 1%) in patients Cases of hepatic failure, including fatal including cases, have been reported 1%)reported in patients see thepackage KYPROLIS insert for full prescribing information.

Please see the Please KYPROLIS insertpackage for full prescribing information. receiving Kyprolis.

Kyprolis can cause increased serum transaminases. receiving Kyprolis.

Kyprolis can cause increased serum transaminases.

Monitor liver Monitor liver INDICATIONS enzymes regularly.

Reduce or as withhold dose as appropriate.

INDICATIONS enzymes regularly.

Reduce or withhold dose appropriate.

Kyprolis inwith combination withand lenalidomide and dexamethasone indicated for theThrombotic Thrombocytopenic Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) Kyprolis in combination lenalidomide dexamethasone is indicated foristhe Purpura/Hemolytic Uremic Syndrome (TTP/HUS) treatment patientsmultiple with relapsed multiple who one havetoreceived treatment of patients withofrelapsed myeloma who myeloma have received three one to three Cases of TTP/HUS, including fatal outcome, have been reported inreceived patients who received Cases of TTP/HUS, including fatal outcome, have been reported in patients who prior lines of therapy. prior lines of therapy.

Kyprolis.

Monitor for signs and symptoms Discontinue of TTP/HUS.Kyprolis Discontinue Kyprolis if TTP/ Kyprolis. Monitor for signs and symptoms of TTP/HUS. if TTP/ WARNINGS AND PRECAUTIONS HUS is evaluate. suspected Ifand diagnosisisofexcluded, TTP/HUS is excluded, WARNINGS AND PRECAUTIONS HUS is suspected and theevaluate. diagnosisIfofthe TTP/HUS Kyprolis may Kyprolis may be restarted.

The safetyKyprolis of reinitiating Kyprolis therapy in patients previously experiencing be restarted. The safety of reinitiating therapy in patients previously experiencing Cardiac Toxicities Cardiac Toxicities TTP/HUS TTP/HUS is not known. is not known.

New onsetoforpre-existing worsening of pre-existing failure (e.g., congestive New onset or worsening cardiac failure cardiac (e.g., congestive heart failure, heart failure, Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES) pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial myocardial ischemia, and myocardial infarction including a day in patients receiving of PRES havein been reported in patients receiving Kyprolis. formally known ischemia, and myocardial infarction including fatalities withinfatalities a day inwithin patients receiving Cases of PRESCases have been reported patients receiving Kyprolis.

PRES, formallyPRES, known Kyprolis.

Withhold Kyprolis Gradeadverse 3 or 4 cardiac events until recovery, as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), can present with seizure, Kyprolis. Withhold Kyprolis for Grade 3 or for 4 cardiac events adverse until recovery, as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), can present with seizure, and consider whether to restart Kyprolis 1 dose level based on a benefit/risk headache, lethargy, confusion, blindness, altered consciousness, and consider whether to restart Kyprolis at 1 dose level at reduction basedreduction on a benefit/risk headache, lethargy, confusion, blindness, altered consciousness, and other visualand andother visual and assessment.

Adequately hydrate alltopatients prior to receiving Kyprolis. neurologicalalong disturbances, along with Perform hypertension.

Perform diagnostic neuroradiological assessment. Adequately hydrate all patients prior receiving Kyprolis. neurological disturbances, with hypertension. diagnostic neuroradiological (MRI) at the onset of visual orsymptoms. neurological symptoms.Kyprolis Discontinue Kyprolis if imaging (MRI)imaging at the onset of visual or neurological Discontinue if Monitor patientsoffor evidence of volume overload, especially at risk for cardiac Monitor all patients for all evidence volume overload, especially patients at risk patients for cardiac PRES is evaluate. suspected The and safety evaluate.

The safetyKyprolis of reinitiating Kyprolis therapy in patients PRES is suspected and of reinitiating therapy in patients failure.

Adjust total fluid intake as clinically appropriate.

Patients ≥ 75 years, with New failure. Adjust total fluid intake as clinically appropriate. Patients ≥ 75 years, with New previouslyPRES experiencing PRES is not known. previously experiencing is not known.

York Heart Association and IVrecent heart myocardial failure, recent myocardial York Heart Association Class III and IVClass heartIIIfailure, infarction, and infarction, and conduction abnormalities may be at greater risk for cardiac complications.

Embryo-fetal Toxicity conduction abnormalities may be at greater risk for cardiac complications.

Embryo-fetal Toxicity Acute Renal Failure Acute Renal Failure

Kyprolis cause fetal harm whentoadministered to a pregnant woman Kyprolis can cause fetal can harm when administered a pregnant woman based on its based on its mechanism of action findings in animals.

There are nowell-controlled adequate and well-controlled mechanism of action and findings inand animals.

There are no adequate and of acute renal failure in have occurred in patients receiving Kyprolis. Renal Cases of acute Cases renal failure have occurred patients receiving Kyprolis.

Renal studies in pregnant women using Kyprolis. studies in pregnant women using Kyprolis. insufficiency events (renal impairment, acuterenal renalfailure) failure,occurred renal failure) occurred insufficiency adverse events adverse (renal impairment, acute renal failure, in approximately patients incontrolled a randomized trial.

Acute renal failureFemales was Females ofpotential reproductive should be potential advised ofhazard the potential hazard in approximately 8% patients in 8% a randomized trial.controlled Acute renal failure was of reproductive shouldpotential be advised of the to the fetus andto the fetus and reported more frequently patients with advanced relapsed multiple and refractory multiple to avoid becoming whilewith being treated with Kyprolis.

If this drug is used during reported more frequently in patients withinadvanced relapsed and refractory to avoid becoming pregnant whilepregnant being treated Kyprolis.

If this drug is used during who received Kyprolis monotherapy.

This risk was greater if the patient becomes while taking Kyprolis, advise myeloma who myeloma received Kyprolis monotherapy.

This risk was greater in patients within patients with pregnancy, or ifpregnancy, the patientorbecomes pregnant whilepregnant taking Kyprolis, advise the patient of the patient of a baseline reduced estimated creatinine clearance.

Monitor with renalregular function with regular the potential hazard to the fetus. a baseline reduced estimated creatinine clearance.

Monitor renal function the potential hazard to the fetus. of the serum creatinine and/or estimated creatinine clearance.

Reduce or measurement ofmeasurement the serum creatinine and/or estimated creatinine clearance.

Reduce or ADVERSE REACTIONS ADVERSE REACTIONS withhold Kyprolis dose as appropriate. withhold Kyprolis dose as appropriate.

The following adverse have been discussed andthe canWarning be found the WarningK The following adverse reactions have reactions been discussed above and can above be found Tumor Lysis Syndrome (TLS) Tumor Lysis Syndrome (TLS) de Precautions section of the package insert. cardiac They include cardiac and Precautionsand section of the package insert.

They include toxicities, acutetoxicities, kidney acute kidney a of TLS, havein been reported patients who received injury, TLS, Pulmonary toxicity, pulmonarydyspnea, hypertension, dyspnea,venous hypertension, venous Cases of TLS, Cases including fatal including outcomes,fatal haveoutcomes, been reported patients whoinreceived injury, TLS, Pulmonary toxicity, pulmonary hypertension, hypertension, b Kyprolis.

Patientsmyeloma with multiple andburden a highare tumor burdenrisk are at greater thromboses, risk thromboses, infusion reactions, thrombocytopenia, toxicity and hepatic failure, c Kyprolis. Patients with multiple and amyeloma high tumor at greater infusion reactions, thrombocytopenia, hepatic toxicityhepatic and hepatic failure, forpatients TLS. Ensure patients arebefore well hydrated before administration of Kyprolis. Consider and PRES. for TLS. Ensure are well hydrated administration of Kyprolis. Consider TTP/HUS and TTP/HUS PRES. d uricdrugs acid lowering drugs in patients risk for TLS. Monitoroffor evidence uric acid lowering in patients at risk for TLS.atMonitor for evidence TLS during of TLS during Trials Safety Experience Clinical Trials Clinical Safety Experience treatment and manage promptly.

Withold Kyprolis until TLS is resolved. treatment and manage promptly.

Withold Kyprolis until TLS is resolved. e Because clinical trials under are conducted under widely varying conditions, adverse reaction Because clinical trials are conducted widely varying conditions, adverse reaction Pulmonary Toxicity Pulmonary Toxicity in theofclinical ofbe a drug cannot be directly rates observed rates in theobserved clinical trials a drug trials cannot directly compared withcompared rates in thewith rates in the N another and may not reflect the rates observed in medical practice. p Acute Respiratory Distress Syndrome acute respiratory failure, and acuteclinical diffusetrials ofclinical anothertrials drug,ofand may drug, not reflect the rates observed in medical practice.

Acute Respiratory Distress Syndrome (ARDS), acute(ARDS), respiratory failure, and acute diffuse infiltrative pulmonary such asand pneumonitis lung of disease, some of infiltrative pulmonary disease such asdisease pneumonitis interstitial and lunginterstitial disease, some The safety of Kyprolis inwith combination withand lenalidomide and dexamethasone (KRd) was G The safety of Kyprolis in combination lenalidomide dexamethasone (KRd) was which fatal, in have than 1% of patients receiving Kyprolis. In the which were fatal, havewere occurred lessoccurred than 1%inofless patients receiving Kyprolis.

