TAP Vol 4 Issue 17 by Harborside Press LLC

San Antonio Preview

| Metastatic Colorectal Cancer

20, 22

VOLUME 4, ISSUE 17

| Cardiovascular Risks in Cancer Survivors 69, 70

NOVEMBER 1, 2013

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

European Cancer Congress 2013

Novel Anti–PD-L1 Antibody Produces Durable Responses in Metastatic NSCLC, Smokers Included By Alice Goodman

ASCOPost.com

The Devastating Impact of Sequestration on Medical Research By Richard J. Boxer, MD, FACS

he engineered monoclonal antibody MPDL3280A achieved encouraging and durable responses in a phase I study in metastatic non–small cell lung cancer (NSCLC) in both smokers and nonsmokers, as well as in cancers of squamous and adenocarcinoma histology. Responses were more robust in smokers than nonsmokers, which is not what usually happens in drug trials for NSCLC, explained lead author Jean-Charles Soria, MD, PhD, Gustave Roussy Cancer Center, Paris, at the European Cancer Congress (ECC) 2013 in Amsterdam.1 MPDL3280A is a monoclonal antibody that acts on the programmed death (PD) pathway by inhibiting PD-L1 signaling, which prevents the immune system’s response to cancer. The monoclonal antibody removes this inhibition, allowing the immune system to respond to the cancer.

Promising Trends Although this is only a phase I trial, experts were enthusiastic about the new approach. Dr. Soria was particularly enthusiastic about the finding that MPDL3280A achieved a better response in smokers than in nonsmokers. Jean-Charles Soria, MD, PhD “This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising,” Dr. Soria said. “This drug allows the lymphocytes to go to war with the tumor,” he added. “I agree that this is great news for patients with lung cancer, both for smokers and nonsmokers. For patients [smokers], there has been primarily chemotherapy and continued on page 15

Issues in Oncology

The Scientific Perils of Sequestration

continued on page 107

Dr. Boxer is Visiting Professor at the David Geffen School of Medicine at UCLA, Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin (Milwaukee), and former Professor of Clinical Urology at the University of Miami. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

Severe federal budget cuts are threatening to derail cancer research in the United States. By Jo Cavallo

he primacy of science and the overwhelming belief in medical research by the American people has sustained the research community and improved quality of life roughly since the turn of the 20th century. Almost without exception, the American people have voted for politicians who promise improved quality of life through improved health care, and they vote against those who disagree. Politicians squander good will and legislate at their own peril if they fail to support medical research. But now Congress has done just that, with this year’s spending cuts enacted under the

MORE IN THIS ISSUE some say its full effects may be irreversible. The ASCO Post recently interviewed ASCO President Clifford A. Hudis, MD, FACP, and others about the effects of sequestration on cancer research. The Budget Control Act of 2011 required These funding reductions present the National Institutes of Health (NIH) to cut a real long-term problem, because 5%—or $1.55 billion—of once scientists, postdoctoral fellows, its fiscal year 2013 budget, which was already at its technicians, and support staff are lowest inflation-adjusted gone, they may go into another appropriations level in more than a decade. Enindustry, and our shared investment actment of the legislain their training in cancer research tion prompted Francis is perhaps gone for good. Collins, MD, PhD, Director of the NIH, to call 2013 —Clifford A. Hudis, MD, FACP

e are just 7 months into the $1 trillion in automatic federal budget spending cuts known as sequestration, and the impact on scientists in all areas of research is already so great,

Oncology Meetings Coverage 2013 Breast Cancer Symposium �� 3, 10 San Antonio Breast Cancer Symposium Preview �� 11, 14 European Cancer Congress �� 16, 17, 20 NCCN Hematologic Malignancies Congress �� 28, 29, 30 Direct from ASCO �� 36–39 Richard Pazdur, MD, on the FDA and the Era of Precision Medicine �� 58 Pioneers in Oncology: Claudia Henschke, MD �� 89

continued on page 47

November Is Lung Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | NOVEMBER 1, 2013

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Joseph S. Bailes, MD Texas Oncology

Louis B. Harrison, MD Continuum Cancer Centers of New York

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

Lynn D. Wilson, MD Yale University School of Medicine

Michael Buckley, Art Director Michael@harborsidepress.com

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

Stanley H. Winokur, MD Singer Island, Florida

Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center

William C. Wood, MD Winship Cancer Institute, Emory University

Terri Caivano, Kristina O’Toole, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Richard Boxer, MD University of Wisconsin School of Medicine and Public Health

Michael P. Link, MD Stanford University Medical Center

International Editors

Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

Wendy McGullam, Director of Production Wendy@harborsidepress.com

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

Harold J. Burstein, MD Dana-Farber Cancer Institute

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Robert W. Carlson, MD National Comprehensive Cancer Network

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

William T. McGivney, PhD Philadelphia, Pennsylvania

Jay S. Cooper, MD Maimonides Medical Center

James L. Mulshine, MD Rush University Medical Center

Jacek Jassem, MD Medical University of Gdansk, Poland

John Cox, DO Texas Oncology

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

E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@ asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@ harborsidepress.com.

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com.

Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $259; Individual International: $499; Institutional Domestic: $319;

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Nagi El-Saghir, MD American University of Beirut, Lebanon

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com Anthony Cutrone, President Anthony@harborsidepress.com John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Contributing Writers: Charlotte Bath, Alice Goodman, Caroline Helwick, Susan London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

Contributing Artists: Portraits by Keith Witmer, Keith Witmer Illustrations. Disclosure information available at ASCOPost.com.

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

Institutional International $559. Contact subscriptions@ harborsidepress.com. Correspondence: Address general inquiries to Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume

liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 3

Breast Cancer Symposium Optimizing Anti-HER2 Treatment for Metastatic Breast Cancer in 2013 By Caroline Helwick

“T

he good news about HER2positive breast cancer is that recurrent disease is plummeting, owing to the impact of adjuvant trastuzumab [Herceptin]. Hopefully, first-line metastatic treatment is becoming a thing of the past,” said Harold Burstein, MD, PhD, of Dana-Farber Cancer Institute, Boston. Meanwhile, however, clinicians still need to understand the optimal treatment of HER2-positive metastatic breast cancer, a topic that was addressed by Dr. Burstein and Eric P. Winer, MD, at the 2013 Breast Cancer Symposium in San Francisco.1,2 Dr. Winer is Chief of the Division of Women’s Cancers and the Thompson Senior Investigator for Breast Cancer Research at Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston. Dr. Burstein is Associate Professor of Medicine at Harvard Medical School.

Power of Trastuzumab Underestimated Dr. Burstein noted that the pivotal trials of trastuzmab for recurrent disease, which showed a 50% reduction

to trastuzumab, therefore, accentuates the need for new anti-HER2 therapies, he said. The conclusion from a series of trials pairing trastuzumab with various chemotherapy regimens is that almost any chemotherapy is effective, though to varying degrees, in combination

The good news about HER2-positive breast cancer is that recurrent disease is plummeting, owing to the impact of adjuvant trastuzumab [Herceptin]. — Harold Burstein, MD, PhD

with trastuzumab. “Almost any chemotherapy will work,” Dr. Burstein said. These studies identified no new toxicity signals and limited clinical impact of “synergy” in laboratory models. Rather than further evaluating chemotherapy/trastuzumab combinations, research should focus on biomarkers and optimization of targeted therapies, he suggested.

New and Improved Anti-HER2 Therapies

Eric P. Winer, MD

in risk, probably underestimated its benefit. The typical Dana-Farber patient is maintained on first-line therapy for close to 9 months, Dr. Burstein said, adding, “This is one of the rare instances in oncology where real-world experience may be superior to clinical trial results.” Trastuzumab maintains remission longer than do the appropriate agents for other subtypes of breast cancer, and virtually renders the risk of recurrence to zero in subcentimeter tumors, he said. But the use of trastuzumab in the adjuvant setting does impact its efficacy in recurrent disease, as median progression-free survival is significantly shorter when patients have previously received the drug. Resistance

fractory disease, but its use earlier in recurrence is anticipated. Similarly, first-line treatment with pertuzumab (Perjeta) plus docetaxel, vs docetaxel alone, significantly delayed progression over trastuzumab/ docetaxel in the CLEOPATRA trial,4 leading to U.S. Food and Drug Ad-

Two new antibody products will further enhance anti-HER2 treatment in metastatic patients. In the first-line setting, (Kadcyla, previously known as T-DM1) reduced the risk of progression by 41%, compared to trastuzumab/docetaxel.3 Perhaps more critically, ado-trastuzumab emtansine improved quality of life and reduced symptoms, important outcomes that have been underrecognized, Dr. Burstein said. Currently, the drug is approved for re-

ministration (FDA) approval for this combination (or pertuzumab with paclitaxel) in the first-line setting. It is possible that the two newest agents will pack a group punch if used together, a concept being evaluated in the first-line, 1,000-patient MARIANNE trial. Patients are receiving ado-trastuzumab emtansine plus pertuzumab, ado-trastuzumab emtansine plus placebo, or trastuzumab plus a taxane.

Anti-HER2 Agents Plus Antiestrogens In patients who are both HER2positive and estrogen receptor–positive, the benefit of pairing trastuzumab with endocrine therapy is there, but it is modest, he said. “Collectively, there is a suggestion that you can get a little bit more from endocrine therapy by adding the anti-HER2 drug, but most people don’t see a major clinical impact,” he said.

Metastatic HER2-Positive Breast Cancer Treatment ■■ Recurrences are plummeting for patients with HER2-positive breast cancer, due to the efficacy of trastuzumab.

■■ Trastuzumab can be combined with virtually any chemotherapy regimen, with benefit for metastatic disease.

■■ There is only a modest effect from pairing anti-HER2 therapy with endocrine therapy.

■■ Continuation of anti-HER2 agents after progression on trastuzumab is beneficial.

■■ The combination of two new anti-HER2 agents—ado-trastuzumab

emtansine and pertuzumab—is being evaluated in the MARIANNE trial.

This was shown in several studies, including TAnDEM, which evaluated anastrozole with and without trastuzumab5; in the study of letrozole plus lapatinib (Tykerb), which led to FDA approval of this combination6; and in Cancer and Leukemia Group B (CALGB) 40302, which actually found no statistically significant benefit to adding lapatinib to fulvestrant (Faslodex).7 The findings support the theme that HER2-expressing tumors are somewhat resistant to endocrinebased therapies, though a substantial fraction of patients can benefit from these combinations, he said.

Refractory HER2-Positive Disease Discussing the treatment of metastatic patients beyond the first line, Dr. Winer said, “The single most important lesson we learned years ago about treating refractory or resistant HER2-positive breast cancer is that anti-HER2 agents continue to work even after progression on trastzumab.” Geyer et al showed this in 2006 by combining lapatinib and capecitabine,8 and Von Minckwitz et al followed in 2009 by demonstrating the value of capecitabine plus trastuzumab.9 Blackwell et al then showed that dual targeting of the HER2 receptor with two biologics, trastuzumab plus lapatinib, could delay progression (with a trend toward a survival benefit) vs lapatinib alone; 28% of refractory patients remained free of progression at 6 months.10 Less is known about the new anti-HER2 agent pertuzumab, but in a small study, the combination of pertuzumab plus trastuzumab in refractory disease yielded a 24% response rate, and an additional 26% of patients were stable at 6 months.11,12 He cautioned that this was a small, nonrandomized study. “These two studies point out,” Dr. Winer said, “that combined targeted therapy can potentially be very effective, and this lesson has played out in the neoadjuvant setting as well…. Dual targeting with trastuzumab/lapatinib or trastuzumab/pertuzumab is a promising approach and may play a role in the refractory metastatic setting.” continued on page 8

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

The ASCO Post | NOVEMBER 1, 2013

PAGE 8

Breast Cancer Symposium Anti-HER2 Treatment continued from page 3

With pertuzumab now indicated for first-line treatment, its place in treating refractory disease is less clear. “I suspect this will mean there is less of a role for all biologic combinations in the refractory setting,” he predicted.

New Paradigm “To some degree, everything changed with the development of [ado-trastuzumab emtansine],” Dr. Winer said. The binding site of the drug (the extracellular domain of HER2) is the same as for trastuzumab, because the drug is trastuzumab packaged as an antibody drug conjugate that delivers high concentrations of the drug to the tumor, sparing surrounding tissues. In the EMILIA trial, median progression-free survival was 9.6 months with ado-trastuzumab emtansine vs 6.4 months with lapatinib/ capecitabine (P < .0001) and median overall survival was 30.9 months vs 25.1 months, respectively (P < .001).13 The additional benefit was observed without an increase in toxicity, especially serious adverse events. “For the most part, [ado-trastuzumab emtansine] is an agent that tends to be remarkably well tolerated,” he noted. Having two new agents has altered the treatment paradigm for refractory HER2-positive disease. Dr. Winer described his preferred approach (Fig. 1). He explained that he selects a taxane plus tratuzumab and pertuzumab in the first-line setting and ado-trastuzumab emtansine in the second-line setting, though depending upon the results of the MARIANNE trial the option of ado-trastuzumab emtansine alone could change, he said. In the third line and beyond, there are more than a halfdozen effective combinations, and the

order in which they are best given remains unclear. “Perhaps we should start with pertuzumab and trastuzumab if the patient has not previously received this combination, and if insurance will pay for it,” he suggested. “There are still clinical trials, because we have by no means answered all the questions.” n Disclosure: Drs. Burstein and Winer reported no potential conflicts of interest.

References 1. Burstein HJ: Treatment of metastatic HER2+ breast cancer in the first- and second-line settings. 2013 Breast Cancer Symposium. Presented September 9, 2013. 2. Winer EP: Treatment of refractory HER2+ breast cancer: Optimal regimens, brain metastases, and new approaches. 2013 Breast Cancer Symposium. Presented September 9, 2013. 3. Hurvitz SA, Dirix L, Kocsis J, et al: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31:1157-1163, 2013. 4. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012. 5. Kaufman B, Mackey JR, Clemens MR, et al: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin Oncol 27:5529-5537, 2009. 6. Johnston S, Pippen J Jr, Pivot X, et al: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptorpositive metastatic breast cancer. J Clin Oncol 27:5538-5546, 2009.

7. Burstein HJ, Barry WT, Cirrincione C, et al: CALGB 40302: Fulvestrant with or without lapatinib as therapy for hormone receptor positive advanced breast cancer: A double-blinded, placebo-controlled, randomized phase III study. San Antonio Breast Cancer Symposium. Abstract PD0501. Presented December 11, 2010. 8. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006. 9. von Minckwitz G, du Bois A, Schmidt M, et al: Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: A German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol 27:1999-2006, 2009. 10. Blackwell KL, Burstein HJ, Storniolo AM, et al: Randomized study of Lapatinib alone or in combination with trastu-

zumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124-30. 11. Baselga J, Gelmon KA, Verma S, et al: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138-1144, 2010. 12. Cortés J, Fumoleau P, Bianchi GV, et al: Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: Activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 30:1594-1600, 2012. 13. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

First line: taxane + trastuzumab + pertuzumab

Second line: T-DM1

Third, fourth, fifth, sixth line: Capecitabine + lapatinib

Capecitabine + trastuzumab Vinorelbine + trastuzumab Lapatinib + trastuzumab

Pertuzumab + trastuzumab (?? if no prior pertuzumab) Other chemotherapy + trastuzmab Endocrine therapy + trastuzumab

Fig. 1: Treatment approach for patient presenting with HER2-positive metastatic breast cancer in 2013. Courtesy of Eric P. Winer, MD.

Don’t Miss These Important Reports in This Issue of The ASCO Post David Cunningham, MD, Older Patients with Metastatic Colorectal Cancer see page 22

Andrew D. Zelenetz, MD, on Relapsed/Refractory Multiple Myeloma see page 28

Visit The ASCO Post online at ASCOPost.com

Richard Pazdur, MD, on FDA and the Era of Precision Medicine see page 58

What if you could use the body’s own T cells to combat Lung Cancer? With Immuno-Oncology it may be possible. Current approaches to lung cancer treatment include radiation, surgery and chemotherapy/targeted therapy, all of which are intended to target the tumor. Through our ongoing clinical program, BMS is investigating an entirely new way to treat lung cancer by targeting the immune system. Our research is focused on transforming the way tumor cells and the immune system communicate, including checkpoint pathways; we hope to find new ways to stop lung cancer from evading the immune system, thereby restoring the body’s natural ability to fight it. If you’re interested in learning more about BMS investigational studies in lung cancer, including a list of study sites, please visit BMS Study Connect to search for lung cancer studies near you. http://www.bms.com/studyconnect/Pages/Home.aspx

ONCUS13UB00863-02-01

06/13

Visit us at BMSimmunooncology.com

Leading the way

The ASCO Post | NOVEMBER 1, 2013

PAGE 10

Breast Cancer Symposium Women Undergoing Mammography Fail to Understand Breast Cancer Risk By Alice Goodman

ore than 90% of women undergoing mammography screening could not give an accurate estimate of their personal risk of developing breast cancer, according to results of a large survey reported at the 2013 ASCO Breast Cancer Symposium and featured in a premeeting presscast. The survey showed that a similar percentage of women overestimated and underestimated their actual risk. Forty percent of respondents also said they had never discussed their personal risk with a health-care provider.

messages aren’t working. It is disconcerting that only 9.4% of respondents could tell us what their risk actually was. We need to encourage health-

an obstetrician and gynecologist at Hofstra North Shore-LIJ Medical School in New Hyde Park, New York. Part of the study’s objective was to

These findings suggest that the pink ribbons, marches, large public health awareness campaigns about breast cancer, and other educational messages aren’t working.… We need to encourage health-care providers to have this discussion with their patients, and patients need to be educated differently. —Jonathan Herman, MD

Objectives and Implications “These findings suggest that the pink ribbons, marches, large public health awareness campaigns about breast cancer, and other educational

care providers to have this discussion with their patients, and patients need to be educated differently,” said lead study author Jonathan Herman, MD,

EXPERT POINT OF VIEW

“T

his is a provocative and compelling study. I applaud Dr. Herman and his team. The take-home message was beautifully articulated,” said presscast moderator Steven J. O’Day, MD, Director of Clinical Research at the Beverly Hills Cancer Center and Adjunct Member of the John Wayne Cancer Institute in Los Angeles. “Decisions about the best surveillance and chemoprevention are difficult to make even when we know the accurate risk, but only 10% of women [in this study] knew their accurate risk, making these decisions much more difficult if not impossible,” Dr. O’Day continued.

Decisions about the best surveillance and chemoprevention are difficult to make even when we know the accurate risk, but only 10% of women [in this study] knew their accurate risk, making these decisions much more difficult if not impossible. —Steven J. O’Day, MD

Much Work to Do “Despite the ongoing extensive awareness campaigns and media coverage, we still have a lot of work to do. A study like this sets the record straight on how far we have to go,” he stated. “Although we have multiple tools that can project risk for a patient and quantify it, implementing this in the primary and tertiary care settings is a huge hurdle to overcome. Chemoprevention is not trivial in terms of cost and side effects, and without accurate information we can’t select an intervention,” Dr. O’Day emphasized. n Disclosure: Dr. O’Day reported no potential conflicts of interest.

determine perceptions of risk among different ethnicities, and responses showed a low level of knowledge across the board for all ethnicities. The level of understanding could be even lower in the general population not concerned enough about breast cancer risk to participate in mammography screening, Dr. Herman noted. If women are not aware of their actual risk of developing breast cancer, they will not make appropriate decisions about interventions, he continued. “Understanding your risk level is an important precursor of care. Women at high risk—if they know their risk—can avail themselves of early detection modalities and chemopreventive medications,” Dr. Herman said. “Accurate understanding will lead to a tailored plan according to risk and, thus, to better outcomes.”

Study Details Approximately 15,000 surveys were given to women aged 35 to 70 years who were having a mammogram at 1 of 21 centers on Long Island, NY. The 25 survey questions were adapted from the National Cancer Institute’s Breast Cancer Risk Assessment Tool that estimates risk of developing invasive breast cancer; the questions cov-

ered demographics, breast cancer risk factors, including personal and family history of breast cancer, and any prior breast cancer risk assessments and discussions. The study sample was based on 9,873 respondents. The researchers calculated the actual lifetime risk of developing breast cancer for each of the 9,873 respondents and compared that with each woman’s personal estimate; a difference of greater than 10% from the calculated value was deemed inaccurate. Only 707 women (9.4%) correctly estimated their risk; 3,359 women (44.7%) underestimated their risk, and 3,454 (45.9%) overestimated it. Of the women who participated, 2,131 estimated they had a 0% to 1% lifetime risk of breast cancer, 2,581 estimated that they had less than a 50% risk, and 223 estimated that they had more than a 90% risk. Analyzing results according to ethnicity, Caucasian women were more likely to overestimate their risk (38.6%) than African Americans (33.7%) or Asians (31%). Minority groups were more likely than Caucasians to underestimate their risk, with underestimation rates as follows: Caucasians (38.6%), African Americans (57.6%), Asians (58.8%), and Hispanics (50.4%). During the question-and-answer session. Dr. Herman said that a family history of breast cancer deserves as much attention as a history of cardiovascular disease. Family history should be part of the questionnaire when a new patient comes into a practice, he said. n Disclosure: Dr. Herman reported no potential conflicts of interest.

Reference 1. Herman JD, Herman SM: Women’s understanding of personal breast cancer history. Does ethnicity matter? 2013 Breast Cancer Symposium. Abstract 4. Presented September 7, 2103.

Breast Cancer Risk Perception ■■ A large survey from Long Island, New York, showed that more than 9 out of 10 women could not accurately estimate their risk of developing breast cancer.

■■ About 45% overestimated their personal risk, and 45% underestimated it; only 9.4% knew their true risk.

■■ Results suggest that health-care providers need to do a better job in educating patients about risk of developing breast cancer.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 11

San Antonio Breast Cancer Symposium Program Co-Directors Highlight Abstracts of Interest for the Upcoming 2013 San Antonio Breast Cancer Symposium By Caroline Helwick

he Co-Directors of the 2013 CTRC-AACR San Antonio Breast Cancer Symposium, which will be held December 10–14, 2013, have highlighted what they consider to be the most important abstracts to be presented

C. Kent Osborne, MD

at the Symposium. In a telebriefing in advance of the December meeting, C. Kent Osborne, MD, called these the “abstracts to keep an eye on.” The meeting, now in its 36th year, is the largest of its kind devoted exclusively to breast cancer research and draws more than 8,000 people, including basic scientists, clinicians, advocates, and news media. It is an annual collaboration of the Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine.

Screening and Locoregional Therapy The value of mammographic screening has been controversial. A metaanalysis (Abstract S1-10) of four pivotal mammographic screening studies, by an international consortium, is a re-analysis of the data that aims for consistency. “I think this paper will come up with some interesting data on the value of mammography, and will address an issue that has become important—over-diagnosis—and whether it’s a problem with regard to these studies,” said Dr. Osborne, Director of the Dan L. Duncan Cancer Center and Director of the Lester and Sue Smith Breast Center at Baylor Col-

lege of Medicine, Houston. Other highlighted studies in the area of locoregional therapy will address the need for radiotherapy after breast-conserving therapy in women aged 65 and older (S201) and the value of resecting the primary tumor in metastatic patients, according to two prospective studies (S2-02, S2-03).

Endocrine Therapy Endocrine therapy will be of particular interest at the meeting, with a number of clinically meaningful presentations, Dr. Osborne said. Investigators will examine the benefit and toxicity of anastrozole in preventing breast cancer in the IBIS-2 continued on page 14

Highlighted Abstracts to Watch in San Antonio ■■ S1-01. Piccart-Gebhart M, Holmes

AP, de Azambuja E, et al: The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06)

■■ S1-02. Hurvitz S, Miller JM,

Dichmann R, et al: Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/ or lapatinib in patients with HER2+ breast cancer (TRIO-US B07)

■■ S1-03. Slamon DJ, Swain SM, Buyse

M, et al: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2positive, node-positive or high risk node-negative breast cancer

■■ S1-04. Tolaney SM, Barry WT, Dang

CT, et al: A phase II study of adjuvant paclitaxel and trastuzumab (APT trial) for node-negative, HER2positive breast cancer

■■ S1-05. Loi S, Michiels S, Salgado R,

et al: Tumor infiltrating lymphocytes indicate trastuzumab benefit in earlystage HER2-positive breast cancer

■■ S1-06. Denkert C, Loibl S, Salat C,

et al: Increased tumor-associated lymphocytes predict benefit from addition of carboplatin to neoadjuvant therapy for triple negative and HER2-

positive early breast cancer in the GeparSixto trial (GBG 66)

■■ S1-07. Adams S, Gray R, Demaria

S, et al: Prognostic value of tumorinfiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199

■■ S2-01. Kunkler IH, Williams LW,

Jack W, et al: The PRIME 2 trial: Wide local excision and adjuvant hormonal therapy ± postoperative whole breast irradiation in women ≥ 65 years with early breast cancer managed by breast conservation

■■ S2-02. Badwe R, Parmar V, Hawaldar

R: Surgical removal of primary tumor and axillary lymph nodes in women with metastatic breast cancer at first presentation: A randomized controlled trial

■■ S2-03. Soran A, Ozmen V, Ozbas S:

Early follow up of a randomized trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer

■■ S4-04. Vora SR, Kim N, Costa C, et

al: Overcoming resistance to PI3K inhibitors in PIK3CA mutant breast cancer using CDK4/6 inhibition: Results from a combinatorial drug screen

■■ S4-05. Shao Z-M, Jiang Y, Yu K-D:

Exome sequencing identifies shift in TP53 and PIK3CA mutation status after paclitaxel-based neoadjuvant chemotherapy in breast cancer

■■ S4-06. Loibl S, Denkert C,

Schneeweis A, et al: PIK3CA mutation predicts resistance to anti-HER2/

chemotherapy in primary HER2positive/hormone-receptor-positive breast cancer—prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies

■■ S5-01. Sikov WM, Berry DA, Perou

CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance)

■■ S5-02. Rugo HS, Olopade O,

DeMichele A, et al: Veliparib/ carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL

■■ S5-04. Mackey JR, Ramos-Vazquez

M, Lipatov O, et al: Primary results of ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer

■■ S5-07. Smerage JB, Barlow WE,

Hayes DF, et al: SWOG S0500 – A randomized phase III trial to test the strategy of changing therapy versus maintaining therapy for metastatic breast cancer patients who have elevated circulating tumor cell levels at first follow-up assessment

■■ S6-01. Balko JM, Giltnane

JM, Schwarz LJ, et al: JAK2 amplifications are enriched in triple negative breast cancers after neoadjuvant chemotherapy and predict poor prognosis

■■ S6-02. Symmans WF, Wei C, Gould

R, et al: Long-term prognostic value of residual cancer burden classification following neoadjuvant chemotherapy

■■ S1-10. Smith RA, Duffy S, Chen THH, et al: Disparities in the estimates of benefits and harms from mammography: Are the numbers really different?

■■ OT2-01. Malorni L, Sanna G, Pestrin

M, et al: Phase 2 study of palbociclib (CDK 4/6 inhibitor) for ER positive, HER2- negative post-menopausal advanced breast cancer patients recurring after hormonal therapy (to reverse endocrine resistance TREnd trial)

■■ OT2-6-11. von Minckwitz G, Bear H, Bonnefoi H, et al: PENELOPE: Phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptorpositive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy (GBG-78/BIG1-13)

■■ OT3-2-11. Chumsri S, Tait N, Shetty J,

et al: A phase II study of letrozole and lapatinib followed by an addition of everolimus in postmenopausal women with advanced endocrine resistant breast cancer

■■ P2-16-20. Clark AS, Lal P, Tan KS, et

al: Biomarkers to predict response to the CDK 4/6 inhibitor, palbociclib (PD 0332991) in a single-agent phase II trial in advanced breast cancer n

MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1282b 09/13

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus kinase.

• Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

The ASCO Post | NOVEMBER 1, 2013

PAGE 14

San Antonio Breast Cancer Symposium Highlighted Abstracts at SABCS continued from page 11

trial (S3-01), the association between baseline symptoms and discontinuation of adjuvant endocrine therapy (S3-02), the effect of exercise on ameliorating arthralgia (S3-03), the effect of mutations in the estrogen receptor on emergence of

treatment resistance (S3-06), and the efficacy of dasatinib (Sprycel) when combined with letrozole (S3-07).

Novel Topics, New Agents to Be Explored Peter Ravdin, MD, PhD, breast cancer researcher and biostatistician in San Antonio, Texas, highlighted abstracts

that will advance the understanding of the role of the immune system in fighting breast cancer. Three such studies pertain to tumor infiltrating lymphocytes (S105, S1-06, S1-07), which could prove to be prognostic. “These papers are an exciting and interesting lead,” he said. New agents on the radar at the symposium include palbociclib, the CDK 4/6 Peter Ravdin, MD, PhD

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions]. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All a Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Grades (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Jakafi is a registered trademark of Incyte Corporation. All rights reserved. U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved. Issued: June 2013 RUX-1216

inhibitor that has received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA). Palbociclib was impressive in a phase II trial reported at this meeting last year, according to Dr. Ravdin, and this year attendees will hear the results of a biomarker analysis (P2-16-20). Several ongoing studies of the drug will also be described (OT3-210, OT2-6-11, OT2-6-01). The question of whether bisphosphonates may help reduce recurrences will be informed by a meta-analysis of nearly 15,000 patients, a late-breaking abstract. And questions regarding the value of using circulating tumor cells in assessing outcomes may be answered by SWOG S0500 (S5-07). “This study could definitively make clear if circulating tumor cells could be used to better tailor therapy, and this could change the standard of care,” Dr. Ravdin said.

Neoadjuvant Setting Carlos L. Arteaga, MD, indicated that a number of neoadjuvant trials will be informative and relevant, in light of the FDA’s position that drugs for HER2positive and triple-negative breast cancer might be considered for approval, based on findings in the preoperative setting.

Carlos L. Arteaga, MD

Dr. Arteaga is President-Elect of the American Association for Cancer Research and Associate Director for Translational/Clinical Research and Director of the Breast Cancer Program at Vanderbilt-Ingram Comprehensive Cancer Center in Nashville. An analysis from NeoALTTO trial will report the correlation between pathologic complete response and continued on page 15

ASCOPost.com | NOVEMBER 1, 2013

PAGE 15

European Cancer Congress Thoracic Oncology

Anti–PD-L1 Antibody continued from page 1

not targeted therapy until now. This agent appears to be a new game-changer,” said Cora Sternberg, MD, moderator of the press conference where these results were discussed. Dr. Sternberg is Chief of the Department of Medical Oncology at San Camillo and Forlanini Hospitals in Rome.

at the time of the ECC meeting. NSCLC patients were heavily pretreated, with about 50% having had three lines of prior therapy; 81% were current or former smokers. The antibody was given as an intravenous infusion every 3

the highest level of PD-L1 expression (IHC3). Objective response rate was 26% among smokers and former smokers (n = 43) vs 10% in never-smokers (n = 10). The 24-week progression-free sur-

This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising. —Jean-Charles Soria, MD, PhD

Cora Sternberg, MD

Study Data The ongoing phase I study includes several other tumor types (renal cell carcinoma, melanoma, gastric cancer, sarcoma, and lymphoma), with a total of 175 patients. The 85 patients who comprise the cohort of NSCLC patients is the largest group of patients to be treated with anti–PD-L1 blockade to date; 85 NSCLC patients were evaluable for safety and 53 for efficacy

weeks for a median duration of 48 weeks. The overall objective response rate was 21% in all 175 patients enrolled in the phase I trial. Objective response rate in NSCLC was 23% (12 of 53 patients). Median duration of response is 48 weeks as of April 2013. Two factors were predictive of response: level of PD-L1 expression on immunohistochemistry (IHC) and smoking status. Objective response rate was increased as PD-L1 expression increased. Conversely, progressive disease decreased with higher PD-L1 expression. Objective response rate was 46% in patients with intermediate PD-L1 expression (IHC2 and IHC3) and 83% in the small number of patients with

Novel Agent for Non–Small Cell Lung Cancer ■■ An anti–PD-L1 antibody achieved striking and durable responses in a preliminary study of metastatic NSCLC.

■■ Response was seen in smokers and nonsmokers, as well as squamous cell and adenomacarcinomatous tumors.

Highlighted Abstracts at SABCS continued from page 14

long-term event-free survival (S1-01). NeoALTTO is evaluating neoadjuvant lapatinib (Tykerb), trastuzumab (Herceptin), or their combination in HER2positive patients. “A positive correlation should generate excitement,” Dr. Arteaga predicted. The same anti-HER2 agents will be paired with docetaxel plus carboplatin in another study called TRIO, deemed important especially for its data on toxicity (S1-02), he said. The first efficacy results for the PARP inhibitor, veliparib, given with carboplatin and standard neoadjuvant therapy to high-risk patients, will come from the much-heralded, adaptive-design I-SPY2 trial (S5-02). Another paper will look

vival rate was 44% in patients with squamous cell NSCLC and 46% in those with nonsquamous NSCLC.

Adverse Events MPDL3280A appeared to be well tolerated in this trial. The majority of adverse events were mild (grade 1 or 2). Adverse events of any grade were report-

Disclosure: Dr. Soria has received honoraria from Abbott Laboratories, Amgen, AstraZeneca, Bristol-Myers Squibb, EOS GmbH, Genentech, Lilly, Merck Serono, MSD Oncology, Pfizer, Roche, and Sanofi. Dr. Sternberg reported no potential conflict of interest.

Reference 1. Soria JC, Cruz C, Bahleda R, et al: Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC). 2013 European Cancer Congress. Abstract 3408. Presented September 29, 2013.

EXPERT POINT OF VIEW

“I

t is very good to have a drug for patients who are smokers and former smokers. The antibody works in both adenocarcinoma and squamous cell carcinoma, and is already very active in phase I with very few side effects. This is such impressive data that [perhaps] we could leap directly to a phase III trial,” said Paul Baas, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, formal discussant of this abstract. Many questions remain, he continued. How does this drug differ from the anti–PD-1 antibodies? How long should we give this treatment? How effective is it in combination, perhaps with a vaccine? “We will have to find out the answers to these questions. It’s a matter for time for the studies to be done,” Dr. Baas said. n Disclosure: Dr. Baas reported no potential conflicts of interest.

at the prognostic value of residual cancer burden after neoadjuvant treatment (S6-02) and perhaps help clarify which patients are at a particularly high risk of recurrence and, as such, need novel therapies to prevent these recurrences.

Important Adjuvant Studies Dennis Slamon, MD, PhD, Professor, Chief, and Executive Vice Chair for Research, Department of Medicine, Hematology/Oncology, at UCLA’s Jonsson Comprehensive Cancer Center, will be a much-anticipated speaker as he presents the primary results of the phase III BETH study of adjuvant chemotherapy and trastuzumab with or without bevacizumab (Avastin) in patients with HER2positive, node-positive, or high-risk node-negative breast cancer (S1-03). Following Dr. Slamon, Sara M. Tolaney,

ed in 56 patients (66%). Grade 3 or 4 adverse events were reported in 9 patients (11%). No dose-limiting toxicities were identified, and there were no reports of grade 3 to 5 pneumonitis or diarrhea. The antibody is moving forward in phase II and III trials. If the preliminary results hold true, for the first time NSCLC will have an immunotherapy that works better in smokers than in never-smokers. n

Dennis Slamon, MD, PhD

MD, MPH, of Dana-Farber Cancer Institute, Boston, will report follow-up of a large single-arm study in patients with small HER2 tumors treated with trastuzumab and chemotherapy (S1-04).

PIK3CA Mutations Mutations in the PI3 kinase pathway are the most frequent mutations in breast cancer, therefore, interest in these muta-

tions is very high, Dr. Arteaga indicated. Investigators from the GeparSixto and GeparQuinto trials will report whether the PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in HER2-positive, hormone receptor–positive tumors, and triple-negative tumors. Other researchers will report on novel approaches to discover ways of overcoming resistance to PI3K inhibitors, which are in development (S4-04, S4-05, S4-06). Finally, a relatively new topic, which may be important for triple-negative tumors, will be JAK2 amplification, its association with worse outcomes after neoadjuvant treatment, and associated clinical implications as JAK2 inhibitors are currently in development(S6-01). n Disclosure: Drs. Arteaga, Osborne, and Ravdin reported no potential conflicts of interest.

The ASCO Post | NOVEMBER 1, 2013

PAGE 16

European Cancer Congress ESMO President Martine Piccart, MD, PhD, on the Importance of Diagnostics in Move From Stratified to Personalized Care By Martine Piccart, MD, PhD

e are now living in an era of stratified oncology. The European Cancer Congress (ECC) 2013 held recently in Amsterdam provided many opportunities to attendees, including chance for discussions with basic and translational scientists, researchers, pathologists, and clinicians, as well as time for exchanges with specialists from all disciplines. As the key platform in the European oncology calendar of events, 23% of the submitted abstracts for Amsterdam were from scientists, making it the ideal place for addressing issues involved in moving from stratification to personalization.

by all disciplines involved and for the European Union and national governments to support practice-changing trials. The European Society of Medi-

cal Oncology (ESMO) is working with the European Union regarding recommendations to the Clinical Trials Regulation knowing that without

clinical research we cannot make progress against cancer. n Disclosure: Dr. Piccart reported no potential conflicts of interest.

Without clinical research we cannot make progress against cancer. —Martine Piccart, MD, PhD

Precise Diagnostics Necessary [In Europe, we] have yet to fully acknowledge the importance of diagnostics, and personalized medicine cannot happen without precise diagnostics. Currently, there is little incentive for pharmaceutical companies to develop molecular diagnostic tests because there is no clear regulatory path. Traditional diagnostic tests are limited and molecular diagnostics has a leading role to play. However, commitment by funders is required for investment in practice-changing trials to better understand which patients benefit from which drugs/treatments to avoid unnecessary expense without benefit to the patient. The move from stratified to personalized oncology requires molecular diagnostics to be taken seriously Martine Piccart, MD, PhD, is President of the European Society of Medical Oncology and Professor of Oncology at the Universite Libre de Bruxelles and Director of Medicine at the Jules Bordet Institute, in Brussels, Belgium.

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | NOVEMBER 1, 2013

PAGE 17

European Cancer Congress Gastrointestinal Oncology

Aspirin Protects Against Colorectal Cancer Recurrence in PIK3CA-Mutant Tumors By Caroline Helwick

t the 2013 European Cancer Congress, two investigative teams attempted to explain how aspirin may protect against colorectal can-

cer recurrences, with one study showing PIK3CA mutations associated with protection from aspirin, but not a COX-2 inhibitor, and the other study

implicating HLA class I antigens but finding no PIK3CA association. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)

are already believed to protect against colorectal cancer, having been associated with reduced disease recurrence following primary treatment. Since these drugs carry toxicity, research has focused on finding a subgroup that might benefit most from the drugs’ potential effects. Biomarkers of benefit have been proposed, including cyclooxygenase-2 (COX-2) overexpression and germline UGT1A6 polymorphisms. Recent data suggest aspirin’s benefit may be limited to patients with PIK3CA-mutant cancers, as reported recently in The New England Journal of Medicine,1 where aspirin use was associated with a hazard ratio (HR) of 0.18 (P < .001) for colorectal-cancer survival in patients with PIK3CA-mutant tumors.

VICTOR Affirms Role of PIK3CA Mutations

Advertisement not displayed in digital edition at advertiser’s request

The VICTOR study sought to determine the benefit of COX-2 inhibition in 2,424 patients who were randomly assigned to receive rofecoxib (Vioxx) at 25 mg/d or placebo following primary resection.2 In a biomarker substudy of 896 patients,3 of whom 11.6% had a PIK3CA mutation, relapse-free survival and overall survival were compared between the rofecoxib and placebo arms, according to mutation status, and between low-dose (< 100 mg/d) aspirin use (14%) and nonuse (86%), as noted at randomization. The study was discontinued after a median duration of rofecoxib therapy of 7.4 months, due to adverse cardiovascular events. “We found no evidence of a greater benefit from rofecoxib treatment compared to placebo in patients whose tumor had PIK3CA mutations, compared to PIK3CA wild-type cancers,” said David Church, MD, of the Oxford Cancer Centre at the University of Oxford in the United Kingdom. Among patients with PIK3CA-mutant tumors, recurrence-free and overall survival were not significantly different, whether they received rofecoxib or not. In contrast to the findings for rofecoxib, regular aspirin use after diagnosis was associated with a reduced rate of recurrence in patients with PIK3CAmutant cancers (HR = 0.11; P = .036) but not in cases lacking PIK3CA mutacontinued on page 18

The ASCO Post | NOVEMBER 1, 2013

PAGE 18

European Cancer Congress Aspirin and Colorectal Cancer continued from page 17

tions (HR = 0.94; P = .71). The test for interaction between the mutation and recurrence was statistically significant (P for interaction = .024). Among the 14 PIK3CA-mutated patients taking low-dose aspirin, there were no relapses, whereas there were 23 relapses among the 90 patients with mutations but not taking aspirin. The hazard ratio for overall survival was 0.29, but due to the small number of deaths (including only one death in the aspirin group), this was not statistically significant, he added. The discordance between the benefits of rofecoxib and aspirin in

PIK3CA-mutant tumors suggests that aspirin’s effects may be, at least partly, COX-2–independent, Dr. Church suggested. “PIK3CA mutation merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant colorectal cancer,” he said.

Aspirin May Affect Immune System Dutch investigators have another theory for how aspirin improves outcomes after a colorectal cancer diagnosis, showing its benefits in patients whose tumor cells express human leukocyte antigen (HLA) class I, a cell-surface protein produced by

EXPERT POINT OF VIEW

lberto Sobrero, MD, who discussed the VICTOR trial at the European Cancer Congress, said that at this point, adjuvant trials may be unethical, if the findings of multiple observational studies are to be trusted. Apparently, Dr. Sobrero is a believer: He introduced his remarks at the ECC session by swallowing an aspirin before the audience. “This is an aspirin. It’s the strongest message I can give. The relevance of this study, to me, is absolutely fantastic,” he said. “Zero out of 14 patients taking aspirin relapsed, vs 23 of 90 patients not taking aspirin.

Alberto Sobrero, MD

If the observational data are true, then for every patient relapsing or dying on aspirin, 8 to 10 relapse or die if they are not using aspirin. —Alberto Sobrero, MD

That’s a hazard ratio of 0.11, which means that those not taking aspirin have more than an eight times increased risk of recurrence,” he pointed out. “If the observational data are true, then for every patient relapsing or dying on aspirin, 8 to 10 relapse or die if they are not using aspirin.” Patients with colorectal cancer are tuning into the data from the observational studies and are not likely to agree to be randomly assigned to placebo, which would convey an eight times greater risk of recurrence, if these data are correct, he pointed out. Others might enroll but then contaminate the study by taking aspirin on the sly, he suggested. To ensure an ethical basis and reliable results from a randomized adjuvant trial, a stringent stopping rule would need to be in place, he said. n Disclosure: Dr. Sobrero reported no potential conflicts of interest.