In the inrandomized an open-label randomized study patientsmultiple with relapsed multiple myeloma. d evaluated in anevaluated open-label study in patients withinrelapsed myeloma. event ofpulmonary drug-induced pulmonary toxicity, discontinue Kyprolis. event of drug-induced toxicity, discontinue Kyprolis.

The median number of cycles wasthe 22KRd cycles forand the14 KRd armfor and 14 cycles for h The median number of cycles initiated was 22initiated cycles for arm cycles Pulmonary Hypertension (PAH) the Rd arm. the Rd arm.

Pulmonary Hypertension (PAH) L Deaths due to adverse events 30 days dose of therapy Cases of PAH(~1%) was reported (~1%) in patients treated with KYPROLIS , <1% experiencing Deaths due to adverse events within 30 dayswithin of the last doseof ofthe anylast therapy in any the KRd armin the KRd arm Cases of PAH was reported in patients treated with KYPROLIS , <1% experiencing vs.

Rd arm was 27/392 (7%) patients vs.

27/389 (7%) patients in the Rd arm.

The most Grade 3 or greater PAH..

Evaluate with cardiac imaging and/or other tests as indicated.

In vs.

Rd arm was 27/392 (7%) patients vs.

27/389 (7%) patients in the Rd arm.

The most Grade 3 or greater PAH.. Evaluate with cardiac imaging and/or other tests as indicated. In of deaths occurring patients 10 (3%) vs. 7 (2%), infection 9 the discontinue event of PAH, discontinue Kyprolisor until resolved or returned to baseline.

Perform a causecommon common of deathscause occurring in patients (%) in cardiac 10(%) (3%)cardiac vs. 7 (2%), infection 9 the event of PAH, Kyprolis until resolved returned to baseline.

Perform a (2%) vs. 10 (3%),vs.renal (0%)and vs. other 1 (< 1%), andevents other adverse events 9 (2%) vs. 10 (3%). benefit/risk assessment when considering restarting Kyprolis.

(2%) vs. 10 (3%), renal 0 (0%) 1 (<01%), adverse 9 (2%) vs.

10 (3%). benefit/risk assessment when considering restarting Kyprolis. events in were reported vs. 54% of KRd patients theRd KRd arm vs. Rd Serious adverseSerious events adverse were reported 60% vs. 54%inof60% patients in the arminvs.

Dyspnea Dyspnea The most common the KRd arm. The mostarm. common serious adverseserious events adverse reportedevents in the reported KRd arminverses the arm Rd verses the Rd arm were pneumonia vs. 11%), tractvs. infection vs. 1.5%), pyrexia arm were pneumonia (14% vs. 11%),(14% respiratory tractrespiratory infection (4% 1.5%),(4% pyrexia Dyspnea(28%) was reported (28%) in patients treated with Kyprolis, with 4% of cases being Dyspnea was reported in patients treated with Kyprolis, 4% of cases being (4%pulmonary vs. 2%), and pulmonary (3% vs. 2%). Discontinuation due to any adverse (4% vs. 2%), and embolism (3% embolism vs. 2%). Discontinuation due to any adverse GradeEvaluate 3 or greater.

Evaluate dyspnea to exclude cardiopulmonary conditions including Grade 3 or greater. dyspnea to exclude cardiopulmonary conditions including occurred in 26% the25% KRdinarm the Rd events arm. Adverse leading to in 26% in the KRd arminvs. the vs.

Rd 25% arm. in Adverse leading events to failure and pulmonary syndromes.

Stop Kyprolis Grade 3until or 4 dyspneaevent untiloccurredevent cardiac failure cardiac and pulmonary syndromes.

Stop Kyprolis for Grade 3 or for 4 dyspnea of Kyprolis occurred in 12% of patients. discontinuationdiscontinuation of Kyprolis occurred in 12% of patients. resolved or returned to baseline.

Performassessment a benefit/risk assessment when considering resolved or returned to baseline.

Perform a benefit/risk when considering restarting Kyprolis. restarting Kyprolis.

Common Adverse (≥ 10% the KRd Arm) Occurring Common Adverse Events (≥ 10% inEvents the KRd Arm)inOccurring in Cycles 1–12 in Cycles 1–12 (Combination Therapy) (Combination Therapy)

Hypertension Hypertension

KRd Arm Rd Arm KRd Arm Rd Arm Hypertension, includingcrisis hypertensive crisis andemergency, hypertensive emergency, Hypertension, including hypertensive and hypertensive some of whichsome of which System Organ Class (N = 392) (N = 392) (N = 389) System Organ Class (N = 389) has been observed with Kyprolis. pressure were fatal, has were been fatal, observed with Kyprolis.

Monitor blood Monitor pressure blood regularly in all regularly in all patients. Ifcannot hypertension cannot controlled, be adequately controlled, withhold Kyprolis and evaluate. Preferred Term Preferred Term patients. If hypertension be adequately withhold Kyprolis and evaluate.

Grade Grade ≥ Grade ≥ Grade 3 Any Grade Any Grade3 ≥Any Grade 3 ≥Any Grade 3 Performassessment a benefit/risk assessment when considering restarting Kyprolis.

Perform a benefit/risk when considering restarting Kyprolis.

Venous Thrombosis Venous Thrombosis

Blood System and Lymphatic System Disorders Blood and Lymphatic Disorders

138 (35%) 53 (14%)

53 (33%) (14%) 127

127(12%) (33%) 47

47 (12%)

124(27%) (32%) 104

104(30%) (27%) 115

115(23%) (30%) 89

89 (23%)

100 (26%) 58 (15%)

58(19%) (15%) 75

75(10%) (19%) 39

39 (10%)

115 (29%) 7 (2%)

(2%) 1057 (27%)

105 (27%) 12 (3%)

680(17%)

0 53 (14%)

53 (14%) 1 (0%)

1 (0%)

Infusion reactions, including life-threatening have occurred in patients receiving Infusion reactions, including life-threatening reactions, havereactions, occurred in patients receiving Nausea (15%) (0%) Nausea 60 (15%) 160(0%) 391(10%) Kyprolis.

Symptoms include fever, chills, arthralgia, Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facialmyalgia, flushing,facial facialflushing, edema, facial edema, General Disorders and Administration Site Conditions General Disorders and Administration Site Conditions vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. reactions can occurfollowing immediately or up to administration 24 hours after administration These reactionsThese can occur immediately or upfollowing to 24 hours after Fatigue 109(5%) (28%) 21(27%) (5%) Fatigue 109 (28%) 21 104 of Kyprolis. with Pre-medicate with dexamethasone to reduceand the severity incidence of Kyprolis. Pre-medicate dexamethasone to reduce the incidence ofand severity of Pyrexia 93 (24%) 5 (1%) Pyrexia 93 (24%) 5 (1%) 64 (17%) infusion reactions Inform patients of the risk and symptoms of an infusion reaction and to infusion reactions Inform patients of the risk and symptoms of an infusion reaction and to contact a physicianif immediately of an infusion contact a physician immediately symptoms ofifansymptoms infusion reaction occur.reaction occur.

(16%) (1%) Edema PeripheralEdema Peripheral 63 (16%) 263(1%) 572(15%)

39 (10%) 3 (1%)

3 (1%)

104 (27%) 20 (5%)

57 (15%) 2 (1%)

2 (1%)

Thrombocytopenia Thrombocytopenia

Anemia

Anemia

138 (35%)

Venous thromboembolic events, deep venous Venous thromboembolic events, including deepincluding venous thrombosis andthrombosis pulmonaryand pulmonary Neutropenia 124 (32%) have been observed with Kyprolis.

In thestudy, combination study, the incidenceNeutropenia embolism, haveembolism, been observed with Kyprolis.

In the combination the incidence of venous thromboembolic events in the was first 13% 12 cycles was vs. 6% in the Kyprolis of venous thromboembolic events in the first 12 cycles vs. 6% in 13% the Kyprolis Thrombocytopenia Thrombocytopenia 100 (26%) combination control armWith respectively.

Kyprolisthe monotherapy, combination arm and controlarm armand respectively.

Kyprolis With monotherapy, incidence the incidence Disorders GastrointestinalGastrointestinal Disorders of venous thromboembolic was 2%. Thromboprophylaxis is recommended and of venous thromboembolic events was 2%.events Thromboprophylaxis is recommended and based onpatient an individual patient assessment. should be basedshould on anbe individual assessment.

Diarrhea Diarrhea 115 (29%) Infusion Reactions Infusion Reactions

Constipation

Constipation

64 (17%) 1 (0%)

P

T K si re 12 (3%) a

D

K a a 20 (5%) in 1 (0%)

53 (14%)

53(3%) (14%) 11

(3%) 4611(12%)

46 (12%) 7 (2%)

7 (2%)

Cases of thrombocytopenia caninoccur (40%) in patients receiving Cases of thrombocytopenia can occur (40%) patients receiving Kyprolis, with Kyprolis, platelet with platelet Infections and Infestations Infections and Infestations observed 8 and 15 of eachwith 28-day cycle, to with recovery to baseline nadirs observednadirs between Day 8between and DayDay 15 of eachDay 28-day cycle, recovery baseline Upper Infection Upper Respiratory TractRespiratory Infection Tract85 (22%) plateletoccurring count usually occurring by the of the next cycle.

Monitor platelet count usually by the start of the nextstart cycle.

Monitor platelet counts platelet counts frequently during Kyprolis.

Reduce or as withhold dose as appropriate. Nasopharyngitis Nasopharyngitis frequently during treatment with treatment Kyprolis. with Reduce or withhold dose appropriate.

63 (16%)

(22%) 785(2%)

(2%) 527(13%)

52 (13%) 3 (1%)

3 (1%)

630(16%)

0 43 (11%)

43 0(11%)

0

Asthenia

Asthenia

68 (17%)

K de

U

P

K p

F b ri

ASCOPost.com | SEPTEMBER 25, 2015

Announcements

tors and characterizes how T cells respond in patients undergoing immunotherapy. Recently, Dr. Weber has led or been a major participant in multiple cutting-edge trials using immune effector cells called tumorinfiltrating lymphocytes and other agents to boost cancer immunity utilizing novel agents (such as CTLA-

B:16.75” T:16.25” S:14.625”

Bronchitis

Bronchitis

Pneumonia

Pneumonia

a

a

4 and PD-1) to inhibit important checkpoint molecules on T cells.

Roles in Research, Treatment, Education, and Administration Prior to joining NYU Langone and its Perlmutter Cancer Center, Dr. Weber served since 2007 as a Senior Member of the H. Lee Moffitt Can-

54 (14%)

(14%) 554(1%)

(1%) 395(10%)

39 (10%) 2 (1%)

54 (14%)

54(9%) (14%) 35

(9%) 4335(11%)

43(7%) (11%) 27

and Nutrition Disorders Metabolism andMetabolism Nutrition Disorders Hypokalemia

Hypokalemia

78 (20%)

78(6%) (20%) 22

22(9%) (6%) 35

Hypocalcemia

Hypocalcemia

55 (14%)

55(3%) (14%) 10

(3%) 3910(10%)

39 (10%) 5 (1%)

43 (11%)

43(5%) (11%) 18

18(9%) (5%) 33

33(4%) (9%) 15

(22%) 388(1%)

(1%) 733(19%)

73 (19%) 3 (1%)

(11%) 743(2%)

(2%) 377(10%)

37 (10%) 4 (1%)

(16%) 663(2%)

(2%) 506(13%)

50 (13%) 8 (2%)

Hyperglycemia Hyperglycemia

35(3%) (9%) 12

and Connective and Connective Tissue DisordersTissue Disorders gMusculoskeletalMusculoskeletal

,

d

PAGE 81

Muscle Spasms Muscle Spasms

88 (22%)

Psychiatric Disorders Psychiatric Disorders Insomnia

Insomnia

63 (16%)

Respiratory, Thoracic, and Mediastinal Disorders Respiratory, Thoracic, and Mediastinal Disorders Cough

Cough

85 (22%)

(22%) 185(0%)

(0%) 461(12%)

46 0(12%)

Dyspneac

Dyspneac

70 (18%)

(18%) 970(2%)

(2%) 589(15%)

58 (15%) 6 (2%)

45 (12%)

(12%) 545(1%)

(1%) 535(14%)

53 (14%) 5 (1%)

EmbolicEvents, and Thrombotic49Events, (13%) Embolic and Thrombotic Venousd Venousd

49(4%) (13%) 16

16(6%) (4%) 22

(6%) 922(2%)

41(3%) (11%) 12

12(4%) (3%) 15

(4%) 415(1%)

Skin andTissue Subcutaneous Tissue Skin and Subcutaneous Disorders Disorders Rash

Rash

Vascular Disorders Vascular Disorders

Hypertensione

Hypertensione

41 (11%)

during pregnancy, if the patient becomes while taking Kyprolis, advise the during pregnancy, or if the patientorbecomes pregnant whilepregnant taking Kyprolis, advise the 2 (1%) patient ofhazard the potential hazard to the fetus. patient of the potential to the fetus.

27 (7%)

Lactation

Lactation

There is no information regardingofthe presence of Kyprolis human milk, the effects There is no information regarding the presence Kyprolis in human milk,inthe effects (3%) the breastfed infant,on ormilk the effects on milk production.

The developmental and health on12the breastfedoninfant, or the effects production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for benefits 5 (1%) of breastfeeding should be considered along with the mother’s clinical need for Kyprolis andadverse any potential effects oninfant the breastfed infant from Kyprolis or from Kyprolis and any potential effectsadverse on the breastfed from Kyprolis or from (4%) the underlying maternal condition. the15underlying maternal condition.

ContraceptionContraception

System Disorders Nervous SystemNervous Disorders b b Peripheral Neuropathies NEC 43 (11%) Peripheral Neuropathies NEC

cer Center and Director of its Donald A. Adam Comprehensive Melanoma Research Center. He also held the title of Professor in the Department of Oncologic Sciences at the University of South Florida. In addition, he has been the Principal Investigator and Director of Moffitt’s Skin Cancer SPORE (P50) NCI grant.

3 (1%) can cause Kyprolis cause fetal harm whentoadministered to pregnant Kyprolis fetal can harm when administered pregnant women Advisewomen femalesAdvise females reproductive use effectivemeasures contraception measures to prevent pregnancy of reproductiveofpotential to usepotential effectivetocontraception to prevent pregnancy during withfor Kyprolis for atfollowing least 2 weeks following completion of therapy. during treatment with treatment Kyprolis and at leastand 2 weeks completion of therapy.

4 (1%)

Pediatric Use Pediatric Use safety andofeffectiveness of Kyprolis in pediatric patients have not been established.

The safety andThe effectiveness Kyprolis in pediatric patients have not been established.

8 (2%)

Geriatric Use Geriatric Use 392 patients treated in with Kyprolis inwith combination withand lenalidomide and Of 392 patientsOf treated with Kyprolis combination lenalidomide 0 dexamethasone, 185 patients (47%) ≥ 65 years of age and 43 patients dexamethasone, 185 patients (47%) were ≥ 65 yearswere of age and 43 patients (11%) were (11%) were ≥75No years of age.

No overall differences inwere effectiveness observed ≥75 years of age. overall differences in effectiveness observed were between these between these 6 (2%) and younger patients. of The incidence of serious events was 50% and younger patients.

The incidence serious adverse events adverse was 50% in patients ≤ 65in patients ≤ 65 years age, 70% patients 65age, to 74and years ofin age, and 74% patients ≥ 75 years of age. years of age, 70% in of patients 65 toin74 years of 74% patients ≥ 75inyears of age.

Renal Impairment Renal Impairment 5 (1%)

Noadjustment starting dose adjustment is required patientsmild, with moderate, baseline mild, moderate, or severe No starting dose is required in patients withinbaseline or severe renal or patients on chronic dialysis based on a phase 2 pharmacokinetic and renal impairment or impairment patients on chronic dialysis based on a phase 2 pharmacokinetic and 9 (2%) safety trialThe of Kyprolis.

The pharmacokinetics Kyprolis was not influenced by the safety trial of Kyprolis. pharmacokinetics of Kyprolis wasofnot influenced by the degree of impairment, baseline renal impairment, whenreceiving patients were receiving dialysis. degree of baseline renal including whenincluding patients were dialysis.

Administer KYPROLIS after the dialysis procedure.

Administer KYPROLIS after the dialysis procedure.

4 (1%)

Hepatic Impairment Hepatic Impairment = Kyprolis, and low-doseRd dexamethasone; Rdand = lenalidomide and low-dose KRd = Kyprolis, KRd lenalidomide, andlenalidomide, low-dose dexamethasone; = lenalidomide low-dose

dexamethasone dexamethasone y The safety, efficacy and pharmacokinetics of not Kyprolis have not been evaluated in patients The safety, efficacy and pharmacokinetics of Kyprolis have been evaluated in patients a Pneumonia terms of pneumonia, bronchopneumonia Pneumonia includes preferredincludes terms ofpreferred pneumonia, bronchopneumonia with baseline hepaticPatients impairment.

Patients withlaboratory the following laboratory with baseline hepatic impairment. with the following values were values were b Peripheral NEC includes preferred underneuropathies HLT peripheral Peripheral neuropathies NECneuropathies includes preferred terms under HLT terms peripheral NECneuropathies NEC fromclinical the Kyprolis clinical trials: ≥ 3of× normal upper limit of normal (ULN) excluded from excluded the Kyprolis trials: ALT/AST ≥ 3 ×ALT/AST upper limit (ULN) c Dyspnea of dyspnea, dyspnea exertional Dyspnea includes preferredincludes terms ofpreferred dyspnea,terms dyspnea exertional bilirubin ≥and 2 × bilirubin ULN. ≥ 2 × ULN. d Embolicevents, and thrombotic events,preferred venous include terms MedDRA SMQ narrowand scope Embolic and thrombotic venous include terms inpreferred MedDRA SMQinnarrow scope of embolicevents, and thrombotic search of embolicsearch and thrombotic venous. events, venous.

Cardiac Impairment Cardiac Impairment e Hypertension terms hypertensive of hypertension, hypertensive crisis, hypertensive emergency Hypertension includes preferredincludes terms ofpreferred hypertension, crisis, hypertensive emergency

B:11.25”

S:10”

T:10.875”

DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION

Rd (N = 389) Adequately hydrate alltopatients prior to the andadministration following the administration Adequately hydrate all patients prior and following of Kyprolis of Kyprolis

182 (46%)

182 (46%) 119 (31%)

withintravenous both oral and intravenous (IV) fluids.with Premedicate with dexamethasone prior to with both oral and (IV) fluids. Premedicate dexamethasone prior to 119 (31%)

Decreased Absolute Decreased Absolute Neutrophil CountNeutrophil Count152 (39%)

152 (39%) 140 (36%)

140 (36%) at baseline.