New from The ASCO Post

Aspirin benefit was not associated with a PIK3CA mutation or COX-2 expression of the tumor. Low-dose aspirin use after diagnosis improved survival only in patients with tumors expressing HLA class I. —Marlies S. Reimers, MD

genes involved in immune function. Marlies S. Reimers, MD, of Leiden University Medical Center in The Netherlands, and colleagues examined the expression of HLA class I proteins and COX-2 in 999 tumor samples of colorectal cancer from patients whose aspirin use was known. They also examined PIK3CA gene mutations in 663 tumors. Tumor markers were related to survival.4 Dr. Reimers reported that low-dose (80 mg/d) aspirin use after diagnosis was associated with a 47% better overall survival in patients with tumors expressing HLA class I, at a median time of 4 years postdiagnosis. “Aspirin benefit was not associated with a PIK3CA mutation or COX-2 expression of the tumor. Low-dose aspirin use after diagnosis improved survival only in patients with tumors expressing HLA class I,” Dr. Reimers reported. “We think that platelets are involved in metastasis by shielding tumor cells in the bloodstream, so that they cannot be recognized by the immune system. Aspirin could help to ‘unmask’ those tumor cells by attacking platelet formation, so that the immune cells can detect and eliminate them,” she suggested. Interestingly, their investigation did not find a preferential benefit of aspirin in patients with PIK3CA mutations, nor was it related to COX-2 expression. It is possible that aspirin is acting on two different pathways in colon cancer: one related to the evolution of polyps to cancer and to cancer recurrence (PI3KCA, COX2), and the other (HLA class I) related to metastasis by influencing platelets in the bloodstream, Dr. Reimers commented.

“Although speculative, it may be that the interaction of platelets with HLA-positive tumor cells circulating in the blood promotes the metastatic potential of these cells,” she said. Dr. Reimers added that it is easier to measure HLA class I on tumor cells than to determine PIK3CA mutation status. “It is important to acknowledge that the data presented by Dr. R eimers are preliminary and await publication,” said senior author Gerrit-Jan Liefers, MD. “Also, our data need to be validated, preferably in published cohorts. However, we feel that designing a randomized aspirin trial on the basis of PIK3CA mutations is premature. It would be better to stratify patients for various molecular markers (eg, PIK3CA, HLA1). n

Disclosure: Drs. Church, Reimers, and Liefers reported no potential conflicts of interest.

References 1. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-606, 2012. 2. Church D, Domingo E, Sieber O, et al: Evaluation of PIK3CA mutation as a predictor of benefit from NSAID therapy in colorectal cancer. 2013 European Cancer Congress. Abstract 2161. Presented September 29, 2013. 3. Domingo E, Church DN, Sieber O, et al: Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. September 23, 2013 (early release online). 4. Reimers MS, Bastiaannet E, Langley RE, et al: Low dose aspirin use after a colon cancer diagnosis and survival in HLA class I expressing tumors. 2013 European Cancer Congress. Abstract 2183. Presented September 30, 2013.

May 30-June 3, 2014 | McCormick Place | Chicago, Illinois

EXCLUSIVE FOR MEMBERS

Register and Reserve Your Hotel ASCO members enjoy early access, offering discounted registration rates, first choice of ticketed sessions, and access to the closest and most sought-after hotels.

Take full advantage of your ASCO membership: register and reserve your hotel today.

am.asco.org KEY DATES November 15, 2013 December 4, 2013 February 4, 2014 April 23, 2014

Abstract Submitter Opens General Registration and Hotel Open Abstract Submission Deadline Hotel Reservation and Early Registration Deadline

Not an ASCO Member? Join ASCO at benefits.asco.org.

The ASCO Post | NOVEMBER 1, 2013

PAGE 20

European Cancer Congress Gastrointestinal Oncology

Panitumumab vs Cetuximab in Chemorefractory Colorectal Cancer: Survival Benefits Comparable By Caroline Helwick

or the treatment of wild-type KRAS metastatic colorectal cancer in previously treated patients, a head-to-head comparison of the two antibodies—cetuximab (Erbitux) and panitumumab (Vectibix)—that target the epidermal growth factor receptor (EGFR) concluded that they convey similar overall survival advantages. The results of the international phase III ASPECCT trial were presented at the 2013 European Cancer Congress by Timothy Price, MD, of the Queen Elizabeth Hospital in Adelaide, Australia.1

Timothy Price, MD

Prior to ASPECCT, cetuximab had prospectively demonstrated an overall survival benefit, but panitumumab had not, presumably because of heavy crossover in the pivotal panitumumab trials, Dr. Price explained. “The crossover potentially diluted the overall survival benefit, and this has often been a discussion point regarding the two drugs,” he noted.

ASPECCT, therefore, was designed as a noninferiority trial to determine if one of these agents might be preferred over the other. The study enrolled 999 patients with KRAS wild-type metastatic colorectal cancer who had previously received irinotecan-, oxaliplatin-, and fluorouracil-based treatment (or bevacizumab [Avastin]) for metastatic disease, but no prior anti-EGFR regimens. Patients were randomized to receive panitumumab at 6 mg/kg every 2 weeks or cetuximab at 400 mg/ m2 followed by 250 mg/m2 weekly. Crossover between the arms was not allowed in the protocol, though a small and equal proportion of patients in each arm did so. For the primary endpoint, overall survival, noninferiority was determined if panitumumab preserved at least 50% of the cetuximab overall survival effect, compared with best supportive care, found in the prior NCIC CTG C0.17 trial.

Panitumumab Noninferior to Cetuximab At a median follow-up of 9 months, panitumumab proved noninferior to cetuximab, yielding a median overall survival time of 10.4 months vs 10.0 months with cetuximab (hazard ratio [HR] = 0.97; P = .0007). The Z score of –3.19 satisfied the criteria of noninferiority (< –1.96), Dr. Price reported.

Panitumumab vs Cetuximab in Chemorefractory Colorectal Cancer ■■ A head-to-head comparison of the two EGFR antibodies in previously

treated metastatic colorectal cancer patients found panitumumab to be noninferior to cetuximab in overall survival, progression-free survival, and response rates.

■■ Median overall survival was approximately 10 months with each agent, and median progression-free survival was about 4 months. Approximately 20% of patients responded to either agent.

EXPERT POINT OF VIEW

t the European Cancer Congress (ECC), Josep Tabernero, MD, PhD, Head of the Medical Oncology Department at Vall d’Hebron University in Barcelona, Spain, noted that the ASPECCT study asks a “reasonable question about the efficacy and safety of the two clinically approved anti-EGFR antibodies” and “may be the setting to provide an important amount of clinical and translational information. “ASPECCT showed that the results are completely comparable in terms of response rate, progression-free survival, and overall survival in the chemorefractory setting,” he said, but he cautioned that the findings should not be applied to other Josep Tabernero, MD, PhD Eric Van Cutsem, MD, PhD treatment settings or other tumors, where the agents have not been shown equally effective. Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven in Belgium, also commented. “There is probably not a big difference between these agents in the different markers we have seen. In the head-to-head trial presented here at ECC 2013, we saw no difference. We know that preclinically, cetuximab has shown some antibody-dependent cellular cytotoxicity, but we don’t know the contribution of this. Looking at the activity of these drugs, I think they are very similar and can be interchanged in this setting.” n

Disclosure: Dr. Van Cutsem has received research funding paid to his institution by Amgen, Merck Serono, and Roche. Dr. Tabernero has served in an advisory role for Amgen, Genentech, Merck Serono, and Roche..

Median progression-free survival was also similar—4.1 months with panitumumab and 4.4 months with cetuximab—as were response rates: 22.0% and 19.8%, respectively. For both agents, the safety profiles were consistent with previously reported studies. Serious adverse events were observed in 30.4% of the panitumumab arm and 33.6% of the cetuximab arm, with 13.9% and 12.1%, respectively, discontinuing the drug. Grade 3 or 4 skin toxicity (12.5% vs 9.5%) as well as hypomagnesemia (7.2% vs 2.6%) were more common

with panitumumab, but infusion reactions (0.2% vs 1.8) were more common with cetuximab. There was no difference in the rate of diarrhea. n

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

Reference 1. Price T, Peeters M, Kim TW, et al: ASPECCT: A randomized, multicenter, open-label, phase 3 study of panitumumab vs cetuximab for previously treated wildtype KRAS metastatic colorectal cancer. 2013 European Cancer Congress. Abstract LBA18. Presented September 28, 2013.

Visit The ASCO Post website at

ASCOPost.com

REMEMBER 3 DISTINCT COMPONENTS IN THE VEGF-SIGNALING PATHWAY 1-3

Component 1: VEGF ligands circulating in the body1-3

Component 2: The receptors’ extracellular VEGF-binding domains1-3

Component 3: The receptors’ intracellular tyrosine kinase domains1-3

VEGF=vascular endothelial growth factor.

In an effort to improve the care of people living with cancer, Lilly Oncology remains committed to studying different VEGFsignaling events needed for angiogenesis. References: 1. Olsson AK, et al. Nat Rev Mol Cell Biol. 2006;7(5):359-371. 2. Youssoufian H, et al. Clin Cancer Res. 2007;13(suppl 18):5544s-5548s. 3. Kowanetz M, Ferrara N. Clin Cancer Res. 2006;12(17):5018-5022. OC85945

07/2013

PRINTED IN USA

The ASCO Post | NOVEMBER 1, 2013

PAGE 22

Journal Spotlight Gastrointestinal Oncology

Bevacizumab/Capecitabine Improves Progression-Free Survival in Older Patients With Treatment-Naive Metastatic Colorectal Cancer By Matthew Stenger

lderly patients are often underrepresented in clinical trials of metastatic colorectal cancer. In the phase III AVEX trial reported in The Lancet Oncology,1 David Cunningham, MD, of Royal Marsden Hospital in London and colleagues assessed the addition of bevacizumab (Avastin) to capecitabine in patients aged ≥ 70 years with previously untreated metastatic colorectal cancer who were not considered candidates for oxaliplatin- or irinotecan-based chemotherapy. The bevacizumab/capecitabine combination significantly improved progressionfree survival and was associated with more frequent adverse events than capecitabine alone.

primary tumor, received previous adjuvant treatment, and had been treated with radiotherapy.

Prolonged Progression-Free Survival Median follow-up was 24.8 months for the combination group and 21.6 months for the capecitabine-alone group. Progression-free survival was significantly longer with bevacizumab/capecitabine (median, 9.1 vs 5.1

Median overall survival did not differ significantly in the combination vs capecitabine-alone groups (20.7 vs 16.8 months, HR = 0.79, P = .18). Overall survival was 73.6% vs 60.0% at 1 year and 44.3% vs 35.1% at 2 years. The proportions of patients who had subsequent treatment after progression were similar in the two groups, including treatment with fluoropyrimidine monotherapy (17% vs 18%), bevacizumab (6% vs 8%),

Bevacizumab plus capecitabine represents an additional therapeutic option in elderly patients with metastatic colorectal cancer, particularly in those who are unsuitable for upfront oxaliplatin-or irinotecanbased combination regimens.

Study Details In this international open-label trial, 280 patients were randomly assigned to receive capecitabine at 1,000 mg/ m2 orally twice a day on days 1 to 14 alone (n = 140) or with bevacizumab at 7.5 mg/kg intravenously on day 1 (n = 140) given every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival. Median ages were 76 years in the combination group (61% ≥ 75 years) and 77 years in the capecitabine-alone group (67% ≥ 75 years), and 60% of patients in both groups were male. The groups were generally well matched for other baseline characteristics, including Eastern Cooperative Oncology Group (ECOG) performance status, site of metastatic disease, synchronous metastatic disease, primary tumor location, time since diagnosis of primary and metastatic disease, history of other medical conditions, and use of any concomitant drugs. However, more patients in the combination group had undergone surgical resection of the

Overall Survival Outcomes

—David Cunningham, MD

months, hazard ratio [HR] = 0.53, P < .0001). Progression-free survival was 66.7% vs 44.2% at 6 months, 34.8% vs 10.3% at 12 months, and 16.2% vs 3.6% at 18 months. Exploratory subgroup analyses of progression-free survival were consistent with the overall findings. Analysis by age suggested improved outcomes with the combination in patients aged 70 to 74 years (HR = 0.52, 95% confidence interval [CI] = 0.32–0.83), 75 to 79 years (HR = 0.60, 95% CI = 0.40–0.89), and ≥ 80 years (HR = 0.36, 95% CI = 0.19–0.71). More patients in the combination group achieved response (19% vs 10%, P = .04) and disease control (74% vs 58%, P = .01), with duration of response being similar in the two groups (median, 9.0 vs 9.4 months).

AVEX Trial in Colorectal Cancer ■■ The addition of bevacizumab to capecitabine significantly prolonged

progression-free survival in elderly patients with previously untreated metastatic colorectal cancer who were not considered candidates for oxaliplatin- or irinotecan-based chemotherapy.

■■ No significant difference in overall survival was observed between the two groups.

■■ Adverse events were more common with bevacizumab/capecitabine.

irinotecan doublets (6% vs 3%), oxaliplatin doublets (2% vs 1%), cetuximab (Erbitux; 3% vs 1%), and panitumumab (Vectibix; 1% vs 4%).

Adverse Events Treatment-related adverse events of grade 3 or higher occurred in 40% of patients in the combination group and 22% of patients in the capecitabinealone group, and treatment-related serious adverse events occurred in 14% and 8%, respectively. The most com-

mon grade 3 or higher adverse events of special interest for bevacizumab or chemotherapy were hand-foot syndrome (16% vs 7%), diarrhea (7% vs 7%), and venous thromboembolic events (8% vs 4%). Treatment-related deaths occurred in 3.7% of patients in the combination group and 2.9% in the capecitabine-alone group. The most common adverse event of any grade of special interest for bevacizumab was hemorrhage (25% vs 7%). Adverse events led to dose interruption or modification in 55% of combination patients vs 43% of capecitabine patients and to discontinuation in 25% vs 15%. The investigators concluded, “[O] ur data suggest that bevacizumab plus capecitabine represents an additional therapeutic option in elderly patients with metastatic colorectal cancer, particularly in those who are unsuitable for upfront oxaliplatin-based or irinotecan-based combination regimens.” n

Disclosure: The study was funded by F Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com/ journals/lanonc.

Reference 1. Cunningham D, Lang I, Marcuello E, et al: Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 14:1077-1085, 2013.

The AVEX Trial By Stuart M. Lichtman, MD, FACP

s reported in The Lancet Oncology by Cunningham and colleagues and reviewed in this issue of The ASCO Post, the AVEX trial was an openlabel randomized phase III trial limited to patients over the age of 70 years with previously untreated, unresectable metastatic colorectal cancer who were not deemed candidates for oxaliplatin- or irinotecan-based chemotherapy regimens.1 The primary endpoint was progression-free survival. A total of 280 patients with a median age of 76 years were included from 10 countries in Europe. Progression-free survival was significantly longer with bevacizumab (Avastin) and capecitabine compared with capecitabine alone (9.1 vs 5.1 months). More patients treated with the combination had grade III or worse toxicity (40% vs 22%), and the most common any-grade adverse event in the bevacizumab group was hemorrhage (25% vs 7%). continued on page 23

ASCOPost.com | NOVEMBER 1, 2013

PAGE 23

Journal Spotlight

The AVEX Trial continued from page 22

Bevacizumab and Older Patients

The role of bevacizumab in treating older patients with malignancy is still uncertain. There has always been concern about the risks of bevacizumab treatment, including thromboembolic events, particularly in those over the age of 65 years and those with comorbidities that may predict their increased chance of adverse outcomes. Cunningham and colleagues should be commended for performing a prospective trial focusing on patients over the age of 70 years. These kinds of trials have rarely been done and are sorely needed due to the aging of the population, particularly in colorectal cancer, for which the median age of patients is in the early 70s.

Design and Interpretation This study, however, also raises issues about clinical trial design and clinical trial interpretation that should be considered when evaluating its results. First, despite the fact that the study was limited to patients over the age of 70 years, it did not include any form of geriatric assessment. Even a rudimentary geriatric assessment, such as the activities of daily living or instrumental activities of daily living scales or just a listing of comorbidities, would be helpful in interpreting this trial and what type of patients were studied. The other issue is that patients who were eligible for the study were those not deemed to be candidates for combination chemotherapy with either irinotecan or oxaliplatin. However, the paper does not address how this decision was made. It is not clear whether these were arbitrary decisions made by the clinician or the decision was based on objective criteria. Over 90% of the participants had Dr. Lichtman is Attending Physician, 65+ Clinical Geriatric Program, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, New York.

a performance status of 0 or 1. Why were these patients with good performance status not eligible for oxaliplatin or irinotecan? It is well known that the standard performance status measures (ie, Eastern Cooperative Oncology Group or Karnofsky scores) may not be an accurate reflection of the older patient’s functional status,2 but knowing why these patients were considered ineligible for such treatment would help in interpretation of the study results. Moreover, a prospective trial of older patients showed that objective assessment was superior to clinical judgment in predicting toxicity.3

Further Considerations Additional potential issues raised by the study results include questions

of at least 30 mL/minute. This is an important issue in dosing capecitabine and avoiding toxicity.8

Conclusions Prospective randomized trials of older patients with cancer are important to advancing the field of geriatric oncology. With the aging of the population and increased incidence of malignancies in older patients, studies like the AVEX trial are extremely important. However, to get the most value out of patient participation in these trials, some form of geriatric assessment is critical for clinicians to be able to use the data from such trials in a clinically meaningful fashion. Recently published articles regarding clinical trial design and clinical trial reporting in older

Studies like the AVEX trial are extremely important. However, to get the most value out of patient participation in these trials, some form of geriatric assessment is critical for clinicians to use the data from such trials in a clinically meaningful fashion. —Stuart M. Lichtman, MD, FACP

raised by the fact that the response rates were quite low, with objective response seen in only 10% of patients given capecitabine alone and in 19% given bevacizumab/capecitabine. These rates are lower than previously reported.4-7 Also, two-thirds of the patients did not receive any second-line therapy. There is also an issue in terms of dosing, with the authors pointing out that the study-mandated dose of capecitabine (2,000 mg/m2) was less than the standard dose used in clinical practice (2,500 mg/m2). This is an interesting comment, since most clinicians in the United States do not use the 2,500-mg/m2 dose in patients of any age, particularly in older patients. It should be noted that the inclusion criteria required a creatinine clearance

patients have presented recommendations that should be followed.9-11 The number of patients—particularly older patients—entering clinical trials is disappointingly low. Therefore, studies should be designed so that the maximum amount of data can be obtained from the patients who do participate. The study of oral anticancer therapy is critically important, as this has become more common in oncology. Cost and compliance are other factors that need to be considered in study design and data acquisition. It is hoped that prospective trials of older patients will continue to be performed. Study design needs to be adapted to reflect the specific needs of these patients. n Disclosure: Dr. Lichtman reported no potential conflicts of interest.

References 1. Cunningham D, Lang I, Marcuello E, et al: Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 14:1077-1085, 2013. 2. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16:1582-1587, 1998. 3. Hurria A, Togawa K, Mohile SG, et al: Predicting chemotherapy toxicity in older adults with cancer: A prospective multicenter study. J Clin Oncol 29:3457-3465, 2011. 4. Feliu J, Safont MJ, Salud A, et al: Capecitabine and bevacizumab as firstline treatment in elderly patients with metastatic colorectal cancer. Br J Cancer 102:1468-1473, 2010. 5. Vrdoljak E, Omrcen T, Boban M, et al: Phase II study of bevacizumab in combination with capecitabine as first-line treatment in elderly patients with metastatic colorectal cancer. Anticancer Drugs 22:191-197, 2011. 6. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001. 7. Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90:1190-1197, 2004. 8. Lichtman SM, Wildiers H, Chatelut E, et al: International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of chemotherapy in older patients-an analysis of the medical literature. J Clin Oncol 25:1832-1843, 2007. 9. Lichtman SM: Clinical trial design in older adults with cancer. The need for new paradigms. J Geriatr Oncol 3:368-375, 2012. 10. Lichtman SM: Call for changes in clinical trial reporting of older patients with cancer. J Clin Oncol 30:893-894, 2012. 11. Wildiers H, Mauer M, Pallis A, et al: End points and trial design in geriatric oncology research: A joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology position article. J Clin Oncol 31:3711-3718, 2013.

FOR THE TREATMENT OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) WHO HAVE PREVIOUSLY RECEIVED DOCETAXEL

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss

of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ďŹ&#x201A;ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe

Convenient, oral, once-daily administration • Dosed as four 40 mg capsules (160 mg) without food restrictions or steroid requirements. Each capsule should be swallowed whole. Patients should not chew, dissolve, or open the capsules1,2 Comparable overall rate of grade 3-4 adverse reactions • No increased overall rate of grade 3-4 adverse reactions with XTANDI vs placebo (47% vs 53%, respectively)1 37% reduced risk of death • HR = 0.63 (95% CI, 0.53-0.75); P < 0.00011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.3

in XTANDI patients and included nonpathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event. Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is

coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed March 11, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Learn L earn more more a att XtandiHCP.com XtandiHCP.c com

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 1, 2013

PAGE 26

Awards

Gastric Cancer Foundation Announces Research Partnership With AGA

he Gastric Cancer Foundation recently announced the formation of a research partnership with the American Gastroenterological Association (AGA) and a confirmed timeline for awarding newly funded research grants for upper gastroin-

testinal tract cancers. Wayne Feinstein, Chairman of the Board of Directors, Gastric Cancer Foundation, announced the development of a significant research partnership with the American Gastroenterological Association. He noted that

in 2014 the first AGA-GCF Research Scholar Award in Gastric and Esophageal Cancer will be awarded to fund young investigators with the tools needed to focus their research on gastrointestinal tract cancers. Members of the AGA Research

Awards Panel and representatives of the Gastric Cancer Foundation will jointly review proposals and select award recipients. Applications are due by December 13, 2013. Additional information is available at www.gastro.org/foundation. n

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders Asthenic Conditionsa 9.0 44.4 9.3 Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 1, 2013

PAGE 27

Announcements

Roswell Park Cancer Institute, University of Pittsburgh Cancer Institute, Receive $11 Million Spore Grant for Joint Research in Ovarian Cancer

he National Cancer Institute has awarded more than $11 million in funding to Roswell Park Cancer Institute (RPCI), in collaboration with the University of Pittsburgh Cancer In-

stitute (UPCI), to begin an aggressive, multipronged search into preventing and treating ovarian cancer. Distributed over 5 years, the funds will come through a Specialized Program

of Research Excellence (SPORE) grant. The research team, led by Kunle Odunsi, MD, PhD, Principal Investigator of the RPCI/UPCI Ovarian Cancer SPORE grant, will study novel immunotherapy

Kunle Odunsi, MD, PhD

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

Live: 7"w Ă&#x2014; 10"h

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

approaches for the treatment of and risk assessment for ovarian cancer.