Administer over 10-minuteDo IVnot infusion. Do not surface area at surface baseline.area Administer Kyprolis over aKyprolis 10-minute IVainfusion.

Decreased Lymphocytes Decreased Lymphocytes

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

B:11.25”

KRd Rd (N = 392) (N = 389)

Wants to Hear From You

S:10”

Laboratory Abnormality Laboratory Abnormality

KRd (N = 392)

The ASCO Post

T:10.875”

Safety patients New York Heart Association and IV Safety of patients withofNew Yorkwith Heart Association Class III and IVClass heartIIIfailure orheart failure or No relevant new clinically relevantin ARs in the later treatment cycles in the 274recent (70%)myocardial No new clinically ARs emerged theemerged later treatment cycles in the 274 (70%) recent myocardial infarction (within 3has to not 6 months) has not been evaluated. infarction (within 3 to 6 months) been evaluated. patients the KRd armtreatment who received treatment beyond Cycle 12. patients in the KRd arminwho received beyond Cycle 12.

OVERDOSE OVERDOSE Gradeadverse 3 and higher adverse reactionsduring that occurred during Cycles 1-12 with a substantial Grade 3 and higher reactions that occurred Cycles 1-12 with a substantial difference 2%) between the two arms werethrombocytopenia, neutropenia, thrombocytopenia, difference (≥ 2%) between(≥the two arms were neutropenia, of chills,renal hypotension, renalthrombocytopenia insufficiency, thrombocytopenia and lymphopenia Acute onset of Acute chills, onset hypotension, insufficiency, and lymphopenia hypokalemia, and hypophosphatemia. hypokalemia, and hypophosphatemia. hasfollowing been reported following a dose of 200 mg of Kyprolis administed in error. has been reported a dose of 200 mg of Kyprolis administed in error.

Laboratory Abnormalities Laboratory Abnormalities Thereantidote is no specific antidote for KyprolisInoverdosage. the event overdose, the patient There is no specific for Kyprolis overdosage. the event of In overdose, theofpatient m should specifically be monitored, the adverse in the adverse reaction section. should be monitored, forspecifically the adversefor reactions in thereactions adverse reaction section.

Grade Abnormalities 3–4 Laboratory( Abnormalities ( ≥1-12 10%) in Cycles 1-12 Grade 3–4 Laboratory ≥ 10%) in Cycles (Combination Therapy) (Combination Therapy)

Before his time at Moffitt, Dr. ­Weber served for over 10 years at the University of Southern California (USC) Norris Comprehensive Cancer Center, rising to the positions of Chief of Medicine and Chief of the Division of Medical Oncology.

Dr. Weber has published more than 150 peer-reviewed articles. He has also served on the NCI’s Clinical Oncology Study Section, as well as the boards of the Melanoma Research Foundation and the Melanoma Therapeutics Foundation, and was Chair of the U.S. Veterans Administration’s Clinical Oncology Study Section.

Dr. Weber earned his doctorate in molecular cell biology at The Rockefeller University, and his medical degree from NYU School of Medicine.

He completed internship and residency training at the University of California San Diego and fellowship training in medical oncology and tumor immunology at the NCI. n

administering Kyprolis.

Calculatedose the using Kyprolis using the patient’s administering Kyprolis.

Calculate the Kyprolis the dose patient’s acutal body acutal body

Decreased Phosphorus Decreased Phosphorus

122 (31%)

122 (31%) 106 (27%)

as athe bolus.

Flush IV line withor normal saline orinjection 5% dextrose injection administer as aadminister bolus. Flush IV line withthe normal saline 5% dextrose 106 (27%)

Decreased Platelets Decreased Platelets

101 (26%)

101 (26%) 59 (15%)

59 (15%) administer as another infusion with other medicines. Thromboprophylaxis is recommend for administer as an infusion with medicines.

Thromboprophylaxis is recommend for

immediately and administration. after Kyprolis administration.

Do notwith mix or Kyprolis with or immediately before and afterbefore Kyprolis Do not mix Kyprolis

Decreased Total Decreased Total White Blood CellWhite CountBlood Cell Count 97 (25%)

97 (25%) 71 (18%)

patientswith being with theofcombination of Kyprolis,and lenalidomide and dexamethasone. patients being treated thetreated combination Kyprolis, lenalidomide dexamethasone.

71 (18%)

Decreased Hemoglobin Decreased Hemoglobin

58 (15%)

58 (15%) 68 (18%)

68 (18%)

Decreased Potassium Decreased Potassium

41 (11%)

41 (11%) 23 (6%)

23 (6%) product can be found at www.kyprolis.com or 1-877-669-9121. product labeling can belabeling found at www.kyprolis.com or 1-877-669-9121.

Consider antiviral in treated patientswith being treated with Kyprolis.

Consider antiviral prophylaxis in prophylaxis patients being Kyprolis.

The riskprovided information here is not comprehensive.

The FDA-approved The risk information hereprovided is not comprehensive.

The FDA-approved

KRdlenalidomide, = KYPROLIS, and low-doseRd dexamethasone; Rdand = lenalidomide KRd = KYPROLIS, andlenalidomide, low-dose dexamethasone; = lenalidomide low-dose and low-dose This product, its production, and/or its use may be covered or more US Patents, This product, its production, and/or its use may be covered by one or moreby USone Patents, dexamethasone dexamethasone including Patent Nos. 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346; including US Patent Nos.US 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346;

Post-marketing Post-marketing Experience Experience

8,207,125; 8,207,126; andwell 8,207,297 well asorother patents or patents pending.

8,207,125; 8,207,126; 8,207,127; and8,207,127; 8,207,297 as as otheraspatents patents pending.

following adverse were in the post-marketing experience with The following The adverse reactions were reactions reported in thereported post-marketing experience with Kyprolis.

Because these reactions are reported voluntarily fromofauncertain population of uncertain Kyprolis. Because these reactions are reported voluntarily from a population size, itpossible is not always possible to reliably estimate their frequency or establish a causal ize, it is not always to reliably estimate their frequency or establish a causal to drug exposure:TTP/HUS, dehydration, elationship to relationship drug exposure: dehydration, TLSTTP/HUS, including TLS fatal including outcomes,fatal outcomes, and PRES. and PRES.

DRUG INTERACTIONS DRUG INTERACTIONS

Kyprolis is primarily viaepoxide peptidase and epoxide hydrolase activities, and as Kyprolis is primarily metabolized viametabolized peptidase and hydrolase activities, and as a result, the pharmacokinetic profile of Kyprolis unlikelyby to concomitant be affected by concomitant a result, the pharmacokinetic profile of Kyprolis is unlikely to beis affected cytochrome inhibitors Kyprolis and inducers. administration administration of cytochrome of P450 inhibitorsP450 and inducers. is notKyprolis expectedistonot expected to influence exposure nfluence exposure of other drugs. of other drugs.

USE IN SPECIFIC POPULATIONS USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy

Kyprolis cause fetalare harm.

There areand nowell-controlled adequate and well-controlled studies in Kyprolis may cause fetalmay harm.

There no adequate studies in pregnant women using Kyprolis. pregnant women using Kyprolis.

Females ofpotential reproductive potential should be advised to avoid becoming Females of reproductive should be advised to avoid becoming pregnant whilepregnant while being treated with Kyprolis.

Consider benefits and risks Kyprolis and possible being treated with Kyprolis.

Consider the benefits andtherisks of Kyprolis andofpossible risks to the fetus when prescribing Kyproliswoman. to a pregnant woman.

If Kyprolis is used isks to the fetus when prescribing Kyprolis to a pregnant If Kyprolis is used

Write to The ASCO Post at editor@ASCOPost.com Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

The ASCO Post | SEPTEMBER 25, 2015

PAGE 82

Art of Oncology

Let It Be Hard

By Andrea M. Watson, MD, MS

The ASCO Post is pleased to reproduce installments of the “Art of Oncology” as published previously in the Journal of Clinical Oncology ( JCO). These articles focus on the experience of suffering from cancer or of caring for people diagnosed with cancer, and they include narratives, topical essays, historical vignettes, poems, and photographic essays.

To read more, visit http://jco. ascopubs.org/ and search “Art of Oncology.” For information on how you can submit your own essay for consideration in JCO’s Art of Oncology, visit http:// jco.ascopubs.org/site/ifc/ determine-my-article-ty pe. xhtml#art-of-oncology

L

ong before he relapsed, and quite out of the blue, Alexander told me that he was not afraid to die. “I just don’t want to be in pain when it happens,” he said, matter of factly. I smiled and reassured him that he was not going to die and that once his counts recovered, he would go home from the hospital. “I will be expecting an invitation to your high school graduation party,” I added. For a time, I was right. Alexander got better in a few days and went home. However, several months later, his leukemia relapsed, and death was imminent.

I walked into his room early on a Sunday morning. Alexander was sitting up in a chair and with big eyes and a quiet smile he looked up and asked if he could go swimming. “Yes,” I said, instinctively. I was ignoring the fact that he was in no condition to leave his intensive care room. His strength was fading, and he had not been out of bed in days. His frail body, ravaged by months of unsuccessful treatments for relapsed leukemia, was just skin and bones under

Dr. Watson is a pediatric oncologist at Essential Health Cancer Center in Duluth, Minnesota.

his hospital gown. His bald head accentuated his big brown eyes and endearing smile. At 14, he seemed wise beyond his years, yet truly a child at heart, despite all that he had been through.

“Yes,” I said, sitting down beside him.

“You should go swimming today.”

While caring for Alexander during his final days, I tried to keep him comfortable, although I struggled with grief and sadness. I sought counsel from a seasoned palliative care colleague. “It is just so hard,” I said, defeated. He listened, let me cry, and said, “It is hard.

Let it be hard—it is rich.”

Caring for dying children is both a great privilege and a heavy burden.

The dying process is unpredictable, and the desire to alleviate suffering can be overwhelming. At a time when parents desperately want control, our offerings feel inadequate. We can only walk the road with our patients, try to keep them comfortable and, when possible, break the rules to honor their requests. We do our best to ease suffering, but we cannot prevent death.

During treatment we become intimately involved in the lives of our patients. From the first moments of a new diagnosis to the day-to-day routine of treatment, the relationship deepens.

Tensions slacken, children warm up to us, and we inevitably fall in love with our patients. There is hope on the horizon. There are cancer survivors in the waiting room. Parents confer with one another about how it was for their child while undergoing chemotherapy.

We counter their fear with confidence, reassurance, and optimism. But then there is relapse.

When Kelly’s rhabdomyosarcoma relapsed, she was angry and swore she would never agree to more chemo. After talking about what it would mean to stop, she changed her mind and chose to proceed with nearly 3 more years of salvage therapies that ultimately failed to cure her very aggressive cancer. During that time, she graduated early from high school, completed a year of college, and joined a sorority. I attended her high school graduation party on the family

farm and bent rules to get her out of the hospital early for her prom. I listened to stories of first college roommate disasters and watched the unfolding of young love. As teenagers undergoing cancer treatment often do, she tested the limits of how late she could show up for appointments and admissions—but she never missed a treatment.

Caring for Kelly during the final days of her life was exhausting, challenging, and at times frustrating, yet there is nowhere in the world that I would rather have been. The night before she died, she asked to go out on pass from the hospital so that she could see her animals at the farm and get snow cones. Friends and family gathered at her house on that hot July evening, and there were snow cones for everyone. She returned to the hospital

rounded by flowers and encircled by a brick path. Names of children, quotes, or sayings are engraved on the bricks that surround the angel, dedicated to those who have died. Alexander’s family chose to have a brick engraved with his name, followed by the simple words: “He lived. He loved. He left.”

For the care team, each death brings lessons, and the richness deepens. My appreciation for each and every child I care for increases. The tragedy of childhood death is by no means limited to the world of pediatric oncology. Innocent children die in wars and accidents every day. Although we may live in a world sheltered from the daily violence that shatters many families, communities, and countries, the end result is the same—the pain of losing your child is universal.

Walking with our patients and their families during those final weeks, days, and moments is some of the most important work we do.

—Andrea M. Watson, MD, MS

near midnight, in pain and exhausted, but happy. She died quietly the next day. I wept with the family and helped them make funeral arrangements. I watched as the nurses lifted her lifeless hand to make a thumbprint for a keepsake medallion to give to her devastated parents and young boyfriend.

We ate snow cones at her funeral.

Continuing to foster relationships with families after the death of their child can be healing for both families and the care team. One of the ways that our program supports grieving families is to remember their child with an engraved brick, placed in the “Angel of Hope” garden in our community. A bronze statue of an angel stands just yards from Lake Superior, sur-

At times the orb of sadness is so great, so intense, that I want to escape.

As pediatric oncologists we remind ourselves that we did not cause the cancer, that relapse can happen despite optimal treatment, and that it is our duty to continue to provide care when even our best therapies fail. It takes wisdom and perspective not to see these events as personal failure. It is hard, but it is rich.

When we embrace the richness, we find humility and courage. Walking with our patients and their families during those final weeks, days, and moments is some of the most important work we do. In return, we carry the lessons from each child forward: go swimming, eat snow cones, be with those you love, and do not fear death. n

To read more of the Art of Oncology, visit http://jcoascopubs.org and search Art of Oncology.

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The ASCO Post | SEPTEMBER 25, 2015

PAGE 84

Patient’s Corner

My Positive Attitude Is Keeping Me Alive

Despite three recurrences of renal cell carcinoma, I don’t believe the cancer will kill me.

By Robert Bonney, as told to Jo Cavallo

U

ntil I was diagnosed with stage III renal cell carcinoma in early 2008, I had no firsthand experience with cancer. To my knowledge, there is no history of cancer in my immediate family, and despite a smoking habit I picked up when I was young, I had been in relatively good health in the 56 years leading up to my diagnosis.

So it came as a complete shock when I went to the bathroom one night and saw blood filling the toilet bowl. I was so frightened and immediately went to the emergency room, only to be told to make an appointment with my primary care physician. But before I could see him, I continued to pass blood, and the pain in my lower back became so severe, I headed back to the emergency room to find out what was wrong.

This time, a computed tomography (CT) scan was performed, which showed a large tumor in my right kidney that extended over my right adrenal gland and part of my renal vein.

A biopsy of the tumor confirmed advanced-stage renal cell carcinoma, and 3 weeks later, a surgical oncologist removed the kidney, adrenal gland, and part of my renal vein. No other treatment was recommended.

Although I was still feeling a bit fatigued, I went back to work soon af-

ter the surgery but had to quit several months later as my level of fatigued increased.

Facing Multiple Recurrences During conversations with my oncologist about my diagnosis and treatment plan, I never received a prognosis and was not sure what I could

fer me material I could take with me.

The fact that I was closely monitored the first 2 years following my diagnosis—I had a CT scan every 3 months—gave me confidence that any recurrence of the cancer would be found at an early enough stage that my life wouldn’t be threatened.

And that has basically been true so

After my diagnosis of renal cell carcinoma, my oncologist praised my positive attitude in facing the disease head-on, but when you are dealing with a life-threatening illness like cancer, what other attitude can you have?

—Robert Bonney

expect in the future, although I knew I was at high risk for cancer recurrence. And because coping with such a serious illness was all so new to me, I didn’t know what questions to ask or even where to find information about my cancer. Unlike the more common cancers, such as breast, prostate, and lung cancers, my doctor’s waiting room didn’t include pamphlets about renal cell carcinoma, and he didn’t of-

far.

Eighteen months after my primary diagnosis, the cancer recurred in my left adrenal gland, necessitating surgical removal of that gland as well. I was prescribed hydrocortisone to manage my adrenal insufficiency.

I remained in remission for 5 years, and during that time, other than not being able to work full time, I lived my life without too many constraints

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

and generally felt well. But in 2014, I began experiencing a sharp pain in my left shoulder, and an imaging scan showed a peach-sized tumor: The cancer was back again.

This time the treatment was more intense. Because the tumor was large, one-third of my shoulder blade had to be excised along with the cancer, followed by 20 rounds of radiation therapy. Four months later, the cancer showed up in my liver, and I was prescribed 800 mg/d of pazopanib (Votrient), which has been effective in shrinking the seven lesions peppered throughout my liver.

Looking Toward the Future After my diagnosis of renal cell carcinoma, my oncologist praised my positive attitude in facing the disease head-on, but when you are dealing with a life-threatening illness like cancer, what other attitude can you have?

I want to live, and despite my three recurrences—and the fact that I’ll probably have more—I don’t believe the cancer will kill me.

There are goals I still want to achieve in my life, and I believe I have time to see those goals realized. n Robert Bonney lives in Coos Bay, Oregon.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

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April 20, 2015

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Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. D.T. Le et al. Editorial: H.L. Kaufman PIK3CA Mutations Are Associated With Decreased Benefit to Neoadjuvant Human Epidermal Growth Factor Receptor 2–Targeted Therapies in Breast Cancer. I.J. Majewski et al. Editorial: D.W. Cescon et al Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in NSABP B-31 Trial. K.L. Pogue-Geile et al. Editorial: D.W. Cescon et al Circulating Tumor Cell Biomarker Panel As an Individual-Level Surrogate for Survival in Metastatic Castration-Resistant Prostate Cancer. H.I. Scher et al Editorial: A.J. Armstrong et al Radiographic Progression-Free Survival As a Response Biomarker in Metastatic Castration-Resistant Prostate Cancer. M.J. Morris et al. Editorial: A.J. Armstrong et al Increased Incidence of Fractures in Recipients of Hematopoietic Stem-Cell Transplantation X.N. Pundole et al Understanding the Pathway: Deciphering the Role of Phosphatidylinositol 3–Kinase Mutations in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer. S. Goel et al

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The ASCO Post | SEPTEMBER 25, 2015

PAGE 86

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER ‘Encouraging Results’ With Newer EGFR TKIs in Patients With NSCLC Who Progressed After Prior EGFR TKI Therapy Two studies of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors among patients with non–small cell lung cancer (NSCLC) who had progressive disease following treatment with a first-generation EGFR tyrosine kinase inhibitor “show encouraging results,” according to an editorial accompanying the studies in The New England Journal of Medicine. The editorial was written by Ramaswamy Govindan, MD, of the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis.