Research With Potential to Change Lives â&#x20AC;&#x153;The NCI has recognized that our research has very high potential for changing the lives of ovarian cancer patients around the world,â&#x20AC;? said Dr. Odunsi, who is Chair of Gynecologic Oncology and Director of the Center for Immunotherapy at Roswell Park Cancer Institute. Dr. Odunsi is an expert in the field of immunotherapy. The RPCI/UPCI Ovarian Cancer SPORE program will focus exclusively on harnessing the immune system. The overall goal is to prolong the survival of ovarian cancer patients through innovative translational research.

Co-Principal Investigators The Ovarian Cancer SPORE CoPrincipal Investigators are Kirsten B. Moysich, PhD, Professor in the Department of Immunology and Professor of Oncology in the Department of Cancer Prevention and Control at Roswell Park,

Kirsten B. Moysich, PhD

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716 Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 0HGLYDWLRQ ,QF 6DQ )UDQFLVFR &$ Issued: August 2012 $ (1= %56 Rx Only ÂŠ 2012 Astellas Pharma US, Inc. XTANDIÂŽ is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

Robert P. Edwards, MD

and Robert P. Edwards, MD, Executive Vice Chair of Gynecologic Services and Director of the Ovarian Cancer Center for Excellence, Gynecologic Program at Magee-Womens Hospital of the University of Pittsburgh Medical Center. n

The ASCO Post | NOVEMBER 1, 2013

PAGE 28

NCCN Congress on Hematalogic Malignancies

New Strategies for Relapsed/Refractory Multiple Myeloma Explored By Alice Goodman

lthough upfront therapy can achieve remission in multiple myeloma, most patients will ultimately relapse. Newer targeted therapies and genomic analysis are moving the management of relapsed/refractory multiple myeloma forward, according to Kenneth C. Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Center/Brigham and Women’s Cancer Center, and Kraft Family Professor of Medicine, Harvard Medical School, Boston. Dr. Anderson discussed management of relapsed/refractor y multiple myeloma at the National Com-

prehensive Cancer Network (NCCN) 8th Annual Congress on Hematologic Malignancies, held recently in New York.1

Decade of Progress “There are many protocols of novel immune and targeted agents that show promise alone and in combination. Genomic analyses are both defining the basis for evolution of disease leading to relapse and identifying new targets for therapeutic approaches,” he explained. Over the course of the past decade, progress has come from U.S. Food and Drug Administration (FDA) approval of bortezomib (Velcade), lenalidomide (Revlimid), thalidomide (Thalomid), liposomal doxorubicin,

EXPERT POINT OF VIEW

“I

n the past, we considered multiple myeloma the poor sibling among lymphoid malignancies. We have seen an amazing amount of change in this field, and Dr. Anderson and colleagues have contributed to that progress. But despite the progress, most patients still relapse,” noted Andrew D. Zelenetz, MD, PhD, Vice Chair of Informatics in the Department of Medicine at Memorial Sloan-Kettering Cancer Center, New York, and Chair of the NCCN Congress on Hematologic Malignancies. “Dr. Anderson gave a great overview of current and future strategies that may pan out to improve outcomes in multiple myeloma,” he noted at the NCCN Annual Congress. n Disclosure: Dr. Zelenetz reported no potential conflicts of interest.

carlfilzomib (Kyprolis), and pomalidomide (Pomalyst) in the treatment of multiple myeloma. “These drugs were first tested in advanced and relapsed disease, but more

recently have shown efficacy as initial, consolidation, and maintenance therapy. These drugs target both the tumor and the microenvironment and can overcome resistance to conventional

Take-Home Messages From the NCCN Hematologic Malignancies Conference By Alice Goodman

s the National Comprehensive Cancer Network (NCCN) 8th Annual Congress: Hematologic Malignancies was drawing to a close, The ASCO Post spoke with Andrew D. Zelenetz, MD, PhD, about the themes of the meeting and the takehome messages for attendees and for our readers. Dr. Zelenetz is Vice Chair for Informatics in the Department of Medicine at Memorial Sloan-Kettering Cancer Center, New York, and Chair of the NCCN Congress on Hematologic Malignancies.

Explosion in Genomics The main theme of the meeting, as at many medical meetings these days, was the wealth of knowledge now at our fingertips, given the ability to sequence the whole genome and the subsequent explosion in genomics. Sticking with that theme, three presentations focused on genomics in hematologic malignancies: Ross L. Levine, MD, on “Genomics and the Era of Personalized Medicine,” Richard M. Stone, MD, on “Clinical Genomics in Myeloid Malignancies,” and Jeffrey Jones, MD, MPH, on “Targeting Novel Signaling Pathways in B-Cell Malignancies.” “By itself, Dr. Levine’s talk was indicative of where the field is moving, which is trying to understand the molecular pathways involved in a range of

hematologic malignancies as well as solid tumors. Dr. Stone’s talk tempered our current enthusiasm, since our ability to act on specific mutations that can be identified is limited at present. The reality is first we need to identify the mutations, then identify the target, and then develop drugs or use available drugs to target the targets,” Dr. Zelenetz explained. “Dr. Jones’ talk opened the door to the future. Drugs targeting novel

Novel Agents, Molecular Modeling Updates “At Memorial Sloan-Kettering Cancer Center, we are starting to see the fruits of our research in relapsed/ refractory acute myeloid leukemia (AML). As a consequence of identifying the isocitrate dehydrogenase (IDH) mutations, we are targeting a new pathway with an IDH inhibitor in a very early study. Before this, we had no idea of what the targets might be in

Overall, we are seeing the increasing impact of understanding specific pathways of mutation. This is beginning to shape not only our biological appreciation of these illnesses, but also our treatment options. —Andrew D. Zelenetz, MD

signaling pathways will revolutionize our treatment of chronic lymphocytic leukemia and will have an important impact on other B-cell malignancies. The recognition that signaling via the B-cell pathway was an important target gave us tremendous insight. We have multiple tools to inhibit that signaling,” Dr. Zelenetz continued.

AML,” he explained. Other presentations at the NCCN Congress included updates on molecular modeling for the use of tyrosine kinase inhibitors in chronic myeloid leukemia and monitoring responses, management of Philadelphia chromosome–positive acute lymphocytic leukemia and use of tyrosine kinase

inhibitors in that malignancy, interim PET scanning in Hodgkin lymphoma, a discussion on how to integrate new agents in relapsed/refractory multiple myeloma, and a talk on management of bone health in multiple myeloma.

Rare Diseases Two speakers focused on rare lymphoid malignancies. Ranjana H. Advani, MD, discussed lymphocyte predominant Hodgkin lymphoma, another B-cell lymphoma that behaves like an indolent lymphoma. About half the audience was not able to identify this disease as a B-cell lymphoma before Dr. Advani’s talk, Dr. Zelenetz noted. Leo Gordon, MD, discussed rare lymphomas. “He told listeners that the marked sensitivity of patients with Waldenstrom macroglobulinema to ibrutinib who have the MYD88 (L265P) mutation might herald a treatment breakthrough,” he commented. “Overall, we are seeing the increasing impact of understanding specific pathways of mutation. This is beginning to shape not only our biological appreciation of these illnesses, but also our treatment options,” Dr. Zelenetz concluded. n Disclosure: Dr. Zelenetz reported no potential conflicts of interest.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 29

NCCN Congress on Hematalogic Malignancies therapies,” Dr. Anderson said. Experience has shown that bortezomib, the first proteasome inhibitor to be FDA-approved for multiple myeloma, can be given more safely once a week in a subcutaneous administration, instead of twice a week with intravenous administration. This strategy retains the efficacy of the drug, but causes significantly less peripheral neuropathy.

Newest Drug Approvals Carlfilzomib and pomalidomide are the most recent drugs to be granted accelerated FDA approval for multiple myeloma. Carlfilzomib has improved antitumor activity with consecutive-day dosing and does not cause neurotoxicity in animal models. Durable responses lasting 8 months have been reported in relapsed/refractory multiple myeloma patients without attendant peripheral neuropathy. “These findings were in patients who had run out of other options,” Dr. Anderson said. Going forward, the ASPIRE trial, which is now fully enrolled, is evaluating the combination of carlfilzomib with lenalidomide and dexamethasone in relapsed multiple myeloma.2 Moreover, overall response rate after 12 cycles of carfilzomib, lenalidomide, and dexamethasone as initial treatment was 100%, with an 80% rate of complete response or nearcomplete response. Pomalidomide, the second new drug recently approved, is a potent stimulator of autologous T cells and natural killer cells. The drug directly targets regulatory T cells and enhances the immune response. Pomalidomide with low-dose dexamethasone is now FDA-approved for treatment of relapsed/refractory multiple myeloma. The triple combination of pomalidomide/bortezomib/low-dose dexamethasone shows promise, with a 73% response rate in relapsed multiple myeloma, including

rapid and ongoing responses even in patients with adverse cytogenetic features. This triple combination is being studied in a phase III trial. Experience shows that secondgeneration drugs are difficult, if not impossible, to dose-escalate, he continued. “These agents are stronger than first-generation agents, and it is difficult to escalate and maintain a therapeutic index,” Dr. Anderson said. “Although we have made progress to date, patients still relapse and new treatments are therefore urgently needed,” he added.

Novel Approaches Elotuzumab and daratumumab are two monoclonal antibodies being

Progress in Multiple Myeloma ■■ Progress in treating multiple myeloma has come from new drugs and combinations approved by the FDA over the past decade.

■■ Despite these advances, patients still relapse, and more effective strategies are needed.

proteasome inhibitors ixazomib and oprozamib, Dr. Anderson noted. Marizomib is a broader proteasome inhibitor that has also achieved response rates in advanced multiple myeloma, even in the setting of bortezomib/lenalidomide resistance. Two new classes of drug under investigation for multiple myeloma include Bruton’s tyrosine kinase inhibitors and BET bromodomain

We should learn from our lymphoma colleagues and use drug combinations at the outset to prevent resistance from developing [in multiple myeloma patients]. —Kenneth C. Anderson, MD

evaluated in multiple myeloma. Dr. Anderson expects FDA approval of a three-drug regimen of elotuzumab, lenalidomide, and dexamethasone in the future, and early studies of daratumumab are ongoing. A promising immune approach entails a vaccine that fuses a patient’s own myeloma cells with their dendritic cells. This strategy triggered an anti-myeloma immune response and disease stabilization in 70% of patients with relapsed/refractory myeloma.3 New proteasome inhibitors and new immunomodulatory drugs are also under study. Patients who don’t respond to bor tezomib may respond to new agents that include the chymotryptic oral

inhibitors. Experimental studies of these agents show promising activity, and they are being studied clinically. Finally, combinations such as proteasome inhibitors with histone deacetylase inhibitors are demonstrating promise.

Genomic Studies “In multiple myeloma, whole-genome sequencing has identified mutations consistent with myeloma cell biology. A new and surprising finding is that BRAF mutations found in malignant melanoma were also present in 4% of multiple myeloma patients,” Dr. Anderson told the audience. Preliminary studies of BRAF inhibitors in multiple myeloma patients with this mutation have achieved responses.

“We have learned [from genomic sequencing] that a newly diagnosed multiple myeloma patient has multiple abnormalities, various mutations, and marked clonal heterogeneity even at the outset. As the disease evolves, the situation becomes more complex, with new mutations, copy number changes, and translocations occurring. When we talk about personalized medicine, we need to characterize genomics not only at the time of diagnosis, but also at the time of relapse. We should learn from our lymphoma colleagues and use drug combinations at the outset to prevent resistance from developing,” Dr. Anderson stated. “Once we have defined active combination novel targeted therapies, we will need to move to very early in the disease to make an impact on outcomes,” he noted. n

Disclosure: Dr. Anderson is on the advisory board for Millennium Takeda.

References 1. Anderson KC: Management of relapsed/refractory multiple myeloma. NCCN 8th Annual Congress: Hematologic Malignancies. Presented September 21, 2013. 2. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012. 3. Rosenblatt J, Vasir B, Uhl L, et al: Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood 117:393402, 2011.

Contact The ASCO Post Editorial Office

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

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

The ASCO Post | NOVEMBER 1, 2013

PAGE 30

NCCN Congress on Hematalogic Malignancies

Options for Management of Bone Health in Patients With Multiple Myeloma By Alice Goodman

one health is critical in patients with multiple myeloma, since up to 85% will suffer bone damage. Options for management include two FDA-approved bisphosphonates— pamidronate and zoledronic acid—and possibly the RANK-L inhibitor denosumab (Xgeva, investigational use).

Importance of Supportive Care “With modern treatments, multiple myeloma has become a chronic disease, but it can have potentially devastating effects on bone. Oncologists need to give attention to supportive care, which includes bone health,” said Noopur Raje, MD, Associate Professor of Medicine at Dana-Farber/Harvard Cancer Center and Director of the Multiple Myeloma Program at Massachusetts General Hospital, Boston. Dr. Raje spoke at the NCCN 8th Annual Congress on Hematologic Malignancies.1 Recent studies suggest that pamidronate and zoledronic acid are equivalent in preventing skeletal-related events in multiple myeloma, and that zoledronic acid may have a survival advantage. Studies using the bone biomarker N-telopeptide (NTx) suggest that it is possible to dose zoledronic acid less frequently after 2 years of regular bisphosphonate therapy, reducing the risk of concerning side effects unrelated to multiple myeloma that include spontaneous fracture and osteonecrosis of the jaw. “We don’t have all of the answers when it comes to bone disease. We don’t know how long to treat with bisphosphonates, nor do we know how frequently to treat,” said Dr. Raje. Denosumab is not FDA-approved for reducing skeletal-related events in multiple myeloma but has approval for that indication in some solid tumors. An international randomized trial is currently comparing denosumab vs zoledronic acid in multiple myeloma patients. Bone remodeling is a constant and dynamic process in the human body, Dr. Raje explained. “In multiple myeloma, the balance is tilted. The osteoblasts are hyperactive, leading to thinning of the bone, and osteoblasts that re-form the bone are dysfunctional. This results in sequelae associated with significant morbidity and mortality. About 50% of patients with multiple myeloma who are not treated for

their disease will develop some form of skeletal-related event within the first year. Pathologic fracture is the most common symptom, and patients with fracture have double the mortality,” she continued. The goal in treating multiple myeloma patients with bone-targeted agents is to avoid skeletal-related events, especially vertebral compression fractures, which occur in 3% to 4% of patients. These fractures are extremely painful and interfere with daily activities. NCCN guidelines recommend a skeletal survey annually throughout a patient’s lifetime, but x-rays fail to identify clinically silent skeletal-related events in

Bone Health and Multiple Myeloma ■■ The first priority for managing bone health in multiple myeloma is to treat the disease itself. In addition, upfront treatment with a bisphosphonate is recommended regardless of x-ray findings.

■■ Both zoledronic acid and pamidronate are approved bisphosphonates in this setting; zoledronic acid may have a survival advantage.

■■ Less frequent dosing of bisphosphonates may be possible. treated with multiple myeloma should also receive zoledronic acid to reduce the incidence of new osteolytic lesions.2 “Studies show for the first time that a nonmyeloma approach (ie, zoledronic acid) can affect the microenvironment and

With modern treatments, multiple myeloma has become a chronic disease, but it can have potentially devastating effects on bone. Oncologists need to give attention to supportive care, which includes bone health. —Noopur Raje, MD

about 30% of patients. She advised having a lower threshold for use of MRI and PET scans in patients with multiple myeloma, especially those with back pain.

Treatment Recommendations Recommended management of multiple myeloma includes bisphosphonates, vertebroplasty and kyphoplasty for vertebral fractures, limited use of radiation, and treatment for the myeloma itself. “I cannot overemphasize the importance of treating multiple myeloma. These treatments can mitigate bone problems,” Dr. Raje stated. Several large, randomized studies have demonstrated the efficacy of zoledronic acid in this setting, she continued. These studies suggest that all patients being

improve overall survival,” Dr. Raje said. It is important for patients taking bisphosphonates to have good oral hygiene and to be sure their dentists know they are taking that drug. Also, tooth extraction is not recommended during bisphosphonate treatment.

Toxicity Considerations Osteonecrosis of the jaw and stress fractures unrelated to myeloma are concerns with bisphosphonates, but Dr. Raje believes this is probably a consequence of overtreatment. Thus, it is important to determine the optimal duration of treatment with bisphosphonates. Patients usually receive bisphosphonates every 4 weeks. A study by Dr. Raje and colleagues suggested that less fre-

IMWG Recommendations

he International Myeloma Working Group (IMWG) recommends intravenous zoledronic acid as first-line therapy and intravenous pamidronate as second-line therapy for all patients being treated for multiple myeloma, regardless of imaging findings.1 These drugs are given monthly for 2 years and can be discontinued at 2 years if complete response or very good partial response

is achieved. It is not clear how long to continue bisphosphonate treatment for patients with a partial response. n Reference 1. Terpos E, Morgan G, Dimopoulos MA, et al: International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol 31:23472357, 2013.

quent dosing of a bisphosphonate is feasible, based on measurements of bone marker (NTx) levels.3 In this study of multiple myeloma patients with up to 2 years of prior bisphosphonate treatment, treatment every 12 weeks for an additional 2 years was feasible (up to 4 years of bisphosphonate treatment). The rate of skeletal-related events was about 4% in this study, and the rate of osteonecrosis of the jaw was about 3%.

Looking Ahead Future directions of research in this field include combining drugs that target the osteoblasts and osteoclasts, and combining other drugs with bisphosphonate. Also, use of imaging and incorporation of biomarkers will be refined, said Dr. Raje. “As more patients with multiple myeloma are living longer, the disease is becoming more chronic. And the majority of patients have bone damage, whether it is evident on imaging or not,” said conference Chair Andrew D. Zelenetz, MD, of Memorial Sloan-Kettering Cancer Center, New York. “As Dr. Raje explained, the most important thing to do for newly diagnosed patients is to treat the myeloma first and also treat them upfront with bisphosphonates.” n Disclosure: Drs. Raje and Zelenetz reported no potential conflicts of interest.

Reference 1. Raje N: Management of bone health in multiple myeloma. NCCN 8th Annual Congress: Hematologic Malignancies. Presented September 21, 2013. 2. Richardson PG, Laubach JP, Schlossman RL, et al: The Medical Research Council Myeloma IX trial. Eur J Haematol 88:177, 2012. 3. Raje N, Vescio R, Montgomery CW, et al: Bone marker directed dosing of zoledronic acid for the prevention of skeletal complications in patients with multiple myeloma: Primary analysis results of the Z-MARK study. Blood 118(ASH Annual Meeting Abstracts):Abstract 5122, 2011.

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

The ASCO Post | NOVEMBER 1, 2013

PAGE 36

Direct from ASCO

International Cancer Corps Provides Valuable First-Time Volunteer Experience

ven as oncologists try to tackle the changing landscape of health care in the United States, many realize that both physicians and patients in this country are still in a better position than those fighting cancer abroad in low- and middle-income countries. In 2009, ASCO joined with Health Volunteers Overseas to create its International Cancer Corps (ICC), designed to provide oncologists with opportunities to volunteer their time and expertise in some of the countries that need it most. The World Health Organization currently estimates that low- and middle-income countries bear the burden of more than half of the estimated 12.7 million new cancer cases and 7.6 million cancers deaths occurring each year.

Through programs like the ICC, ASCO is able to connect more of its members with areas of need, and in so doing help lessen the suffering for people with cancer worldwide. —Sandra M. Swain, MD, FACP

“There is an urgent need to address this growing crisis,” said ASCO Immediate Past President Sandra M. Swain, MD, FACP. “Through programs like the ICC, ASCO is able to connect more of its members with areas of need, and in so doing help lessen the suffering for people with cancer worldwide.” The ICC originally launched three

education and training sites in Tegucigalpa, Honduras; Addis Ababa, Ethiopia; and Hue, Vietnam. Due to the success of the ICC program at these

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

ASCO Teams Up with the GetWell Network to Provide More Patients With Education Resources

hrough a new initiative and partnership with the GetWell Network, ASCO has begun to offer patient education content from its patient information website, Cancer. Net, to patients treated at hospitals within the GetWell Network community. The GetWell Network provides tools to hospitals to help administrators, nurses, and clinicians better manage patients’ needs, education, and overall experience in the hopes of improving patient outcome through patient and family engagement. Through this partnership, select content from Cancer.Net will be available to patients via programming for the GetWell Network in-house TV channel and through GetWell Network’s Internet-based platform, accessible to patients at home on computers and mobile devices. The goal of this initiative is to broaden the audience for and increase access to important Cancer. Net content to help patients better manage their own treatment and care. Ultimately, ASCO hopes

that patients become empowered through education so that they can be more actively involved in their medical decision-making.