In a study of the EGFR inhibitor AZD9291 (mereletinib), the overall objective tumor response rate among 239 patients who could be evaluated was 51%. The rate was 61% among the 127 patients with centrally confirmed T790M resistance mutations vs 21% among 61 patients without centrally detectable EGFR T790M. In a study of rociletinib, the objective response rate among 49 patients with T790M-positive disease who could be evaluated was 59% vs 29% among 17 patients with T790M-negative disease.

“Despite initial responses to EGFR tyrosine kinase inhibitors, the majority of patients will have disease progression within 1 to 2 years after treatment initiation (acquired resistance). In approximately 60% of patients, the mechanism

of acquired resistance is the development of an additional EGFR mutation, EGFR T790M,” Pasi A. Jänne, MD, PhD, of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, and colleagues noted in their report on the AZD9291 study.

Mereletinib Study Details AZD9291, shown in preclinical models to be effective against both EGFR tyrosine kinase inhibitor–sensitizing and T790M resistance mutations, was administered at doses of 20 to 240 mg once daily in patients with advanced lung cancer and radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. “Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated,” the investigators stated.

In addition to these patients, 222 were enrolled in expansion cohorts at 33 sites in 9 countries, including the United States. Among the total of 253 patients, 62% were Asian; 62% were women; and 96% had adenocarcinoma.

All patients had at least one prior EGFR tyrosine kinase inhibitor, and 80% had received prior chemotherapy.

The median progression-free survival was 9.6 months in EGFR T790M–positive patients and 2.8 months in EGFR T790M–negative patients. The most common adverse events were diarrhea, rash, nausea, and decreased appetite.

Rociletinib (CO-1686) Study Details The phase I/II study of rociletinib (CO-1686), shown to be active in

© Eldon Dedini/The New Yorker Collection/www.cartoonbank.com

preclinical models of EGFR-mutated NSCLC with or without T790M, enrolled 130 patients at 10 centers in the United States, France, and Australia. All patients had at least one line of EGFR tyrosine kinase inhibitor therapy, most commonly erlotinib, and the median number of prior treatments was four.

“The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt form (500 mg twice daily to 1,000 mg twice daily),” the investigators explained. A maximum tolerated dose was not identified. “The only common dose-limiting adverse event was hyperglycemia,” they added.

“In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the hydrogen bromide salt form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59%,” the authors stated. The disease control rate, including patients with a complete or partial response or stable disease, was 93% (43 of 46 patients). The estimated median progression-free survival at the time of analysis was 13.1 months.

The response rate among the 17 patients with T790M-negative disease who could be evaluated was 29%, and the disease control rate was 59%. The median progression-free survival was 5.6 months.

“The most common grade 3 toxic effect associated with rociletinib was hyperglycemia. Most hyperglycemia events were successfully managed with dose reduction, oral hyperglycemic therapy (most commonly metformin), or both, and no hyperglycemia events led to rociletinib discontinuation,” the researchers reported.

“Finding EGFR T790M in tumor specimens after initial therapy with firstgeneration EGFR tyrosine kinase inhibitors now has practical relevance,” Dr. Govindan wrote in the editorial. “In the immediate future, before the drugs are approved and widely available, these patients should be considered for ongoing clinical trials with T790M-specific EGFR tyrosine kinase inhibitors. Patients with EGFR inhibitor–resistant NSCLC whose tumor cells are activated through other oncogenes should be enrolled in appropriate clinical trials when possible.”

The AZD9291 trial was funded by AstraZeneca and is registered at Clini-

calTrials.gov as NCT01802632. The rociletinib trial was funded by Clovis Oncology and is registered at ClinicalTrials.gov as NCT01526928.

Govindan R: N Engl J Med 372:17601761, 2015.

Jänne PA, et al: N Engl J Med 372:16891699, 2015.

Sequist LV, et al: N Engl J Med 372:17001709, 2015.

ACUTE MYELOID LEUKEMIA Azacitidine Increased Median Overall Survival Among Patients Aged 65 and Older With > 30% Blasts A multicenter, randomized, openlabel, phase III trial among the difficultto-treat population of patients aged aged 65 and older with acute myeloid leukemia (AML) with > 30% bone marrow blasts “showed that azacitidine was associated with a clinically meaningful improvement” in median overall survival and 1-year survival, researchers reported in Blood. Among 488 patients with newly diagnosed AML, median overall survival was 10.4 months for those receiving azacitidine (Vidaza) vs 6.5 months for those treated with commonly used current AML treatments (P = .1009), and the respective 1-year survival rates were 46.5% vs 34.2%.

The trial was conducted by an international team of researchers from 18 countries in Asia, Australia, Europe, and the United States, including ­Richard M. Stone, MD, of Dana-Farber Cancer Institute, Boston.

Study Details Before randomization, a conventional care regimen was preselected by a physician for each patient. Patients then were assigned 1:1 to receive azacitidine (n = 241) or conventional care (n = 247). Those assigned to conventional care received their preselected treatment, with 158 receiving low-dose cytarabine, 45 receiving best supportive care, and 44 receiving standard induction chemotherapy. Those assigned to azacitidine received 75 mg/m2/d for 7 consecutive days per 28-day treatment cycle, completing at least six cycles.

“Adverse events were consistent with the well-established safety profile of azacitidine,” the researchers reported. Treatment-emergent adverse events occurred in 99.2% of patients receiving azacitidine and 100% of those

ASCOPost.com | SEPTEMBER 25, 2015

PAGE 87

In the Literature

receiving conventional care. Grade 3-4 treatment-emergent adverse events occurring in ≥ 10% of patients receiving azacitidine were febrile neutropenia, neutropenia, and thrombocytopenia.

Treatment-emergent adverse events leading to study discontinuation occurred in 9.3% of patients in the azacitidine group, 13.1% in the low-dose cytarabine group, and 11.9% in the induction chemotherapy group.

Overall, adverse events were the most common reason for early discontinuation in the trial, leading to 89 patients (37%) in the azacitidine group and 66 patients (28%) in the conventional care group discontinuing. The second most common reasons for discontinuation was the death of 53 patients (22%) receiving azacitidine and 58 patients (24%) receiving conventional care. By the end of the study, 394 patients (80.7%) had died, 193 patients (80.1%) in the azacitidine group and 201 patients (81.4%) in the conventional care group.

with conventional care across all subgroups defined by baseline demographic and disease features,” the authors stated. They also acknowledged, “the primary endpoint was not met (stratified hazard ratio = 0.85 [95% confidence interval: 0.60–1.03], P = .1009) influenced by the convergence of the Kaplan-Meier curves at around 22

months. Such convergence is not unexpected in a disease with no cure and a patient population with poor overall survival,” the researchers wrote.

“Combination treatment regimens may further improve outcomes for older patients with AML,” the investigators noted, citing promising response rates of 30% to 40% in early trails of azaciti-

NCCN 10th Annual Congress:

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Subgroup Analyses In a prespecified analysis censoring patients who received AML treatment after discontinuing the study drug, 1-year survival rates were 50.7% for azacitidine and 37.7% for conventional care. Median overall survival in these patients was 12.1 months for azacitidine vs 6.9 months for conventional care (P = .0190).

“Univariate analysis showed favorable trends for azacitidine compared

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dine in combination with lenalidomide (Revlimid), panobinostat (Farydak), and sorafenib (Nexavar). “Larger studies are need to confirm these findings,” the authors stated.

The study is registered at www.ClinicalTrials.gov as NCT01074047.

Dombret H, et al: Blood 126:291299, 2015. n

This congress is approved for AMA PRA Category 1 Credit™ and is also certified for nurses and pharmacists. Learn more at NCCN.org/hem.

This activity is supported by educational grants from Actelion Pharmaceuticals US, Inc.; Astellas Scientific and Medical Affairs, Inc.; Celgene Corporation; Novartis Pharmaceuticals Corporation; Seattle Genetics; Spectrum Pharmaceuticals, Inc.; and Takeda Oncology.

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Perspective Ronald A. DePinho, MD continued from page 1

low, and more states need to pass laws restricting tanning bed use to protect our youth from harmful ultraviolet (UV) radiation exposure and an increased risk of melanoma. These are serious issues to overcome.

The Centers for Disease Control and

Prevention has worked diligently to educate Americans about cancer risks and prevention. The same is true for numerous other groups, including comprehensive cancer centers, hospitals and health-care systems, K-12 schools, advocacy groups, insurance companies, and the pharmaceutical industry. And when it comes to making prevention services more accessible,

the Patient Protection and Affordable Care Act has created a framework to make a difference for millions of people, particularly the underserved.

However, much more is needed to ensure the conversion of knowledge into cultural transformation. Consider our efforts with traffic safety and the use of seat belts, where a comprehen-

sive, decades-long strategy of policy, education, and technology services has led to permanent societal change that saves lives. We need to do the same for cancer prevention, emphasizing its value through new public policies to protect children, comprehensive educational initiatives to impart knowledge during captive K-12 years, and preventive services that are accessible and affordable.

Making Cancer Prevention a National Priority

News, Advocacy and Analysis on Cancer Policy

YOUR SOURCE FOR

Cancer-Related Policy News ASCO in Action is the American Society of Clinical Oncology’s (ASCO) online information hub for the critical policy issues that affect cancer practice, research, and patient care in the United States today.