Educational Tools for Patients Cancer.Net’s Patient Education Video series (www.cancer.net/ videos), and select fact sheets (www .cancer.net/factsheets) and podcasts (www.cancer.net/podcasts) that focus on various aspects of cancer care and treatment including treatment options, clinical trials, managing side effects, coping, caregiving, and more, will be available to patients as educational tools through this initiative. In addition, a video series made in collaboration with the LIVESTRONG Foundation focused on patients age 15 to 39, entitled Moving Forward: Perspectives from Survivors and Doctors, will also be made available. n © 2013. American Society of Clinical Oncology. All rights reserved.

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

locations, ASCO recently decided to expand its efforts to three new sites in San José, Costa Rica; Asunción, Paraguay; and Thimphu, Bhutan. With assignments at each site ranging from as short as 1 week to as long as 1 month, volunteering with the ICC provides an opportunity that can fit the needs of both first-time volunteers and experienced volunteers looking to share their time and expertise.

Providing Interaction and Education in Costa Rica Volunteers looking to take a continued on page 37

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

What’s Hot in

JOP

JCO.org Reduction in Chemotherapy Order Errors With Computerized Physician Order Entry by Barry R. Meisenberg, et al

Potential Benefits of Treatment Summaries for Survivors’ Health and Information Needs: Results From a LIVESTRONG Survey by Ruth Rechis, et al

Skin Cancer Surveillance and Malignancies of the Skin in a Community-Dwelling Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia by Aaron S. Mansfield, et al

Financial Distress, Use of Cost-Coping Strategies, and Adherence to Prescription Medication Among Patients With Cancer by Leah L. Zullig, et al

Improving Quality of Cancer Care at Community Hospitals: Impact of the National Cancer Institute Community Cancer Centers Program Pilot by Michael T. Halpern, et al

ASCOPost.com | NOVEMBER 1, 2013

PAGE 37

Direct from ASCO

International Cancer Corps continued from page 36

shorter trip, or stay closer to home, might find an ideal location at the ICC site in Costa Rica’s Hospital del Mexico, San Juan de Dios Hospital or the Women’s Hospital in San José. “Because the travel is not too arduous and there is not too great of a language barrier, traveling to Costa Rica is a great way to have a U.S. medical oncologist introduced to volunteerism with Health Volunteers Overseas,” said Costa Rica Program Director John Pippen, MD, of US Oncology.

John Pippen, MD

Highlights on Quality Cancer Care for Patients

Oncologists in Costa Rica are well trained and enthusiastic, but are hungry for interaction with U.S. oncologists, according to Dr. Pippen. Despite their very long and busy days spent in clinics, many local oncologists are still undercompensated for their time and are forced

education of other medical professionals who are part of a multidisciplinary treatment team is also a priority, according to local site Director Luis Corrales-Rodriguez, MD, a medical oncologist at Hospital San Juan de Dios. continued on page 38

INVESTIGATIONAL PHASE 3 TRIALS CURRENTLY ACCRUING

Cabozantinib phase 3 trials in castration-resistant prostate cancer (CRPC) for patients with bone metastases KEY ELIGIBILITY CRITERIA • Diagnosis of CRPC • Presence of bone metastases • Prior treatment with docetaxel • Prior treatment with abiraterone and/or MDV3100 (enzalutamide) • No limit to the number of prior therapies

n advance of the 2013 Quality Care Symposium, ASCO released a second Top Five List in Oncology, as part of the ongoing Choosing Wisely® campaign that brings together the American Board of Internal Medicine (ABIM) Foundation, ASCO, and other medical specialty organizations. Cancer.Net provides detailed background information on each of the items on this list, including an explanation of the recommendations, what they mean for patients, and a list of questions to ask their doctors. These summaries, as well as a podcast on the list are available at www. cancer.net/expertsoncancernews. Patients can also find summaries and a podcast explaining the research highlights from this year’s Quality Care Symposium at www.cancer. net/qualitysymposium. n

to maintain a second job working at private clinics in the evening. “They do not always have the time and resources to do aB:8.25” lot of continuing medical education,” T:7.5”Dr. Pippen said. “The ICC volunteers S:6.75”are hoping to supply that piece that is missing.” In addition, improvement in the

COMET-1

COMET-2

PRIMARY ENDPOINT

Overall Survival

Confirmed Pain Response CRPC (N=246)

CRPC (N=960) • Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies

Cabozantinib 60 mg QD Randomization Prednisone

Randomized, double-blind, controlled trial

• Prior docetaxel treatment • Prior abiraterone and/or MDV3100 treatment • No limit to number of prior therapies • Pain related to bone metastases

Cabozantinib 60 mg QD Randomization

Randomized, double-blind, controlled trial

Mitoxantrone + Prednisone

The ASCO Post | NOVEMBER 1, 2013

PAGE 38

Direct from ASCO

International Cancer Corps continued from page 37

In September, the Costa Rican site will have its first volunteer, a nurse, visiting to contribute to

Luis Corrales-Rodriguez, MD

nurses’ education and spend time at two of the hospitals in the program. Dr. Pippen anticipates a second group of volunteers to visit in January. “I expect us to discuss individual cases with the oncologists there, make rounds and visit with some of the hospital administrators,” Dr. Pippen said. “We also hope to have volunteers take the physicians’ books and journals, audiovisual aids, or cases on their computers to discuss in an effort to supply that interaction needed by local oncologists.” At the Costa Rican sites, Dr. Pippen said that volunteers typically work about an 8-to-5 schedule each day, and then are free to explore the lively city of San Jose.

Making an Immediate Difference in Paraguay For those volunteers interested in participating in ICC but looking to expand their horizons to another continent, the site at the Instituto

Nacional del Cancer near Asuncion, Paraguay, may be a good fit. Paraguay is a small country located in the middle of South America with a population of about 7 million. Cancer is the second leading cause of death there, and the Instituto Nacional del Cancer is the only public hospital with the necessary equipment to treat patients with cancer, according to local site director, José Duarte, MD. “The cancer institute determined that it should initially concentrate the ICC efforts on the treatment of two common cancers that occur in women: breast and cervical can-

Thomas Openshaw, MD

cer,” said Program Director Thomas Openshaw, MD, of Eastern Maine Healthcare Systems. “Patients with these diseases present with advanced disease and there are many obstacles to delivering quality care.” Since the first volunteer visit to Paraguay, Dr. Duarte said that practice change is already apparent. “We adopted a center in the institution managed by a multidisciplinary team—including a surgeon, medical oncologist, radiation oncologist, and nurse—to see all new patients with cervical cancer to assure a centralized processing, to delineate

plans of treatments and to assure proper follow-up,” Dr. Duarte said. Since then, the center has reduced current wait time for commencing treatment from 6 to 8 weeks to only 2 weeks. They have also created a database used for tracking patients and have established specific treatment protocols for cervical cancer. Up next, Drs. Duarte and Openshaw hope to use future volunteers to begin to translate what they have set up for cervical cancer into a comprehensive central breast cancer program.

Building From the Ground Up in Bhutan Finally, for those volunteers really looking to stretch their experience beyond the Western Hemisphere, a visit to the National Referral Hospital in Thimpu, Bhutan, may be just the ticket, providing an opportunity to have a big effect on a country with great need. Bhutan is a small country located in the southern Himalayas with a population of about 700,000 people. Despite the government funded health-care system, the country is lacking in health-care professionals due to its relatively recent adoption of Western medicine. “Currently, there are two oncologist specialists there, a surgical oncologist and a gynecologic oncologist,” said Bhutan Program Director Miklos Simon, MD, of Compass Oncology. “They try to handle all of the oncology care for the whole country together with six oncology nurses.” With the current system, many patients each year are sent to India at the government’s expense to receive

Miklos Simon, MD

cancer care. With the help of the ICC, it is expected that some of this treatment can be transferred back to physicians within Bhutan. Because so many patients in Bhutan will present with advanced cancers, developing a palliative care program is a priority. One of the first volunteers scheduled to visit Bhutan is a psycho-oncologist who will begin to provide communication and education training about some of the psychosocial issues of cancer. “She will dig deeper and work closely with a local psychologist who is interested in developing a palliative care program,” Dr. Simon said. In addition, many of the nurses in Bhutan received their training about a decade ago and are in need of an updated curriculum and refresher courses. Dr. Simon has recruited two volunteer nurses who will go to Bhutan in November and March to help to train nurses and teach oncology courses at the local nursing school. “We see huge potential in the Bhutan site and are grateful to ASCO for helping us to meet some of its needs,” Dr. Simon said. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Submits Comments on Numerous Federal Initiatives

SCO helps shape the regulatory framework in which oncologists practice by reviewing and commenting on a wide range of rules, guidelines, and system changes issued by federal agencies, including the U.S. Food and Drug Administration (FDA), the

Centers for Medicare and Medicaid Services (CMS), and the Office of the National Coordinator for Health Information Technology (ONC). In recent months, the society has submitted comments in the following areas: ■■ FDA’s guidance for the standard-

ization and evaluation of Risk Evaluation and Mitigation Strategies (REMS). ■■ ONC’s and FDA’s development of a risk-based regulatory framework and strategy for health information technology (HIT). ■■ CMS’ proposed changes to its Medicare Physician Fee Schedule (MFPS) and Hospital Outpatient Prospective Payment System (HOPPS) for fiscal year 2014. CMS issued both sets of

proposed changes in mid-July of this year. ■■ FDA’s Draft Guidance for Industry on Expedited Programs for Serious Conditions – Drugs and Biologics. To view the comments and read the latest news on ASCO’s policy and quality efforts, please visit: www. asco.org/advocacy. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 39

Direct from ASCO

Zhe-Bin Liu, MD, PhD, of China Receives 2013 Long-Term International Fellowship in Breast Cancer

he-Bin Liu, MD, PhD, of Shanghai Cancer Center, Fudan University, China, is the recipient of the 2013 Conquer Cancer Foundation of ASCO Long-Term International Fellowship (LIFe) in

Zhe-Bin Liu, MD, PhD

Breast Cancer, generously supported by The Breast Cancer Research Foundation. The LIFe provides early-career oncologists in low- to middle-income countries with the support and resources needed to advance their training by helping them deepen their relationship with a United States or Canadian colleague and his or her institution. Through a 1-year medical fellowship, the recipient earns valuable training and experience with which they can affect change in cancer care in their home country.

MD, Director of the Cancer Center at The Methodist Hospital and Chief of the hospital’s oncology division. Dr. Liu’s research project seeks to identify the key molecules and signaling pathways that drive the resistance of a tumor to chemotherapy in patients with triplenegative breast cancer, which she hopes will serve as appropriate targets for the development of therapies that can overcome chemoresistance. For Dr. Liu, the benefit of LIFe is the potential to make a meaningful impact in the lives of patients with breast cancer in China. “In China, treatments for triple-negative breast cancer are currently limited compared with other subtypes of breast cancer. In particular, the prevalence of locally advanced triple-negative breast cancer has increased significantly,” she noted.

The

Breast Cancer

Research

Foundation

Clifford Hudis, MD, FACP, Chairman of The Breast Cancer Research Foundation’s Scientific Advisory Board, and ASCO President, stated, “This LIFe award to Dr. Liu demonstrates the shared dedication of The Breast Cancer Research Foun-

Research Will Target TripleNegative Breast Cancer Dr. Liu will be training at The Methodist Hospital Research Institute in Houston, Texas, under the mentorship of Jenny C. Chang,

dation, ASCO, and the Conquer Cancer Foundation to the promotion of research worldwide aimed at the prevention, control, and cure of breast cancer. We are delighted that the LIFe award fellowship will allow Dr. Liu to enhance her knowledge and skills so that she can contribute to improved treatment of patients in China.” Visit www.conquercancerfoundation.org/LIFe for updates on the 2014 LIFe application and to make a donation in support of aspiring investigators like Dr. Liu who are working to improve the quality of cancer care. For additional infor mation about The Breast Cancer Research Foundation, please visit www.bcrfcure.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO Develops Educational Article Series on Research Funding

uring this and the coming year, ASCO is ramping up its advocacy efforts in calling for increased federal funding to support clinical cancer trials. As part of an extensive effort to educate and mobilize its membership to call for a renewed national investment in federally funded cancer research, ASCO has developed an educational series of articles that explores the decadelong decline in federal funding for cancer research—and why this de-

cline must be reversed. Cancer treatment is poised to become targeted to each tumor’s molecular profile, but this leap will be out of reach unless we sustain the federally funded research that has brought cancer care to this point. The U.S. clinical cancer infrastructure is under threat as never before. Federal funding for clinical cancer research has remained flat for more than a decade, and when adjusted for inflation, funding has actually de-

creased. National Institutes of Health Director Francis Collins, MD, recently called 2013 the “darkest ever” year for agency funding. ASCO is raising the alarm about continuing erosion of cancer research funding and urging the federal government to take bold new action

to ensure the pace of progress is not stalled. To read this series, and learn more about how to get involved, please visit www.asco.org/advocacy/ nih-funding. n © 2013. American Society of Clinical Oncology. All rights reserved.

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

ASCOPost.com | NOVEMBER 1, 2013

PAGE 43

FDA Update

FDA Grants Volasertib Breakthrough Therapy Designation in AML

oehringer Ingelheim Pharmaceuticals, Inc, has announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to volasertib, an investigational inhibitor of polo-like kinase (Plk), which being evaluated

for the treatment of patients aged 65 or older with previously untreated acute myeloid leukemia who are ineligible for intensive remission induction therapy. Volasertib is designed to inhibit the activity of Plk1, an enzyme in the

Plk family that regulates mitosis. This inhibition is intended to result in prolonged cell cycle arrest, ultimately leading to cell death. “This FDA Breakthrough Therapy designation provides Boehringer Ingelheim the opportunity to engage in

Advertisement not displayed in digital edition at advertiser’s request

an ongoing dialogue with the FDA to help expedite the development of volasertib as a potential treatment option for these patients with [acute myeloid leukemia],” said Sabine Luik, MD, Senior Vice President, Medicine & Regucontinued on page 44

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; NOVEMBER 1, 2013

PAGE 44

FDA Update

Volasertib continued from page 43

latory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc.

Clinical Trials Results from a phase II study in newly diagnosed patients with acute myeloid leukemia considered ineligi-

ble for intensive remission induction therapy demonstrated higher rates of objective response and an improvement in event-free survival in patients receiving volasertib in combination

with low-dose cytarabine compared to patients receiving low-dose cytarabine alone. The results were presented at the 54th American Society of Hematology Annual Meeting in December 2012. These results led to the initiation in January 2013 of a phase III trial, POLO-AML-2, to assess the efficacy

and safety of volasertib in combination with low-dose cytarabine, compared to placebo in combination with low-dose cytarabine, in patients aged 65 or older with previously untreated acute myeloid leukemia who are ineligible for intensive remission induction therapy. The trial is currently enrolling eligible patients. n

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

ASCOPost.com | NOVEMBER 1, 2013

PAGE 45

FDA Update

FDA Announces Class-Wide Safety Labeling Changes for Long-Acting Opioid Analgesics to Combat Abuse

he U.S. Food and Drug Administration (FDA) announced class-wide safety labeling changes and new postmarketing study re-

quirements for all extended-release and long-acting opioid analgesics intended to treat pain. “The FDA is invoking its authority

to require safety labeling changes and postmarket studies to combat the crisis of misuse, abuse, addiction, overdose, and death from these potent drugs that

Advertisement not displayed in digital edition at advertiser’s request

have harmed too many patients and devastated too many families and communities,” said FDA Commissioner continued on page 46

The ASCO Post | NOVEMBER 1, 2013

PAGE 46

FDA Update

Long-Acting Opioids

Updated Indication

continued from page 45

Given the serious risks of using extended-release and long-acting opioids, the class-wide labeling changes, when final, will include important new language to help health-care professionals tailor their prescribing decisions based on a patient’s individual needs. The updated indication states that

Margaret A. Hamburg, MD. “Today’s action demonstrates the FDA’s resolve to reduce the serious risks of long-acting and extended-release opioids while still seeking to preserve appropriate access for those patients who rely on these medications to manage their pain.”

extended-release and long-acting opioids are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The updated indication further clarifies that, because of the risks of addiction, abuse, and misuse, even at

recommended doses, and because of the greater risks of overdose and death, these drugs should be reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient

management of pain. Extended release and long-acting opioid analgesics are not indicated for as-needed pain relief.

Further Studies Required to Assess Risks

Advertisement not displayed in digital edition at advertiser’s request

Recognizing that more information is needed to assess the serious risks associated with long-term use of extended-release and long-acting opioids, the FDA is requiring the drug companies that make these products to conduct further studies and clinical trials. The goals of these postmarket requirements are to further assess the known serious risks of misuse, abuse, hyperalgesia, addiction, overdose, and death. The FDA is also requiring a new boxed warning on extended-release and long-acting opioid analgesics to caution that chronic maternal use of these products during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening and require management according to protocols developed by neonatology experts.

Labeling Changes In addition, the FDA is notifying extended-release and long-acting opioid analgesic application holders of the need for changes to the following sections of drug labeling: Dosage and Administration, Warnings and Precautions, Drug Interactions, Use in Specific Populations, Patient Counseling Information, and the Medication Guide. Once the safety labeling changes are finalized, modifications will also be made to the Extended Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS), which requires companies to make available to health-care professionals educational programs on how to safely prescribe these agents and to provide medication guides and patient counseling documents regarding the safe use, storage, and disposal of opioids. n

ASCOPost.com | NOVEMBER 1, 2013

PAGE 47

Issues in Oncology

Perils of Sequestration continued from page 1

the “darkest ever” year for the agency in an interview with The New York Times.1 While the original reduction to the NIH budget was expected to result in more than 700 fewer research grants, failure by Congress to pass new legislation setting funding levels for fiscal year 2014—which led to a government shutdown on October 1—could mean that the reduction in new grants could balloon to over 1,000 as the NIH absorbs an additional 2% budget cut. According to a Fact Sheet issued by the NIH earlier this year,2 the loss of revenue is delaying progress in medical breakthroughs, including the development of more effective targeted cancer therapies, a universal flu vaccine that could be effective against every strain of influenza without the need for an annual shot, and a delay in the development of better treatments for common and rare diseases.

Unprecedented Funding Reduction A survey of cancer researchers conducted by ASCO in August shows the devastating consequences of multiyear stagnation in federal cancer research funding coupled with sequestration on U.S. cancer research.3 According to the survey results: ■■ More than 75% of respondents said cuts to NIH or NCI funding have impacted their ability to conduct oncology research. ■■ More than 44% have had to look for nonfederal sources of funding to replace sequestered funds. ■■ More than 38% have reduced their time spent on research. ■■ More than 35% have had to lay off or terminate lab or clinical staff. ■■ More than 28% have closed or participated in fewer federally funded clinical trials. ■■ Nearly 27% have postponed the launch of a clinical trial. ■■ More than 23% have had to limit patient enrollment on a clinical trial. “We’ve just never seen this kind of withdrawal of federal support before,” said ASCO President Clifford A. Hudis, MD, FACP, who is Chief of the Breast Cancer Medicine Service and Attending Physician at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College in New York. “Federal funding of the NIH in the post–World War II era was a unique American accomplishment,” he continued. “It supplemented and supported the for-profit business world in the develop-

ment of scientific advances for the greater good. Now, at the individual investigator level, these funding reductions present a real long-term problem, because once scientists, postdoctoral fellows, technicians, and support staff are gone, they may go into another industry, and our shared investment in their training in cancer research is perhaps gone for good.”

Losing U.S. Scientists to Other Countries Scientists may be contemplating not just transitioning their talents to another field, but fleeing the country altogether. In a large survey by the American Society for Biochemistry and Molecular Biology (ASBMB) of over 3,700 scientists from all 50 states,4 nearly one in five respondents said they were considering moving to another country to continue their scientific career. According to the survey report, Unlimited Potential, Vanishing Opportunity, while the United States globally invests more real dollars in research and development than any other country, in terms of percentage of gross domestic product (GDP), the nation is reducing its investment in scientific research. Of the 10 countries investing the most money in scientific research—China, Brazil, South Korea, India, the United Kingdom, France, Japan, Germany, Russia, and the United States—only the U.S. has reduced its investment in scientific research as a percentage of GDP since 2011. “First off, the U.S. is still number one in global science and innovation, but the gap is closing,” said Benjamin Corb, Director of Public Affairs for the ASBMB. “The concern I have is that we still train the overwhelm-

Benjamin Corb

ing majority of scientists throughout the world. Students come to our universities because they are some of the best on the planet. Young scientists get their training through an NIH or National Science Foundation grant, so we are funding them to become the next generation of innovators. For young scientists to take their education and training that we paid for and go to another country and compete against us is disheartening and frightening.”

Loss of Young Investigators Roland L. Dunbrack, Jr, PhD, Professor at the Institute for Cancer Research at Fox Chase Cancer Center in Philadelphia, agrees that the greatest problem facing researchers now is sequestration. A researcher in computational structural biology, Dr. Dunbrack’s current research is focused on the protein structural bioinformatics and protein structure prediction in cancer biology. Last year, Dr. Dunbrack applied for two NIH grants; one,

Roland L. Dunbrack, Jr, PhD

a continuation of an existing grant, was approved, but the other was not. “The NIH cut the number of new grants it funds by about 20% from 2012 to 2013. My grant probably would have been funded if it were not for the sequester. The loss of that funding cuts my lab budget by 50%,” said Dr. Dunbrack. “I’ve had to lay off a couple of postdoctoral fellows who were productive; I would have kept them if I had the funding.” According to Dr. Dunbrack, the budget impasse in Congress and continuing funding uncertainty is taking its greatest toll on young investigators just starting their careers. “I was lucky that my first grant came along when the NIH budget was increasing in 2000. Now I’m 50 and in the middle of my career, and I have had some accomplishments. But if you are just starting out, the climate is tough. I know students at universities here in Philadelphia who are having trouble finding labs to work in because so many are having funding difficulties,” said Dr. Dunbrack. “I have tenure, but if I can’t pay between 40% and 50% of my salary from a grant, I could lose my job. So there will be fewer labs, fewer investigators, and cancer research will decrease significantly.”

Slowdown in Cancer Advances In the current environment, what research is undertaken may be less risky, resulting in fewer advances. “It is hard for scientists who can’t count on a steady revenue stream to build out research programs and make commitments to staff,” said Dr. Hudis. “What that means is that over time there can only be a more and more conservative approach to taking

risk—that is to say, advances will come more slowly.” According to the ASBMB report, since private companies and organizations have neither the funds nor the desire to supplement the funding gaps caused by sequestration, once laboratories shutter their doors and scientists look to other countries for investment, it may be impossible to regain America’s position as a global leader in research and innovation. “In the 1960s and 1970s, we were going to the moon on a regular basis. We couldn’t do that now—not only because we don’t have the technology, but because we don’t have the brainpower. I worry that the same thing will be true in other industries and [scientific endeavors] in the future,” said Mr. Corb.

Taking Action On September 18, 2013, ASCO, the American Association for Cancer Research, and more than 100 other medical research institutions and advocacy organizations joined together in a Rally for Medical Research Hill Day to urge Congress to make medical research a national priority. To keep the momentum going, ASCO has made it possible for members to take continued action through its Alert Congress Today (ACT) Network at asco. org/advocacy/making-difference. By joining the ACT Network, ASCO members can e-mail legislators directly from the website and stay current on important legislation and emerging public policy issues affecting oncology. Updated information about sequestration’s impact on cancer care can also be found on the ASCO in Action Web pages (asco.org/ advocacy/news). n

Disclosure: Drs. Hudis and Dunbrack reported no potential conflicts of interest. Mr. Corb reported no potential conflicts of interest.

References 1. Lowery A: Budget battles keep agencies guessing. NY Times, September 4, 2013. 2. National Institutes of Health: Fact sheet: Impact of sequestration on the National Institutes of Health. June 3, 2013. Available at www.nih.gov/news/health/jun2013/nih03.htm. Accessed October 9, 2013. 3. American Society of Clinical Oncology: Impact survey: Federal funding cuts to cancer research. September 2013. Available at www.asco.org/sites/www.asco.org/files/ results_of_asco_federal_research_funding_ survey.pdf. Accessed October 9, 2013. 4. American Society for Biochemistry and Molecular Biology: Nondefense discretionary science 2013 survey: Unlimited potential, vanishing opportunity. Available at www.asbmb.org/uploadedFiles/Advocacy/Events/ UPVO%20Report%20V2.pdf. Accessed October 9, 2013.

The ASCO Post | NOVEMBER 1, 2013

PAGE 48

Announcements

Penn Medicine Names D. Gary Gilliland, MD, PhD, First Leader of Precision Medicine

r. Gary Gilliland, MD, PhD, has been named the inaugural Vice Dean and Vice President for Precision Medicine, at Penn Medicine, University of Pennsylvania in Philadelphia. Dr. Gilliland is a cancer genetics expert and pioneer in the development of targeted therapies.

contributed to the understanding of the genetic basis of leukemias and other hematologic cancer. He has worked to help apply these findings into the development of new investi-

gational cancer treatments. Dr. Gilliland’s work has earned him numerous honors, S:6.75” including the William Dameshek Prize from the American Society of Hematology,

the Emil J. Freireich Award from the MD Anderson Cancer Center, and the Stanley J. Korsmeyer Award from the American Society for Clinical Investigation. n

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

Gary Gilliland, MD, PhD

“We are proud to be among the first institutions in the country to create a position to oversee the tremendous opportunities and challenges that face us as our physicians and scientists work to hone the promise of the burgeoning and exciting field of precision medicine,” said J. Larry Jameson, MD, PhD, Executive Vice President of the University of Pennsylvania for the Health System and Dean of the Perelman School of Medicine. “Dr. Gilliland’s experience as a leader in both academic medicine and the pharmaceutical industry will help Penn Medicine forge a roadmap for the most effective and efficient ways to conduct research and deliver care in this new field.”

Prior Experience Dr. Gilliland joins Penn Medicine from Merck, where he was Senior Vice President of Merck Research Laboratories and Oncology Franchise Head. Prior to joining Merck, Dr. Gilliland was a long-time member of the faculty at Harvard Medical School, where he served as Professor of Medicine and a Professor of Stem Cell and Regenerative Biology. He was also an Investigator of the Howard Hughes Medical Institute, Director of the Leukemia Program at the Dana-Farber/Harvard Cancer Center, and Director of the Cancer Stem Cell Program of the Harvard Stem Cell Institute. As an investigator studying hematologic malignancies, Dr. Gilliland made seminal discoveries that have

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. 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: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 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. 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. 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. 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 (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). 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: 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.

B:17

T:1

Announcements

Surgeon David Chang, MD, Joins University of Chicago Medicine avid W. Chang, MD, FACS, an authority on the surgical treatment of lymphedema, was recently appointed Professor of Plastic Surgery at the University of Chicago Medicine.

Dr. Chang has played a key role in introducing the procedure known as lymphaticovenular bypass, a novel treatment forS:6.75” lymphedema, to U.S. operating rooms. He was previously Professor of Plastic Surgery, Deputy

David W. Chang, MD, FACS

Chair of the Department, and Director of the Plastic Surgery Clinic and the Center for Microsurgery Research and Education at The University of Texas M.D. Anderson Cancer Center in Houston. n

PROD

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

median

months

11.2

ED AE/AS AD

4.0

COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, 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 ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: 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, 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. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

B:11.25”

S:9.75”

Please see brief summary of full Prescribing Information on next page.

COMETRIQ.com

DATE

SIGNOFF

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

Disk release

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 (≥ 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. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, 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 (<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.

T:10.25”

*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

PharmaGraphics

15”

PAGE 49

S&H

7.5”

ASCOPost.com | NOVEMBER 1, 2013

The ASCO Post | NOVEMBER 1, 2013

PAGE 50

Announcements

The American Society of Hematology Elects New Leadership

he American Society of Hematology (ASH) recently announced the election of three new members to its Executive Committee for terms beginning after the ASH Annual Meeting in December. Charles S. Abrams, MD,

will serve a 1-year term as Vice President, followed by successive terms as President-Elect and President. Michelle Le Beau, PhD, and Martin Tallman, MD, will both serve 4-year terms as Councillor.

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; 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

Great Discoveries in the Midst of Challenges “This is an exciting yet challenging time for the field,” said 2013 ASH President Janis L. Abkowitz, MD, of the University of Washington. “While

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 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% in 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%) of 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 medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity 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

we are poised to make great discoveries, we are also faced with the continual threat of decreased federal research funding and significant changes in the health-care system that allows us to deliver care to our patients. Navigat-

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

ASCOPost.com | NOVEMBER 1, 2013

PAGE 51

Announcements

of Philadelphia Blood Center for Patient Care & Discovery and Associate Chief of Hematology/Oncology at the University of Pennsylvania. His major fields of interest include phosphoinositide sig-

ing these opportunities and challenges requires strong, visionary leaders like Drs. Abrams, Le Beau, and Tallman.”

New Members to ASH Executive Committee Charles S. Abrams, MD, is Director of the University of Pennsylvania School of Medicine and Children’s Hospital

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 All Grade Grades 3-4 Grades 3-4 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 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. 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 1

Charles S. Abrams, MD

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg 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 1

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 singledose 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 singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, 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

Michelle Le Beau, PhD

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. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

Martin Tallman, MD

Janis L. Abkowitz, MD

naling in hematopoietic cells, platelet adhesion and thrombosis, and murine models of hemostasis. Outside of the laboratory, Dr. Abrams is interested in mentoring young hematologists and developing continuing medical education programs in clinical hematology. Dr. Abrams previously served a 4-year term as ASH Secretary from 2009 to 2012. Michelle Le Beau, PhD, is Director of University of Chicago Comprehensive Cancer Center and the University of Chicago Cancer Cytogenetics Laboratory and the Arthur and Marian Edelstein Professor of Hematology/Oncology at the University of Chicago. Her major research interests include cancer cytogenetics and genetics, genetic pathways that lead to myelodysplastic syndromes, acute myeloid leukemia, and therapyrelated myeloid neoplasms. Martin S. Tallman, MD, is Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College in New York. He also served as Chair of the Leukemia Committee of the Eastern Cooperative Oncology Group for 16 years. Dr. Tallman’s fields of interest include clinical investigation in acute myeloid and acute lymphocytic leukemia, acute promyelocytic leukemia, and hairy cell leukemia. n

The ASCO Post Follow us on

@ASCOPost

The ASCO Post | NOVEMBER 1, 2013

PAGE 52

Spotlight on ASCO’s 2014 Presidential Election

President-Elect Candidates Address ASCO’s Challenges and Opportunities in the Coming Decades By Jo Cavallo

n September, ASCO announced the names of 14 ASCO members who have been selected by the ASCO Nominating Committee as candidates for open leadership positions within the Society for the 2014 ASCO Election. The two candidates nominated for President-Elect are Lynn M. Schuchter, MD, FASCO, and Julie M. Vose, MD, MBA, FASCO. Biographic information and interviews with each candidate, as well as instructions for casting a proxy ballot, were made available on October 29. Proxy voting will close on November 26. Election results will be announced in mid-December. All information about the election will be announced on asco.org/election. The new President-Elect will assume office at the 2014 ASCO Annual Meeting in June. The ASCO Post talked with Dr. Schuchter and Dr. Vose about the challenges and opportunities the Society faces in the coming decade and beyond. Lynn M. Schuchter, MD, FASCO

Julie M. Vose, MD, MBA, FASCO

Lynn M. Schuchter, MD, FASCO C. Willard Robinson Professor of Hematology/Oncology, Division Chief of Hematology/Oncology, and Melanoma Program Leader, Abramson Cancer Center, University of Pennsylvania, Philadelphia

Cost of Care and Federal Funding How can ASCO address the high cost of cancer care and diminishing federal resources for basic and translational research? In answer to the first part of this question, the rising cost of cancer care has certainly become a focus of national conversation given the enormous increase in the cost of health care, which is making cancer care less affordable for many patients and their families. ASCO has been actively engaged in addressing this issue through several initiatives. One is ASCO’s Quality Oncology Practice Initiative (QOPI®). I believe that high-quality cancer care will actually result in reducing the cost of oncology care. Initiatives that address the value of cancer care and how to integrate quality improvement into patientcentered clinical practice will have an

impact on reducing high costs. ASCO has also proposed a number of new payment models that promote quality and value and discourage unnecessary testing and overtreatment at the end of life, and these strategies will be important in reining in the cost of care. In addition, ASCO actively participated with the American Board of Internal Medicine (ABIM) Foundation in its Choosing Wisely initiative and identified a Top Five list of common, costly procedures and practices in oncology that are not supported by evidence-based medicine and could reduce widely used and costly procedures and treatments. In the coming years, it will be critical for ASCO members and cancer care providers to embrace and implement the project’s recommendations. Physicians and patients recognize that spiraling costs of cancer is unsustainable, and our collec-

tive efforts are required to change the way we deliver cancer care. For the second part of that question, we are in a very challenging environment with diminishing federal resources for basic and translational research. Resource constraint on multiple dimensions is our collective reality. We are challenged to do more and better with less. One example of trying to do better in clinical research emerged from ASCO’s Cancer Research Committee this year in a project chaired by Lee M. Ellis, MD [Director of the Colorectal Cancer Translational Research Program and Professor of Surgery at The University of Texas MD Anderson Cancer Center]. “Defining Clinically Meaningful Outcomes: ASCO Recommendations to Raise the Bar for Clinical Trials” was an innovative project aimed at raising the bar on how we design our clinical

trials and define clinically meaningful endpoints in clinical trials. This kind of project will likely lead to the development of more strategic and efficient clinical trials in the future. More effective research collaborations with industry and engaging the philanthropic community will also be necessary to continue to fund what is now likely to be the most promising era for cancer research. However, the federal government has and will continue to play a major and vital role in support of basic and translational research. In addition to promoting the obvious and urgent need to restore funding to the National Institutes of Health, ASCO can deliver another important message by continuing to educate Congress that funding for science and technology is important because it drives economic growth. continued on page 53

ASCOPost.com | NOVEMBER 1, 2013

PAGE 53

Spotlight on ASCO’s 2014 Presidential Election Lynn M. Schuchter, MD, FASCO continued from page 52

This is not a simple question to answer, but I would say a couple of efforts are going to be key. One is ensuring that cancer care providers communicate with primary care physicians about the overall treatment summary and follow-up plan for their patients with cancer. ASCO has been a leader in defining what should be included in a survivorship care plan. The Commission on Cancer’s manual for cancer programs, Cancer Program

Biggest Opportunity

Biggest Challenge

What is the biggest opportunity for ASCO to help its members improve cancer outcomes? I would look at that question from two perspectives. One is addressing and defining the issue of quality. What are the metrics to define quality, and how do we measure and improve quality? ASCO is committed to providing this leadership in defining high-quality patient-centered cancer care.

What is ASCO’s biggest challenge, and how do you propose it be addressed? There are many competing agendas, but I would say that what we are all facing—both individually and as a field—are significant resource constraints. We are looking at enormous costs of cancer care, diminishing financial support for basic and clinical research, and limited support for training, so we all need to learn to do more and better with less. ASCO’s current initiatives and those outlined in its “Shaping the Future of Oncology: Envisioning Cancer Care in 2030” document, as well as ASCO’s proposed symposiums and curriculums, all address these big challenges.

We are looking at enormous costs of cancer care, diminishing financial support for basic and clinical research, and limited support for training, so we all need to learn to do more and better with less. ASCO’s current initiatives and those outlined in its [2030 Vision Statement], as well as ASCO’s proposed symposiums and curriculums, all address these big challenges. —Lynn M. Schuchter, MD, FASCO

Standards 2012: Ensuring Patient-Centered Care, has mandated that by 2015, treatment summaries be provided to all patients at the end of their treatment. Providing treatment summaries to primary care physicians will be a valuable tool for the continuing care of cancer survivors, and having this model of a “shared-care” approach that ASCO has put forward is also very important. The other key component is to facilitate team-based care and further expand how we collaborate with nurse practitioners and other physician extenders in the care of patients with cancer. Better utilization of oncology nurse practitioners and physician assistants will be key to providing quality cancer survivorship care.

The second area concerns how we realize precision medicine. There have been remarkable advances in the identification of new molecular targets for new treatments. Developing the technology with which to incorporate advances in genomics into treatment plans and into the medical record to allow for informed treatment decision-making is a great opportunity, but also a great challenge. To that end, ASCO’s CancerLinQ™ initiative is incredibly visionary and bold. Once completed, it will be able to link disparate electronic health records with “Big Data,” and that will lead to better decision-making, better treatment, and improved outcomes for patients.

Focused Initiative ASCO Presidents often have focused initiatives during their term in office. Do you have a particular initiative you would propose putting forward as ASCO President? One important topic to me is the incorporation of palliative care into the continuum of care for patients with cancer. There are still barriers to the integration of palliative care into oncology care. This area would be a major area of focus for me. The second topic is related to my research in melanoma. There is a rising epidemic of melanoma, particularly in young women, and despite remarkable advances in therapy for melanoma we still are seeing increases in mortality. I would like to consider advancing both policy initiatives and education regarding the risks of UV exposure and tanning salons associated with this burgeoning epidemic of melanoma. n

Julie M. Vose, MD, MBA, FASCO Neumann M. And Mildred E. Harris Professor and Chief, Division of Hematology/Oncology, and Professor of Medicine, University of Nebraska Medical Center in Omaha

Cost of Care and Federal Funding How can ASCO address the high cost of cancer care and diminishing federal resources for basic and translational research? We need to work with the Centers for Medicare & Medicaid Services, private insurers, and health-care systems to encourage evidence-based quality care. ASCO’s Quality Oncology Practice Initiative (QOPI®) assists oncology practices in measuring and improving their quality standards against a nation-

al benchmark. With this information, modification of the system for the appropriate reimbursement of cognitive services and supportive care as well as for procedures, treatment, and quality improvement can be accomplished. Information from clinical trials and large data sets from rapid learning systems, such as CancerLinQ™, will inform this quality care so we can provide state-ofthe-art care using evidence-based guidelines and decrease duplication of services throughout the health-care system.

As far as diminishing federal resources for basic and translational research is concerned, it really is an everincreasing problem, and ASCO needs to support maintenance of the current programs by working with the National Cancer Institute (NCI) to use research dollars in high-priority oncology research that is most promising for breakthroughs. In addition, innovative support systems to enhance collaboration with advocacy groups and private donors should be encouraged. We can

look at alternative resources, such as ASCO’s Conquer Cancer Foundation, private groups, and other foundations, to allow additional funding for research while decreasing the duplication of effort and infrastructure. There also needs to be further streamlining of the NCI’s Clinical Trials Cooperative Group–run clinical trials system. The use of a simplified structure would decrease cost and increase efficiency of the Cooperative continued on page 57

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS. Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimens). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

May 2012

ASCOPost.com | NOVEMBER 1, 2013

PAGE 57

Spotlight on ASCO’s 2014 Presidential Election Julie M. Vose, MD, MBA, FASCO continued from page 53

Group trials while focusing on the trials with the most impact potential for patients. Examples of how we could do that would be allowing the use of centralized Institutional Review Board services at cancer care locations, using standardized templates for protocols that are less complicated, and having a simplified and unified contracting system to work with the different universities and cancer centers.

Cancer Research Workforce In ASCO’s Impact Survey: Federal Funding Cuts to Cancer Research, over 38% of respondents said they have reduced the proportion of time they spend on research, 35% said they had to lay off or terminate lab or clinical staff who support their research, and others said they were leaving the field of research entirely. What can ASCO do to prevent cancer researchers from leaving the field and encourage young college graduates thinking about a career in science to consider oncology? There are many different opportunities to consider for optimizing interest in cancer research. As far as the direct support of young investigators, the Conquer Cancer Foundation grant process is an excellent example of private funds being utilized to support innovative research. We also need to expand mentorship support through the Foundation for these young individuals because they need to be in an environment where there is a team-based approach to research, education, and translational cancer care. ASCO and the Conquer Cancer Foundation should also continue to encourage and support research by pharmaceutical companies, medical diagnostic companies, and medical device companies through innovative collaborations. One example of such collaboration is the Leukemia & Lymphoma Society’s Therapy Acceleration Program in which the society partners with different companies to speed drug development. As far as younger college or medical students interested in oncology is concerned, we should support internship and summer programs with oncologists and cancer centers to help students learn early in their careers about the fields of cancer care and oncology research. These programs could be supported by the Conquer Cancer Foundation through its donation program as well as by the institutions and practices.

Cancer Survivorship What can ASCO do to educate primary care physicians and their patients living with cancer about long-term cancer survivorship? And how can ASCO collaborate with primary care physicians and help them address the medical needs of survivors in their practice as part of the oncology team-based care model? Thankfully, more and more patients are surviving cancer for extended periods of time. ASCO’s Oncology Workforce Study demonstrated that oncologists alone are not going to be able to manage both the initial and aftercare of all patients diagnosed with a malignancy. We need to team with primary care physicians, midlevel providers, and other support staff to supply the care that these patients will need. There are several ways we need to approach oncology team-based care.

This process needs to be a two-way street. ASCO will need to collaborate with other professional organizations like the Association of Physician Assistants in Oncology and the Oncology Nursing Society, as well as with primary care organizations such as the American College of Physicians. Also, we need to have representatives from the other health-care professional organizations involved with ASCO so we can determine the best way to have an integrated delivery system of care for patients and survivors.

Biggest Opportunity What is the biggest opportunity for ASCO to help its members improve cancer outcomes? One of ASCO’s initiatives I’m most excited about—and the one that has the potential for the most improvement

“ASCO’s biggest challenge is to assist the oncology health-care team in providing quality cancer care and in keeping up with new information coming out daily, and to do it in a cost-effective environment that meets the needs of the patient. I think the way to overcome that challenge is to continue to develop and update oncologyspecific guidelines that can be used as the basis for quality-care management.” —Julie M. Vose, MD, MBA, FASCO

One would be by building multidisciplinary teams of oncologists, primary care physicians, midlevel providers (including nurse practitioners and physician assistants), and other support staff (such as dieticians, physical therapists, social workers, psychologists, and psychiatrists) to take care of all patient needs during therapy and beyond. There are also provisions in the Patient Protection and Affordable Care Act for the establishment of the Patient-Centered Medical Home. We already have such patient-centered care in oncology to some extent, but formalizing that care into an oncology medical home at institutions and practices would be very beneficial. We need to educate primary care physicians about the team-based approach to care to make sure that they understand not only the diagnosis and treatment of cancer, but the follow-up care for patients and long-term survivorship care as well. We also need to do a better job of educating patients about treatment options and toxicities.

in quality care—is CancerLinQ™. It brings real-world data on the treatment of thousands of patients through different practices across the country to our desktop. ASCO’s research blueprint [Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research, November 2011] laid out a roadmap for the clinical research system to capitalize on new discoveries in cancer biology. This information can be accelerated through the aggregation of data on thousands of patients in the CancerLinQ system. Eventually the analysis of this large dataset will allow the oncology community to modify patients’ treatment to have a much higher chance of success. It will also decrease costs, as therapies predicted to be less successful for an individual patient’s characteristics are avoided.