Updated daily, ASCO in Action is your source for breaking news on developments you most care about:

At The University of Texas MD Anderson Cancer Center, we focus on offering diverse clinical preventive and therapeutic services aimed at reducing risk, identifying disease early, and making a measurable reduction in the cancer burden. Our cross-functional professional teams are charged with executing goal-oriented, milestone-driven efforts to convert current knowledge into drugs, tests, devices, public policies, and educational campaigns that quickly benefit society. These efforts go beyond prevention—they demonstrate cancer control.

Legislative efforts offer significant opportunities to reduce cancer incidence. One prime example is youth tanning and UV exposure. Research shows that tanning bed use starting between the ages of 18 and 24 increases a person’s risk of melanoma by 91%.1 To help protect its young citizens from tanning bed–related UV exposure, California took a bold step and, in 2011, became the first state to prohibit tanning bed

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PAGE 89

Perspective

use for minors under the age of 18.

Sensing an opportunity in our home state to raise public awareness of the dangers of indoor tanning, our multidisciplinary team of legislative experts, prevention specialists, and melanoma researchers worked with numerous organizations to educate Texas legislators about tanning bed risks and, in 2013, Texas became the fourth state to enact such a law. To keep the momentum going, we worked with MD Anderson Can-

offerings targeting UV light protection to reduce skin cancer risk and tobacco use prevention to reduce the risks of multiple cancer types.

We can all be proud of this public/ private investment in our children, which will save many lives across generations, but because CATCH currently is available in so few elementary and middle schools across the country, we are missing an opportunity to reach even more children. Cost-effective,

Cost-effective, proven programs like CATCH should be available in all schools because knowledge is cancer’s greatest vulnerability and education is the essential foundation for success.

—Ronald A. DePinho, MD

cer Network sites around the country and advocacy groups like the American Cancer Society Cancer Action Network to help educate elected officials in other states about the dangers of tanning beds.

At present, nine additional states have passed similar legislation, and many others are considering it. Together, through education and action, we can decrease future cancer risk for our children.

To accelerate that process, we partnered with the Coordinated Approach to Child Health (CATCH), an evidence-based multifaceted program devoted to improving children’s lives through healthy eating and physical activity, and we are working to expand its

proven programs like CATCH should be available in all schools because knowledge is cancer’s greatest vulnerability and education is the essential foundation for success.

As Nelson Mandela once said, “Education is the most powerful weapon, which you can use to change the world.”

I could not agree more.

Reducing the Incidence of Smoking While great strides have been made over the past 50 years to reduce tobacco use, more than 40 million Americans continue to smoke today. What’s even more troubling is that more than 88% of adult

smokers report starting their habitual use of tobacco as children or adolescents.2 Educational efforts have made a difference, but more state and local governments need to explore effective evidence-based policy options like increasing taxes on tobacco products, mandating more smoke-free areas, and raising the minimum legal age to purchase tobacco products. In 2013, lawmakers in New York City passed legislation raising the purchasing age of tobacco products from 18 to 21, which also includes the sale of electronic cigarettes. The state of Hawaii also recently raised the minimum tobacco purchasing age to 21. To the legislative leaders in Hawaii and New York, I say, “Way to go!”

But those efforts are not enough.

We need to spread antitobacco messages where our youth live, work, and play, which means harnessing all available communication mechanisms from video games to social media. We have an obligation to surround them with evidence-based strategies and accurate information to reduce their likelihood of taking that first puff.

cine to protect our children from the merciless pain and suffering caused by these cancers, and we need significant education strategies to ensure parents insist that their pediatricians administer all three doses of the vaccine. Our researchers at MD Anderson have developed programs to support that education, but more must be done.

Other countries have made education about the importance of HPV vaccination a national priority. For example, in 2007, the Australian government launched a major campaign to inform parents about the need to vaccinate, which has been an overwhelming success, with more than 71% of children receiving the vaccine. Mexico also has had tremendous success in getting 67% of its population to vaccinate. That’s a remarkable figure, considering Mexico’s health-care infrastructure is much less developed than ours. With U.S. vaccination rates for women at 32% and those for young men much lower, it’s time for our health-care and policy leaders to stand up for our children and protect them from HPV-related cancers.

Increasing HPV Vaccination Rates

Closing Thoughts

Each year in America, HPV is estimated to cause 26,000 cases of cancer, including cervical, anal, throat, and tonsil cancers, among others. This brings us to a very important subject: HPV vaccination for the prevention of cervical cancer and other cancers resulting from HPV infection. As the father of young children, I can tell you my two daughters and one son received this cancer vaccine.

We have a safe and effective vac-

In Remembrance of September 11, 2001

I have outlined several major public and private efforts, but more needs to be done on an individual level to ensure that children are protected from getting cancer as they age. A daycare teacher who covers kids in sunscreen before sending them outside to play is making a difference. A religious leader who educates his congregation about how the HPV vaccine protects against cancer and has nothing to do with promoting promiscuity is making a difference. A politician who votes to support a bill banning the sale of e-cigarettes to children is making a difference.

We can all make a difference in our everyday lives, and we should challenge ourselves to consider actions we can take across policy, education, and services to empower our children and—to borrow MD Anderson’s tagline here— help in Making Cancer History®. n

PHOTO: THINKSTOCK

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

New York’s Tribute of Light brightens the Manhattan skyline, paying tribute to the Twin Towers and all who were lost on September 11, 2001.

References 1. Lazovich D, Vogel RI, Berwick M, et al: Indoor tanning and risk of melanoma: A case-control study in a highly exposed population. Cancer Epidemiol Biomarkers Prev 19:1557-1568, 2010.

2. Centers for Disease Control and Prevention: Youth and tobacco use. Available at cdc.gov/tobacco/data_statistics/fact_ sheets/youth_data/tobacco_use. Accessed September 3, 2015.

T:7"

PAGE 90 AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

NCI Comprehensive Cancer Centers continued from page 53

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.

Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]

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 (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).]

1.6 Platinum‑Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum‑ resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations and Fistulae 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 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation.

Fatal outcome was reported in <1% of Avastin‑treated patients. In a platinum‑resistant ovarian cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients with evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded.

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Avoid use of Avastin in patients with ovarian cancer who have evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Permanently discontinue Avastin in patients with gastrointestinal perforation.

In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.3% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation.

Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Non‑Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo‑ esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑ marketing experience. Most events occurred within the first 6 months of Avastin therapy.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae.

Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.3 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).]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.4 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal,

5.11 Embryo‑fetal Toxicity Avastin may cause fetal harm based on the drug’s mechanism of action and findings from animal studies. Congenital malformations were observed with the administration of bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10 mg/ kg. Furthermore, animal models link angiogenesis and VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryo‑ fetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose of Avastin [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1).]

5.12 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 (8.3).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations and Fistulae[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Non‑Gastrointestinal Fistulae [See Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Venous Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Posterior Reversible Encephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.9).]

• Infusion Reactions [See Dosage and Administration (2.4), Warnings and Precautions (5.10).]

• Ovarian Failure [See Warnings and Precautions (5.12), Use in Specific Populations (8.1).]

AVASTIN® (bevacizumab) 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 Some of the adverse reactions are commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar‑plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel.

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 4996 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer or platinum‑ resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer including controlled (Studies 1, 2, 4, 5, 8 9 and 10) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 42% male and 86% White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 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, 337 mRCC patients who received a median of 16 doses of Avastin, 218 cervical cancer patients who received a median of 6 doses of Avastin and 179 platinum‑resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of 6 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 1338 adjuvant CRC patients, including 669 female patients, who received a median of 23 doses of Avastin, and 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. 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 6, 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 (5.3).]

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 (5.4).]

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%).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

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 5, 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 6, 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, 5, 8 and 10. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, 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 8).

In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.9).]

Congestive Heart Failure (CHF) 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 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.

T:13"

• Alabama: University of Alabama • Arizona: Arizona Cancer Center • California: Chao Family Comprehensive Cancer Center, City of Hope, Jonsson Comprehensive Cancer Center, UC San Diego Moores Cancer Center, UCSF Helen Diller Family Comprehensive Cancer Center, UC Davis Comprehensive Cancer Center, USC/Norris Comprehensive Cancer Center (Los Angeles) • Colorado: University of Colorado Cancer Center • Connecticut: Yale Cancer Center • District of Columbia: Lombardi Comprehensive Cancer Center • Florida: H. Lee Moffitt Cancer Center • Illinois: Robert H. Lurie Comprehensive Cancer Center, University of Chicago Comprehensive Cancer Center • Iowa: The Holden Comprehensive Cancer Center at Univ. of Iowa • Maryland: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins • Massachusetts: Dana-Farber/Harvard Cancer Center • Michigan: Karmanos Cancer Institute, University of Michigan • Minnesota: Mayo Clinic, Masonic Cancer Center at Univ. of Minnesota • Missouri: Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis • New Hampshire: Norris Cotton Cancer Center • New Jersey: The Cancer Institute of New Jersey • New Mexico: The University of New Mexico Comprehensive Cancer Center • New York: New York-Presbyterian/ Columbia University, Memorial Sloan Kettering, Roswell Park • North Carolina: Wake Forest University, Duke Cancer Institute, UNC Lineberger Comprehensive Cancer Center • Ohio: Case Comprehensive Cancer Center, Ohio State University Comprehensive Cancer Center • Pennsylvania: Abramson Cancer Center, Fox Chase, UPMC Cancer Centers • Tennessee: Vanderbilt-Ingram, St. Jude Children’s Research Hospital • Texas: Dan Duncan Cancer Center at Baylor, MD Anderson, UT Southwestern Medical Center • Utah: Huntsman Cancer Institute • Washington: Fred Hutchinson • Wisconsin: UW Carbone Cancer Center n

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 3.2%.