Biggest Challenge What is ASCO’s biggest challenge and how do you propose it be addressed? ASCO’s biggest challenge is to as-

sist the oncology health-care team in providing quality cancer care and in keeping up with new information coming out daily, and to do it in a cost-effective environment that meets the needs of the patient. I think the way to overcome that challenge is to continue to develop and update oncology-specific guidelines that can be used as the basis for quality-care management, such as through the QOPI system. As evidence-based guidelines are developed and modified, cost-effective information can be added as it is obtained through clinical trials, registries, and the CancerLinQ system. Armed with this information, we can improve the affordability of cancer care by leveraging existing efforts to reform payment and eliminate duplication and waste in oncology care. As part of the quality initiatives, we need to ensure that all oncology professionals have core competencies and work in a collaborative way to enhance comprehensive oncology patient-centered care.

Focused Initiative ASCO Presidents often have focused initiatives during their term in office. Do you have a particular initiative you would propose putting forward as ASCO President? My initiative would be promoting the art of oncology and quality cancer care. This concept includes a number of different aspects. We want to promote personalized quality care with respect to finding the right treatment for the patient by making sure we are looking at patient-specific prognostic information as well as information about the genetic makeup of the tumor. By understanding the important pathways in the tumor, oncology teams will be better able to make wise treatment decisions with an increased probability of success for the patient. Another aspect would be the promotion of quality multidisciplinary care using patient-centered oncology medical homes to make sure we are addressing all the short- and long-term issues of care for patients from diagnosis to survivorship. Personalized care also means individualizing and optimizing education, personal, and financial needs, as well as providing comfort and respect for the patient and family. The art of oncology encompasses how to successfully put all of these aspects of oncology care together to benefit an individual patient and support the family through a stressful time. n

The ASCO Post | NOVEMBER 1, 2013

PAGE 58

Future of Oncology Hematology and Oncology Products

A Look Ahead: How the FDA Is Adapting in the Era of Precision Medicine A Conversation With Richard Pazdur, MD By Jo Cavallo ing the design of clinical trials, his role at the FDA, and his advice to young oncologists considering a career in public service.

New Designation

Richard Pazdur, MD

ubbed “Cancer Czar” by the media, Richard Pazdur, MD, Director of the U.S. Food and Drug Administration (FDA) Office of Hematology and Oncology Products, said he has the “best job in oncology, with a unique vantage point in cancer drug development.” An oncologist for more than 30 years—including 14 years at the FDA—Dr. Pazdur’s commitment to the agency comes at an unprecedented time in the development of more effective oncology drugs and faster drug approvals. As of August 2013, 7 of the 15 new drugs approved by the FDA this year are used to treat or diagnose cancer. Under Dr. Pazdur’s leadership, the FDA has used different regulatory mechanisms, including Priority Review, Accelerated Approval, and Fast Track designations, to speed the development and approval of promising new oncology drugs. A provision in the FDA Safety and Innovation Act of 2012, the new Breakthrough Therapy designation for treatments for serious or life-threatening diseases is designed to improve communication and collaboration between the FDA and the pharmaceutical industry to quicken drug development and the review of marketing applications. ASCO recognized Dr. Pazdur for his dedication to improving the lives of patients with cancer through the approval of safer, more effective medicines with its 2013 Public Service Award, which was presented at ASCO’s Annual Meeting in June. In a wide-ranging interview, The ASCO Post talked with Dr. Pazdur about the Breakthrough Therapy drug designation, how the development of molecularly targeted therapies is alter-

Please explain the new process for expediting the development of oncology drugs given Breakthrough Therapy status? The Breakthrough Therapy designation is given to drugs that are intended to treat a serious or life-threatening condition when preliminary clinical evidence indicates that the drug might demonstrate a substantial improvement over existing therapies on a clinically significant endpoint. Breakthrough Therapy status provides for enhanced communication between the drug sponsor and the

Evolution of Study Designs

Alternative Endpoint

Looking ahead over the next 5 to 10 years, do you see the design of clinical trials changing so as to test targeted drug regimens in small subsets of patients? Yes, the designs of trials are changing, reflecting the greater efficacy of many oncology drugs that are currently being developed. With a transition from conventional chemotherapy to more targeted therapies, we are evaluating drugs that provide greater efficacy with a more favorable toxicity profile. These newer agents may target diseases in specific populations and assist in redefining oncologic diseases and indications based on our enhanced molecular understanding. In an era of more personalized or precision medicine, early identification of patients

Will overall survival continue to be required to approve drugs? Although overall survival has been traditionally considered the “gold standard” for drug approval, we have recognized that it may be increasingly difficult to demonstrate an improvement in overall survival. Hence, the FDA has increasingly accepted progression-free survival as a regulatory endpoint. This might be the case in situations where the natural history of the disease is relatively long, making overall survival impractical to measure, or in situations where multiple therapies are administered after disease progression, possibly confounding the overall survival interpretation.

We at the FDA strongly believe in early access to promising drugs for patients who need them. Various regulatory mechanisms exist that enable patient access to unapproved drugs outside of a clinical trial, including single-patient investigational new drug (IND) applications as well as intermediate-size and largepopulation treatment expanded access programs. —Richard Pazdur, MD

FDA throughout the drug development process rather than at conventional milestone meetings, such as pre-IND or end-of-phase II meetings. Drug development becomes an iterative process, with an “all hands on deck” commitment at the FDA. This involves our senior leadership and members of the review team including clinical, biostatistics, clinical pharmacology, pharmacology-toxicology, and chemistry staff and their counterparts in industry. We are communicating with the sponsor and providing advice on trial designs and discussing potential issues—both clinical and nonclinical— that if addressed earlier in the drug development timeline may expedite the drug’s approval. Approximately half of the Breakthrough Therapies that have been designated by the agency have been in oncology, reflecting the activity of drug development in our discipline.

with specific biomarkers or companion diagnostics will be required. We probably will see smaller randomized clinical trials since the treatment effect of a targeted agent will probably be larger than that observed with conventional chemotherapy agents. To demonstrate a statistically significant therapeutic effect that is relatively small, a larger number of patients is usually required. Generally, to see a larger therapeutic effect, a smaller number of patients is required. We also need to develop and implement adaptive clinical trial designs that take into consideration information that is being developed during the conduct of the trial. The goal is to provide the most efficient trial to demonstrate an improvement in efficacy while limiting the number of patients who may be exposed to a less effective drug.

Role of Randomized Trials Will the ability to identify and validate biomarkers, enabling the matching of investigational drugs with patients who will most benefit and/or be least likely to experience adverse effects, render the traditional randomized clinical trial model obsolete? There will always be a role for randomized trials to evaluate both drug safety and efficacy. Randomized trials provide important comparative safety information. Single-arm trials do not provide this information. Time-toevent endpoints, such as progressionfree survival and overall survival, need to be evaluated in randomized trials. However, there may be clinical situations where conducting a randomized trial may be impractical—for example, if a large unmet medical need exists, and a drug has demonstrated an unprecedented response rate of long duration in a single-arm trial. Randomized trials should only be performed in the setting of clinical equipoise of the treatment arms. If equipoise does not exist, then one should question whether this specific randomized study can or should be conducted.

Evaluating Biosimilars Please discuss the best solution for evaluating and approving biosimilar proteins. Drug companies need to approach the development of biosimilars differently than “stand-alone” product development. The goal is to demonstrate

ASCOPost.com | NOVEMBER 1, 2013

PAGE 59

Future of Oncology biosimilarity between the proposed product and a reference product—not to independently establish safety and effectiveness of the proposed product. Understanding the relationship between protein attributes and the clinical efficacy and safety profile aids in the ability to determine residual uncertainty and to predict “clinical similarity” from the quality data. The FDA has stated it intends to use a risk-based, totality-of-the-evidence approach to evaluate all available data and information submitted to determine the biosimilarity of a proposed product. Advances in analytic sciences and manufacturing technology have enabled some therapeutic protein products to be extensively characterized with respect to their physicochemical and biologic properties. This may provide an appropriate basis for a more targeted approach to subsequent animal and/or clinical studies for a demonstration of biosimilarity.

Impact of Sequestration How is sequestration affecting the FDA, and does it have the potential for slowing drug approval? I really can’t comment on the effect sequestration may have on drug approval. However, the FDA has been under travel restrictions that have pre-

vented many of our reviewers from attending important meetings, including ASCO’s Annual Meeting. For our reviewers to give advice on the development of new drugs, they must have continuing education and communication with our stakeholders, including oncologists in academic and private practice settings, professional societies, commercial sponsors, and patients.

Rewards and Challenges What is the most rewarding and challenging aspect of your job? The most rewarding part is mentoring our young staff. One of my greatest pleasures is to see their enthusiasm, especially that of our review staff who have joined FDA shortly after completing their fellowships. Early in my career, I was the Medical Oncology Fellowship Director at Wayne State University in the 1980s and at MD Anderson Cancer Center in the 1990s. I have always had an interest in medical education, and one of the true highlights of my career has been seeing “my fellows” become leaders in academic oncology centers. In terms of challenges, I’ve been at the FDA long enough to realize that we’re not going to make everybody happy with our decisions. For every

decision, there is going to be a group who believe we made the wrong decision and a group who applaud the decision. Frequently, I hear investigators and others outside of the FDA mischaracterize our positions without having access to FDA documents or discussions. Many times, these comments may result from the FDA’s inability to comment on unapproved drugs because of government confidentiality requirements regarding information disclosure. Within FDA, we spend considerable time reviewing an application and discussing the strengths and weaknesses of each application. I fully understand that there is no such thing as a “perfect” clinical trial. At the end of the day, I tell the staff that we must ultimately ask ourselves the question, “Will the American public be better served with the drug on the market?”

FDA and NCI What is the FDA’s relationship with the National Cancer Institute (NCI)? We have a very good relationship with the NCI—better than any other government agency. Our mutual goals are aligned. We have monthly meetings where we review common drug development issues. We collaborate with the NCI in developing programs

and workshops. Many of our staff have worked at the NCI and have completed their training at the National Institutes of Health (NIH)/NCI Clinical Center. Many FDA staff members also have a professional development day at the Clinical Center to improve and continue development of their clinical expertise.

Expanded Access Is there anything you would like to communicate to readers of The ASCO Post regarding the FDA’s goals for the future of cancer care? We are on the same page as the treating oncologist. We all want safe and effective drugs to treat patients with cancer. There is always a diversity of opinion, and every opinion is heard, but at the end of the day, a decision has to be made. This is a great time to be a medical oncologist. There may be day-to-day frustrations, but we are experiencing unprecedented growth in our understanding of cancer, and this is being rapidly translated into new drugs. Having had a more-than-30-year perspective as a medical oncologist, I firmly believe this is the most exciting time in that 3-decade experience. I envy those who are just beginning their careers continued on page 64

2013 New Drug/Indication Approvals* 1. September 30, 2013: Pertuzumab (Perjeta) Accelerated approval in combination with trastuzumab and docetaxel for the neoadjuvant treatment of HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. 2. September 6, 2013: Paclitaxel protein-bound particles (albuminbound) (Abraxane) in combination with gemcitabine for the first-line treatment of metastatic pancreatic adenocarcinoma. 3. July 12, 2013: Afatinib (Gilotrif tablets) for the first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Therascreen EGFR RGQ PCR Kit (Qiagen) was approved concurrently for detection of EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. 4. June 13, 2013: Denosumab

(Xgeva injection) for the treatment of giant cell tumor of bone. June 5, 2013: Lenalidomide capsules (Revlimid) for the treatment of mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (Velcade). 5. May 29, 2013: Trametinib (Mekinist tablet) for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation. 6. May 29, 2013: Dabrafenib (Tafinlar capsule) for the treatment unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. 7. May 15, 2013: Radium Ra 223 dichloride (Xofigo injection) for the treatment of castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. 8. May 14, 2013: Erlotinib (Tarceva) for the first-line treatment of metastatic non-small cell lung cancer patients

whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. This indication for erlotinib was approved concurrently with the Cobas EGFR Mutation Test, a companion diagnostic test for patient selection. 9. February 22, 2013: Ado-trastuzumab emtansine (Kadcyla for injection) for use as a single agent for the treatment of HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. 10. February 8, 2013: Accelerated approval to pomalidomide (Pomalyst capsules) for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide (Revlimid) and bortezomib (Velcade), and have demonstrated disease progression on or within 60 days of completion of the last therapy. 11. February 4, 2013: Doxorubicin hydrochloride liposome injection, a generic version of Doxil Injection

(doxorubicin hydrochloride liposome) for the treatment of ovarian cancer in patients whose disease has progressed or recurred after platinum-based chemotherapy and for AIDS-related Kaposi’s sarcoma after failure of prior systemic chemotherapy or intolerance to such therapy. 12. January 23, 2013: Bevacizumab (Avastin) for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy for the treatment of metastatic colorectal cancer that has progressed on a first-line bevacizumabcontaining regimen. 13. January 23, 2013: Bevacizumab (Avastin) for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy for the treatment of metastatic colorectal cancer that has progressed on a first-line bevacizumab-containing regimen. n *Approvals as of October 21, 2013.

NOW INDICATED

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

ignite survival in first-line mPAC Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to

patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may

substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dosedependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

Significant and clinically meaningful survival in first-line mPAC ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

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

0.2

P<0.0001b

0.1 0.0 0

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

Patients at risk

A+G: 431 G: 430

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. a

metastasis (yes vs no).

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

B:14.25”

T:14”

S:13”

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%),

headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages. For more information, please visit www.abraxane.com. ABRAXANE® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 09/13 US-ABR130068a

Geriatric • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary for metastatic adenocarcinoma of the pancreas; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level

ABRAXANE (mg/m2)

Gemcitabine (mg/m2)

Full dose

125

1000

1st dose reduction

100

800

2nd dose reduction

600

Discontinue

If additional dose reduction required

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day Day 1 Day 8

ANC Platelet count ABRAXANE / Gemcitabine (cells/mm3) (cells/mm3) < 1500 OR < 100,000 Delay doses until recovery 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at No dose reduction next lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at next Grade 3 mucositis lower dose level or diarrhea

4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions ( 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/Gemcitabined Gemcitabine Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE (125 mg/m2) and gemcitabine (N=421) System Organ Class General disorders and administration site conditions

Gemcitabine (N=402)

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral edema

194 (46%)

13 (3%)

122 (30%)

12 (3%)

Pyrexia

171 (41%)

12 (3%)

114 (28%)

4 (1%)

Asthenia

79 (19%)

29 (7%)

54 (13%)

17 (4%)

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

Diarrhea

184 (44%)

26 (6%)

95 (24%)

6 (1%)

Vomiting

151 (36%)

25 (6%)

113 (28%)

15 (4%)

Skin and subcutaneous tissue disorders

Alopecia

212 (50%)

6 (1%)

21 (5%)

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%)

Nervous system disorders

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

3 (1%)

Dysgeusia

68 (16%)

33 (8%)

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%) 6 (1%)

Gastrointestinal disorders

Metabolism and nutrition disorders

52 (12%)

18 (4%)

28 (7%)

Cough

72 (17%)

30 (7%)

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

1 (<1%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

Depression

51 (12%)

1 (<1%)

24 (6%)

T:14”

B:14.25”

S:13”

Hypokalemia Respiratory, thoracic and mediastinal disorders

Psychiatric disorders a

Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal. Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema

Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

The ASCO Post | NOVEMBER 1, 2013

PAGE 64

Future of Oncology FDA in Era of Precision Medicine continued from page 59

because they may truly witness quantum leaps in cancer therapeutics. One issue I would like to address concerns expanded access (access to investigational drugs outside of a clinical trial), because I believe there

may be questions and misconceptions about this program. Several times we have heard erroneously that the FDA has refused to give an investigational agent to a patient or allow an expanded access trial when, in reality, the pharmaceutical sponsor B:7.5”did not permit the release of the drug. T:7” We at the FDA strongly believe in S:6.5”

early access to promising drugs for patients who need them. Various regulatory mechanisms exist that enable patient access to unapproved drugs outside of a clinical trial, including single-patient investigational new drug (IND) applications as well as intermediate-size and large-population treatment expanded access programs.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: See www.celgene.com. ABR_PANC_HCP_BSv006 9_2013

We have worked with ASCO on education programs to provide information about expanded access. The FDA does not have the authority to compel a pharmaceutical company to give a drug to an individual patient or to have a large expanded access program. We have asked ASCO to develop a policy at the Annual Meeting asking pharmaceutical companies to declare their intentions—positive or negative—regarding expanded access programs when promising results of unapproved drugs are presented. This, along with the company’s rationale for its decision, would provide clarity for patients and physicians and provide transparency on the process.

Closing Thoughts What advice would you give to young oncologists who may be considering a government career? Public service is an extremely rewarding career. When I left MD Anderson Cancer Center in 1999, I thought I would be at the FDA for a few years at most. Well, obviously, I was wrong. I have really enjoyed myself and, most importantly, I have enjoyed working with great staff on interesting issues that have fashioned the field of oncology over the past 14

T:10”

B:10.5”

S:9.5”

At the FDA, we have a public health mission, and as a medical oncologist you can have an impact on the lives of potentially millions of patients... I would encourage young oncologists to come down and see us if they have an interest in public service. —Richard Pazdur, MD

years. Virtually every problem in oncology drug development crosses my desk. At the FDA, we have a public health mission, and as a medical oncologist you can have an impact on the lives of potentially millions of patients in the United States and worldwide. I would encourage young oncologists to come down and see us if they have an interest in public service. n Disclosure: Dr. Pazdur reported no potential conflicts of interest.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 65

Expert’s Corner Thoracic Oncology

‘Master Protocol’ Could Revolutionalize Trials in Lung Cancer, and Eventually Other Cancers By Caroline Helwick

ancer advocates and clinical trialists, for some time, have been proposing a radical change to the laborious drug development process—that industry, academia, funding sources, and other stakeholders actually pool their brain power and financial means and work together, not separately, to develop effective drugs for the evergrowing number of molecular targets. That is about to happen in the lung cancer community.

Ambitious Collaboration The ambitious “Master Protocol” is a collaboration among the lung cancer research community, the National Cancer Institute, the Foundation of the National Institutes of Health, the Food and Drug Administration (FDA), Friends of Cancer Research, and industry. It will be a test of a unique and modern pivotal trial design that could dramatically accelerate the targeted therapy revolution. At this time, it is limited to refractory squamous cell carcinoma of the lung, but if successful, the project could become a model for streamlined trials in other tumors. Slated to launch early next year, the Master Protocol is expected to hasten, refine, and enhance clinical trial enrollment, reduce the cost of drug development, and ultimately—by determining

the best therapeutic fit for patients— improve treatment outcomes. It could be anticipated that, in a race to bring competing drugs to market, pharmaceutical companies would fear loss of autonomy and balk at sharing a database. But the early indication is that industry sees the value in collaborating, and several industry giants have

“The Master Protocol is a public/ private partnership that pulls together a protocol where patients are genotypically selected, then sorted into one of multiple arms of a clinical trial,” he said. “As a practicing oncologist, I can tell you that if you have a patient with a mutation that occurs in 5% or perhaps less of the lung cancer population, it’s

By grouping multiple studies, we can reduce the overall screen failure rate, and multitarget screening by broad-based platforms will provide a sufficient ‘hit rate,’ which allows for uninterrupted accrual. —Roy S. Herbst, MD, PhD

seats on the Oversight Committee. Roy S. Herbst, MD, PhD, who chairs the Master Protocol’s Steering Committee, described the project in an interview with The ASCO Post. Dr. Herbst is the Ensign Professor of Medicine, Chief of Medical Oncology, Director of the Thoracic Oncology Research Program, and Associate Director of Translational Research at Yale Cancer Center.

very hard to get that patient on a clinical trial, and these patients are often very sick and don’t have much time. We want to accelerate that process, and the Master Protocol is expected to do that.”

Precedent and Rationale In the era of biomarker-driven trials, there has been a need for innovative trial design to account for

interpatient tumor heterogeneity and genomic complexity. Squamous cell carcinoma is a perfect test drive, as it constitutes about one-quarter of all lung cancer diagnoses but has few good treatment options beyond surgery. The trial organizers have identified almost two dozen compounds in the pipeline, targeting 16 different molecular abnormalities. The schema evolved from two phase II adaptive screening trials: BATTLE-1 and -2 (Biomarker-Inte grated Approaches of Targeted Therapy for Lung Cancer Elimination), fourarm trials in patients with refractory non–small cell lung cancer using markers to guide adaptive randomization; and I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis), a neoadjuvant trial in breast cancer testing multiple novel drugs and biomarkers over a 5-year time frame. However, the Master Protocol differs from both of these in that patients are assigned to a study arm on the basis of their molecular profile, and it is a phase III investigation. The major difference between the new project and these is that the explicit goal of the Master Protocol is drug registration—not simply identifying promising targets and drugs. “The trial would be designed with the ultimate goal of FDA approval for those drugs that meet prespecified criteria,” according to Friends of Cancer Research. The protocol will also supply registrational data for the next-generation sequencing process, which will be provided by an outside vendor. Next-generation sequencing approval, therefore, could also be an offshoot of the trial.

Who Will Participate?

Fig. 1: Master Protocol: Squamous cell lung cancer, second-line therapy (proposed trial design). CLIA = Clinical Laboratory Improvement Amendments, CT = chemotherapy (docetaxel or gemcitabine), E = erlotinib, NGS = next-generation sequencing, OS = overall survival, PFS = progression-free survival, TT = targeted therapy. Courtesy of Roy S. Herbst MD, PhD (Yale Cancer Center) and Vassiliki A. Papadimitrakopoulou, MD (The University of Texas MD Anderson Cancer Center).