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 occur 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).]

AVASTIN® (bevacizumab) 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 0.4 to 6.9 %. [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).]

5.5 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 was increased in patients with a history of arterial thromboembolism, diabetes, 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 Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).]

5.7 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).]

5.8 Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies.

The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES 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 PRES. Discontinue Avastin in patients developing PRES. 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 PRES is not known. [See Dosage and Administration (2.4).]

5.9 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. [See Dosage and Administration (2.4).]

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).]

5.10 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).]

T:10.25" S:9.5"

AVASTIN® (bevacizumab) In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

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 (5.12), Use in Specific Populations (8.3).]

Post-Treatment Vascular Events In an open‑label, randomized, controlled trial of Avastin in adjuvant colorectal cancer, an indication for which Avastin is not approved, the overall incidence rate of post‑treatment Grade ≥ 3 vascular events was 3.1% (41 of 1338) among patients receiving mFOLFOX6 plus Avastin, compared to 1.6% (21 of 1349) among patients receiving mFOLFOX6 alone. Post‑treatment vascular events included arterial and venous thromboembolic events, ischemic events, and vascular aneurysms.

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) Arm 1 IFL+ Placebo (n = 396)

a

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337) Gastrointestinal disorders Diarrhea 16% 21% General disorders and administration site conditions Fatigue 27% 33% Investigations Weight decreased 15% 20% Metabolism and nutrition disorders Anorexia 31% 36% Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12% Nervous system disorders Headache 16% 24% Renal and urinary disorders Proteinuria 3% 20% Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5% Vascular disorders Hypertension 9% 28%

Arm 2 IFL+ Avastin (n = 392)

74%

87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

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.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) 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

55% 55% 19%

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.

Avastin in Combination with Fluoropyrimidine-Irinotecan or FluoropyrimidineOxaliplatin Based Chemotherapy in Second-line mCRC Patients who have Progressed on an Avastin Containing Regimen in First-line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC.

a

Adverse events were encoded using MedDRA, Version 10.1.

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 ); 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).

Persistent, Recurrent, or Metastatic Carcinoma of the Cervix All grade adverse reactions were collected in Study 9.

Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4.

Table 4 NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone) Grade 1‑4 Grade 3‑4 reactions reactions Chemo Chemo+ Chemo Chemo+ Alone Avastin Alone Avastin (n=222) (n=218) (n=222) (n=218) Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16% General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15% Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16% Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10% Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders Headache 13% 22% Dysarthria 1% 8% Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6% Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12% Psychiatric Disorders Anxiety 10% 17% Reproductive System and Breast Disorders Pelvic Pain 8% 14% Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17% Renal and Urinary Disorders Proteinuria 3% 10%

AVASTIN® (bevacizumab) Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection (8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%).

There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone.

Platinum-Resistant Recurrent Epithelia Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients with evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded in this study.

Grade 2‑4 adverse events occurring at a higher incidence ( ≥5%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone are presented in Table 5.

Table 5 Grade 2−4 Adverse Events Occurring at Higher Incidence [ ≥ 5%] in Chemo + Avastin vs. Chemo Safety−Evaluable Patients System Organ Class Preferred Term Blood And Lymphatic System Disorders Neutropenia General Disorders And Administration Site Conditions Mucosal Inflammation Infections And Infestations Infection Nervous System Disorders Peripheral Sensory Neuropathy Renal And Urinary Disorders Proteinuria Respiratory, Thoracic and Mediastinal Disorders Epistaxis Skin And Subcutaneous Tissue Disorders Palmar−Plantar Erythrodysaesthesia Syndrome Vascular Disorders Hypertension

Chemo Chemo+Avastin (n = 181) (n = 179) 25.4%

30.7%

5.5%

12.8%

4.4%

10.6%

7.2%

17.9%

0.6%

12.3%

0.0%

5.0%

5.0%

10.6%

5.5%

19.0%

Grade 3−4 adverse events occurring at a higher incidence ( ≥ 2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar‑plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%).

There were no Grade 5 events occurring at a higher incidence ( ≥ 2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑ product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and 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.

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, PRES, 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 Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation 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 8, 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 Risk Summary Avastin may cause fetal harm based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. Limited postmarketing reports describe cases of fetal malformations with use of Avastin in pregnancy; however, these reports are insufficient to determine drug associated risks. In animal reproduction studies, intravenous administration of bevacizumab to pregnant rabbits every 3 days during organogenesis at doses approximately 1 to 10 times the clinical dose of 10 mg/kg produced fetal resorptions, decreased maternal and fetal weight gain and multiple congenital malformations including corneal opacities and abnormal ossification of the skull and skeleton including limb and phalangeal defects [see Data]. Furthermore, animal models link angiogenesis and VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2‑4% and 15‑20%, respectively.

Data Animal Data Pregnant rabbits dosed with 10 to 100 mg/kg bevacizumab (approximately 1 to 10 times the clinical dose of 10 mg/kg) every three days during the period of organogenesis (gestation day 6‑18) exhibited decreases in maternal and fetal body weights and increased number of fetal resorptions.

There were dose‑related increases in the number of litters containing fetuses with any type of malformation (42.1%, 76.5%, and 95% in the 0, 30, and 100 mg/kg groups, respectively) or fetal alterations (9.1%, 14.8%, and 61.2% for the 0, 30, and 100 mg/kg dose groups, respectively). Skeletal deformities were observed at all dose levels, with some abnormalities including meningocele observed only at the 100 mg/kg

AVASTIN® (bevacizumab) dose level. Teratogenic effects included: reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb phalanges.

8.2 Lactation No data are available regarding the presence of bevacizumab in human milk, the effects on the breast fed infant, or the effects on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential for serious adverse reactions in breastfed infants from bevacizumab, advise a nursing woman that breastfeeding is not recommended during treatment with Avastin.

8.3 Females and Males of Reproductive Potential Contraception Females Avastin may cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use effective contraception during treatment with Avastin and for 6 months following the last dose of Avastin [see Use in Specific Populations (8.1)].

Infertility Females 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.

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 (5.12), Adverse Reactions (6.1).]

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 5, 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 (5.9).]

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).]

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.

17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

• To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.

• Of increased risk of wound healing complications during and following Avastin.

• Of increased risk of an arterial thromboembolic event.

• Of the increased risk for ovarian failure following Avastin treatment.

Embryo‑fetal Toxicity • Advise female patients that Avastin may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy. [See Warnings and Precautions (5.11), Use in Specific Populations (8.1).]

• Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin. [See Use in Specific Populations (8.3).]

Lactation • Advise nursing women that breastfeeding is not recommended during treatment with Avastin. [See Use in Specific Populations (8.2).]

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

05/15 AVP/111714/0019(1) Initial U.S. Approval: February 2004 Code Revision Date: June 2015 Avastin® is a registered trademark of Genentech, Inc. © 2015 Genentech, Inc.

S:12.5"

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

AVASTIN® (bevacizumab) 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 5. 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 6 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 PRES (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 8. 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 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

FDA Approved in PlatinumResistant Ovarian Cancer The first biologic regimen to demonstrate a significant increase in median PFS vs chemotherapy alone1 AURELIA ITT

Exploratory efficacy analysis by chemotherapy cohort

Primary endpoint:

Avastin + paclitaxel cohort

Median PFS

Avastin + topotecan cohort

Avastin + PLD cohort

6.8

Avastin + chemotherapy Chemotherapy alone

9.6 6.2

(n=179)

(n=55)

HR=0.47 (95% Cl, 0.31–0.72)

(n=182)

HR=0.38 (95% Cl, 0.30–0.49), P<0.0001

(n=60)

Months

Months

Months

3.9

5.1 2.1

(n=57)

(n=63)

HR=0.24 (95% Cl, 0.15–0.38)

Months

3.4

(n=62)

3.5 (n=64)

HR=0.47 (95% Cl, 0.32–0.71)

Cohort analysis based on prespecified endpoint (PFS). Analysis not designed to evaluate statistical significance between treatment arms or compare among the 3 chemotherapy cohorts.

Statistically significant improvement in ITT investigator-assessed PFS was supported by a retrospective independent review analysis PFS=progression-free survival; ITT=intent-to-treat; HR=hazard ratio; CI=confidence interval; PLD=pegylated liposomal doxorubicin.

Indication Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

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 3.2% 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 0.4% to 6.9% — 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 — GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients) — Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastintreated arm vs control included — GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial

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(08/15)

— Hypertension (grade 3–4, 5%–18%) — Posterior reversible encephalopathy syndrome (PRES) (<0.5%) 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 Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

Pregnancy warning

Based on the mechanism of action and animal studies, Avastin may cause fetal harm Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin Advise nursing women that breastfeeding is not recommended during treatment with Avastin Avastin may impair fertility

Most common adverse events

Across indications, the 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

Indication-specific adverse events

In prOC, grade 3–4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs 1.7%). There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. prOC=platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Reference: 1. Avastin Prescribing Information. Genentech, Inc. May 2015.

www.avastin-hcp.com