Participants in the project will include the entire North American Lung Intergroup, with some 500 sites in the United States and Canada, which will screen up to 1,000 patients per year. Patients with previously treated advanced squamous cell carcinoma will be randomized into each treatment arm on the basis of their molecular profile as determined by nextgeneration sequencing and immunohistochemistry (Fig. 1). The primary endpoint will be progression-free survival continued on page 66

The ASCO Post | NOVEMBER 1, 2013

PAGE 66

Expert’s Corner

Lung Cancer Trials continued from page 65

in the phase II component and overall survival in phase III. The trial will be led through SWOG working closely with Vassiliki Papadimitrakopoulou, MD, as the Principal Investigator and David Gandara, MD, the Lung Committee Chair. All candidate drugs will have shown biologic activity against a measurable target (Table 1). Combinations of agents can be used, as appropriate. The goal is to develop each molecule with a companion diagnostic. Having multiple arms in the Master Protocol will improve operational efficiency by providing homogeneous patient populations and consistency in eligibility, a trial infrastructure that will facilitate faster initiation of new trials, and a phase II/III design that allows rapid drug and biomarker testing for the detection of “large effects,” Dr. Herbst said.

“By grouping multiple studies, we can reduce the overall screen failure rate, and multitarget screening by broadbased platforms will provide a sufficient ‘hit rate,’ which allows for uninterrupted accrual,” he said. “With four to six arms open simultaneously, we anticipate a hit rate of about 70% in matching a patient with a drug/biomarker arm.” Dr. Herbst emphasized the modular nature of this protocol, where an arm could be dropped or a new one added based on evolving results. According to Friends of Cancer Research, the study “represents a new opportunity for patients in a setting where few clinical trials may be available or accessible, especially for those patients with very rare mutations.” The nonprofit advocacy group predicts it will be seen as a significant landmark in personalized medicine. n Disclosure: Dr. Herbst reported no potential conflicts of interest.

Master Protocol in Lung Cancer ■■ The Master Protocol is a cooperative effort by academia, the government

Table 1. Master Protocol: Potential targets and drugs Target

Drug

Biomarker

HDM2

Anti-HDM2

HDM2 amplif

RANKL

Denosumab

RANK/RANKL expr

Notch

LY2835219

Notch1 mut

EGFR

CO1686

L858R, Del(19), T790M

1-3%

RAS

MEKi+panPI3K

RAS

CKN2A

LY2835219 (CDK4/6)

CDKN2A mut, deletion, methylation CCND1 amplif

HER3

HER3mAb

HER3 expression

mTOR1/TORC2

MLN0128

STK11,TSC1, TSC2 mut

Raf

MLN2480

TBD

IGFR

LDK378

IGFR expression

60%

PI3K

BKM120 (PI3Ka) MLN1117 (AKT)GSK2110183

PI3K expr/ amplif, PIK3CA mut PTEN loss AKT , PIK3CA fus.

25%. 16% 15%

FGFR

LY2874455 JNJ42756493 FGF TrapGSK3052230

FRGFR expr FGFR1, 2 amplif, FGFR 1, 2 mut

15%. 10%

p53

MK-1775 (+gem)

TP53 mut

81%

MET

AMG337 LY2801653 JNJ38877605 Foretinib (GSK1363089) AMG102

MET expression

50%

HGF

AMG102

HGF expression

PD-1

MEDI4736 (PD-L1)

PDL-1 expression

(NCI and FDA), lung cancer advocacy groups, and industry to evaluate emerging targeted compounds. The parent group for the study is SWOG, but all the North American cooperative groups will be involved.

■■ Tumors of advanced squamous cell carcinoma patients, supplied through

the North American Lung Intergroup, will be genotyped, and patients will be matched to relevant treatments in a randomized, controlled trial.

■■ The ultimate goal is accelerated drug approval.

Prevalence

15%, 30% 21% 13% 2%, 3%, 3%

50%

Courtesy of Roy S. Herbst, MD, PhD.

Don’t Miss These Important Reports in This Issue of The ASCO Post C. Kent Osborne, MD, Peter Ravdin, MD, PhD, and Carlos Arteaga, MD, on the 2013 San Antonio Breast Cancer Symposium see page 11

Stuart M. Lichtman, MD, FACP, on The AVEX Trial see page 23

Lynn M. Schuchter, MD, FASCO, and Julie M. Vose, MD, MBA, FASCO, ASCO President-Elect Candidates see pages 52, 53, and 57

Visit The ASCO Post online at ASCOPost.com

Martine Piccart, MD, PhD, on ESMO 2013 see page 16

Kenneth C. Anderson, MD, on Multiple Myeloma see page 28

Roy S. Herbst, MD, PhD, on Lung Cancer’s Master Protocol see page 65

At Amgen, biologic medicines are rooted in

quality

and nurtured by

reliability.

Robust quality control and a reliable supply are every bit as important as scientific innovation. For more than 30 years, Amgen has poured commitment, passion, and a drive for perfection into every medicine we make. So you can turn to Amgen for the biologic medicines that matter so much to your patients’ treatment…for generations to come. To learn more about Amgen’s commitment to consistent quality and reliable supply, visit biotechnologybyamgen.com ©2013 Amgen Inc. All rights reserved. 73979-R1-V1

The ASCO Post | NOVEMBER 1, 2013

PAGE 68

Health-Care Reform Issues in Oncology

AACR Cancer Progress Report 2013 Highlights Critical Importance of Biomedical Research By Ronald Piana

n September 17, the American Association for Cancer Research (AACR) presented highlights of its 2013 Cancer Progress Report1 at the National Press Club in Washington, DC. AACR Chief Executive Officer Margaret Foti, PhD, MD (hc), opened the program with a double-edged message, first citing the breakthroughs in science and medicine that have produced increasingly better cancer outcomes, then warning that continued scientific progress was in peril due to serious cutbacks in government funding.

1971, 1 in 69 Americans was a cancer survivor. Today, 1 in 23 Americans is a cancer survivor. “We can look toward the future with great optimism,” said Dr. Sawyers. “One promising statistic is that there are now 39 U.S. Food and Drug Administration [FDA]-approved therapies that target specific molecules in cancer; only 17

Charles L. Sawyers, MD

current fiscal course is simply unacceptable,” said Dr. Foti. Next, AACR President Charles L. Sawyers, MD, expounded on the clinical virtues of new, more-targeted therapies and the move toward what he called “precision medicine.” He quantified the advances by noting that in

Compelling Stories The report showcases the compelling stories of nine individuals who have battled, or are still battling, cancer. The program was interspersed with talks by several of these cancer survivors,

Since 2003, the budgets for the NIH and NCI have been steadily shrinking. Sequestration has recently forced the NIH to absorb a direct budget cut of $1.6 billion. This current fiscal course is simply unacceptable.

Funding Crisis “Since 2003, the budgets for the National Institutes of Health [NIH] and National Cancer Institute [NCI] have been steadily shrinking. Sequestration has recently forced the NIH to absorb a direct budget cut of $1.6 billion. This

the $1.6 billion in funding that the NIH lost in March 2013.

—Margaret Foti, PhD, MD (hc)

such therapies were available 5 years ago, and a mere 5 were on the market 10 years ago. This drug pipeline success demonstrates the return on investment from scientific research. Unfortunately, we are in a funding crisis that needs to be turned around if we are to continue making progress in cancer treatment and prevention.” Echoing Drs. Foti and Sawyers’ concerns over budget cuts that directly impact scientific research in cancer, the AACR delivered a “call to action,” urging Congress to designate the NIH and NCI as national priorities by providing annual budget increases at least comparable to the biomedical inflation rate, and to protect the NIH and NCI from another year of the damaging budget cuts from sequestration, and reinstate

Recap of Medical Research Budget Cuts ■■ As a result of the Budget Control Act of 2011 and Congress’ failure to come to an agreement on long-term deficit reduction, across-the-board cuts known as sequestration went into effect March 1, 2013. The cut to the NIH was 5.1 %, or $1.6 billion, and the cut to the NCI, the largest NIH institute, was $293 million.

■■ Following the cut and the completion of fiscal year 2013 appropriations

bills, the budget for the NIH stands at approximately $29 billion, the lowest funding level in terms of actual dollars in more than 5 years.

and others were featured in a video at the start of the event (www.youtube. com/watch?v=MGYjFaCEOfl). One survivor featured in the video, Carol Weinbrom, who was diagnosed with metastatic breast cancer in 2001, amplified the AACR’s passionate call to arms about the need for increased research funding. “I am currently receiving an investigational drug through a phase Ib clinical trial. It is one of very few options left to me. The reality is that I am at the end of approved treatments. I rely on investigational drugs and the researchers who are identifying new ones. To ensure that drugs are constantly entering the pipeline, researchers need a dependable source of funding,” said Ms. Weinbrom. Dr. Sawyers concluded his presentation with an informative update on advances made in targeted therapies. Then he introduced Drew Pardoll, MD, PhD, Director, Cancer Immunology Program, Johns Hopkins University School of Medicine, Baltimore, who gave a comprehensive overview of the rapidly emerging field of cancer immunotherapy, a special feature of this year’s report. “After years of research in this field,

we began to learn that tumors resisted being eliminated by the patient’s immune system by co-opting inhibitory pathways, thus putting the brakes on the immune response,” said Dr. Pardoll, adding, “In fact, the tumors could highly upregulate molecules that would stop a T cell, for example, in its tracks and protect the cancer.”

Adoptive Immunotherapy Dr. Pardoll highlighted exciting work in adoptive immunotherapy, which harnesses the power of the immune system’s T-cells. There are currently no FDA-approved adoptive immunotherapies, but Dr. Pardoll pointed out that a number of leukemia patients on clinical trials using adoptive immunotherapy have been in complete remission after other treatments have failed or led to relapse. “As basic research continues to increase our understanding of how T cells function and how these functions can be exploited, new adoptive immunotherapies are likely to emerge in the near future,” said Dr. Pardoll. Dr. Pardoll captured the essence of the special feature on immunotherapy from the report with his concluding statement: I have such confidence in the potential of immunotherapy that I think by 2015 it will be looked at historically as the time that immunotherapy became the fifth pillar of cancer treatment. There are barriers to this becoming a reality, but they are not scientific. They are regulatory and financial. To use a military analogy, we have the weapons but not the funds to test or manufacture them quickly enough. n Disclosure: Dr. Sawyers is on the Board of Directors of Novartis. Dr. Foti reported no potential conflict of interest.

Reference 1. American Association for Cancer Research: AACR Cancer Progress Report 2013. Clin Cancer Res 19(suppl 1):S1S88, 2013.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 69

Journal Spotlight Survivorship

Modifiable Risk Factors Potentiate Therapy-Associated Risk for Major Cardiac Events in Adult Survivors of Childhood Cancer By Matthew Stenger

Photo credit: St. Jude Children’s Research Hospital

n a study reported in the Journal of Clinical Oncology, Gregory T. Armstrong, MD, of St. Jude Children’s Research Hospital in Memphis, and colleagues assessed the frequency of major cardiac events and cardiovascular risk factors among adult survivors of childhood cancer and their siblings.1 They found that

1.5% for valvular disease, and 1.3% for arrhythmia. The cumulative incidence of cardiac events was significantly associated with exposure to cardiotoxic therapies (P < .001). Among siblings, the cumulative incidence of grade 3 to 5 events by 45 years of age was 0.9% for coronary artery disease, 0.3% for heart failure,

These findings reinforce the need for careful screening of adult survivors for early detection of cardiovascular risk factors.

survivors were at greater risk of cardiac events and had more risk factors, with the findings suggesting an opportunity to reduce cardiovascular risk by addressing modifiable risk factors, and hypertension in particular, in these patients.

Study Details The study included 10,724 5-year survivors of childhood cancer and 3,159 siblings in the Childhood Cancer Survivor Study. Participants were assessed for prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity and the incidence and severity of major cardiac events, including coronary artery disease, heart failure, valvular disease, and arrhythmia. Median age at last follow-up was 33.7 years (range, 11.0–58.9 years) at a median of 25.6 years (range, 7.4–39.3 years) from cancer diagnosis in survivors and 36.0 years (range, 7.1–62.6 years) in siblings. Fifty-two percent of survivors and 48% of siblings were male, and 88% of both groups were white. The most common childhood cancer diagnoses were acute lymphoblastic leukemia (30%), Hodgkin lymphoma (13%), and Wilms tumors (10%). Among survivors, 26% had received chest-directed radiotherapy and 39% had received anthracycline chemotherapy.

Risk for Survivors vs Siblings Among survivors, the cumulative incidence of grade 3 to 5 cardiac events by 45 years of age was 5.3% for coronary artery disease, 4.8% for heart failure,

—Gregory T. Armstrong, MD, and colleagues

0.1% for valvular disease, and 0.4% for arrhythmia. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings; 3.7% vs 2.4% had diabetes, 14.9% vs 9.6% had hypertension, 8.9% vs 6.0% had dyslipidemia, and 21.7% vs 23.1% had obesity. The prevalence of cardiovascular risk factors increased with age among survivors and was significantly greater than that for siblings at age 50 years for hypertension (40.2% vs 25.5%, P < .001) and dyslipidemia (23.0% vs 13.6%, P = .008), whereas the prevalence of obesity was greater among siblings (25.2% vs 31.3%, P = .02).

Comparisons Among Survivors Among survivors exposed to chestdirected radiotherapy, the risk for each type of cardiac event increased with increasing number of cardiovascular risk factors (P < .001 for trend) as did risk for heart failure among those exposed to

anthracycline (P < .001 for trend). The presence of hypertension alone significantly increased risk for coronary artery disease (relative risk [RR] = 6.1), heart failure (RR = 19.4), valvular disease (RR = 13.6), and arrhythmia (RR = 6.0) in patients exposed to chest-directed radiotherapy and risk for heart failure (RR = 12.4) in those exposed to anthracycline therapy (all P < .001). Other significant associations for individual risk factors were dyslipidemia and obesity alone for coronary artery disease, diabetes alone for heart failure, dyslipidemia alone for valvular disease, and diabetes alone for arrhythmia in patients exposed to chest-directed radiotherapy and diabetes alone for heart failure in those exposed to anthracycline therapy. Combinations of risk factors that included hypertension were associated with the highest risk estimates for association with coronary artery disease (hypertension plus diabetes RR = 23.5), heart failure (hypertension plus diabetes RR = 35.3), and valvular disease (hypertension plus obesity RR = 20.6; all P < .001) after exposure to chest-directed radiotherapy.

Analysis of Relative Excess Risk An analysis of relative excess risk due to interaction (RERI) was performed to determine whether the interaction effects of radiotherapy or anthracycline treatment with cardiovascular risk factors were more than additive when present together. Survivors treated with chestdirected radiotherapy who developed two or more cardiovascular risk factors, including hypertension had significantly increased RERI for coronary artery disease (RERI = 27.9, 95% confidence interval [CI] = 14.6–51.0), heart failure (RERI = 18.3, 95% CI = 7.6–37.4),

Late Effects of Cancer Treatment ■■ By age 45, cancer survivors had higher rates of coronary artery disease,

heart failure, valvular disease, and arrhythmia and were more likely to have multiple cardiovascular risk factors.

■■ The presence of hypertension alone significantly increased risk for major cardiac events in patients treated with chest-directed radiotherapy or anthracycline therapy, and hypertension was independently associated with risk of cardiac death.

■■ The authors note that modifiable cardiovascular risk factors, particularly

hypertension, potentiate therapy-associated risk for major cardiac events and should be the focus of future interventional studies.

valvular disease (RERI = 60.9, 95% CI = 18.0–487.0), and arrhythmia (RERI = 8.6, 1.7– 21.7) and those treated with anthracycline had significantly increased RERI for heart failure (RERI = 11.9, 95% CI = 0.3–29.6), with these findings suggesting potentiation of risk for major cardiac events. When survivors had multiple risk factors that did not include hypertension, significantly increased relative excess risks due to interaction were not observed for any of the major cardiac events among patients receiving chest-directed radiotherapy or for heart failure among those receiving anthracycline therapy. In multivariate models, development of hypertension alone (RR = 5.6, 95% CI = 3.2–9.7) or two or more cardiovascular risk factors (RR = 2.4, 95% CI = 1.2–4.9) was significantly associated with cardiac-specific mortality, whereas there was no significant association with diabetes alone (RR = 2.2, 95% CI = 0.8– 6.1), dyslipidemia alone (RR = 1.7, 95% CI = 0.7–3.8), or obesity alone (RR = 1.2, 95% CI = 0.6–2.3). The investigators concluded: “In summary, survivors who received chestdirected radiotherapy or anthracycline chemotherapy are at high risk for serious cardiac events, and when these therapeutic exposures are combined with cardiovascular risk factors, in particular hypertension, risk is significantly increased…. Of note, in individuals treated with chest-directed radiotherapy and who have hypertension, the risk is increased above that expected in a simple additive risk model. These findings reinforce the need for careful screening of adult survivors for early detection of cardiovascular risk factors.” n

Disclosure: The study was supported by the National Cancer Institute, a Cancer Center Support (CORE) Grant to St. Jude Children’s Research Hospital, and the American Lebanese Syrian Associated Charities. The study authors reported no potential conflicts of interest.

Reference 1. Armstrong GT, Oeffinger KC, Chen Y, et al: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol. September 3, 2013 (early release online). See commentary on page 70

The ASCO Post | NOVEMBER 1, 2013

PAGE 70

Journal Spotlight Commentary continued from page 69

Cardiovascular Risk Factors in Cancer Survivors By Smita Bhatia, MD, MPH

rmstrong et al evaluated the prevalence of self-reported hypertension, diabetes mellitus, dyslipidemia, and obesity and the incidence of selfreported major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmias in adult survivors of childhood cancer in the Childhood Cancer Survivor Study.1 They concluded that survivors who received chest radiation or anthracycline chemotherapy are at high risk for serious cardiac events, and when these therapeutic exposures are combined with cardiovascular risk factors, in particular hypertension, risk is significantly increased. In individuals with hypertension and a history of chest radiation, the risk is increased above that expected in a simple additive risk model. These findings are of considerable clinical importance and are almost identical to those observed among patients treated with cardiotoxic therapy during adulthood, as described below, demonstrating that aggressive management of cardiovascular risk factors among recipients of cardiotoxic therapy could help reduce the morbidity associated with cardiac disease among cancer survivors.

Adult Study A study in adults, led by Armenian,2 estimated the magnitude of risk of cardiovascular risk factors after autologous and allogeneic hematopoietic cell transplantation and explored the impact of the cardiovascular risk factors on the subsequent development of Dr. Bhatia is Professor and Chair, Department of Population Sciences, Ruth Ziegler Chair in Population Research, and Associate Director, Population Sciences, Program CoLeader, Cancer Control and Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, California.

cardiovascular disease among hematopoietic cell transplantation survivors. The methodology differed from the Childhood Cancer Survivor Study: For example, cardiovascular risk factors and cardiovascular outcomes were clinically validated using American Heart Association criteria; the cardio-

vors developed dyslipidemia, compared with a prevalence of 40% in the general population. The prevalence of diabetes was 15% vs 10% in the childhood cancer study and 17.3% vs 8.5% in the transplantation survivor study. The conclusion from these comparisons is that cardiovascular risk fac-

Hypertension, diabetes, and dyslipidemia are prevalent in cancer survivors and are critical modifiers of anthracycline-related myocardial injury and radiation-related coronary artery disease, creating targeted populations for aggressive intervention. —Smita Bhatia, MD, MPH

vascular risk factors preceded the diagnosis of the cardiac disease; and the National Health and Nutrition Examination Survey (NHANES) was used for population-based comparison. Median age in the transplantation cohort was 50 years at study participation, with 63% non-Hispanic whites, whereas the Childhood Cancer Survivor Study cohort had a median age of 37 years old, with 88% non-Hispanic whites. The prevalence of hypertension among older childhood cancer survivors was 40.2%, compared with 25% among age-matched siblings. In the transplantation population restricted to the 2005 to 2008 era, hypertension was diagnosed in 37% of the survivors and 35% of the general population. Twenty-three percent of the childhood cancer survivors reported dyslipidemia, compared with 14% of the siblings. Moreover, 46% of the hematopoietic cell transplantation survi-

tors are prevalent among both childhood cancer survivors and survivors of adult-onset cancer and that the prevalence of certain cardiovascular risk factors (dyslipidemia) is higher among the transplantation survivors when compared to childhood cancer survivors at comparable ages.

Key Findings The Childhood Cancer Survivor Study demonstrates that the risk for cardiac events increases with increasing number of cardiovascular risk factors among patients exposed to cardiotoxic therapy (chest radiation and anthracyclines).1 Among hematopoietic cell transplantation survivors, the 10-year incidence of cardiovascular disease increased by the number of cardiovascular risk factors: 4.7% with no cardiovascular risk factors, 7.0% with one cardiovascular risk factor, and 11.2% with at least two cardiovascular risk factors (P < .01); the

risk was especially high (15.0%) in patients with multiple cardiovascular risk factors and pre–hematopoietic cell transplantation exposure to anthracyclines or chest radiation.2 Finally, the Childhood Cancer Survivor Study demonstrated an interaction between cardiovascular risk factors (especially hypertension) and cardiac disease. Again, these findings are similar to those observed among adult autologous hematopoietic cell transplantation recipients,3 in whom the presence of hypertension among recipients of high-dose anthracycline therapy (≥ 250 mg/m2) resulted in a 35-fold increased risk of heart failure. Furthermore, the risk was nearly 27fold higher among high-dose anthracycline recipients with diabetes. These findings demonstrate conclusively that hypertension, diabetes, and dyslipidemia are prevalent in cancer survivors across the entire age spectrum and are critical modifiers of anthracycline-related myocardial injury and radiation-related coronary artery disease, creating targeted populations for aggressive intervention. n Disclosure: Dr. Bhatia reported no potential conflicts of interest.

References 1. Armstrong GT, Oeffinger KC, Chen Y, et al: Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol. September 3, 2013 (early release online). 2. Armenian SH, Sun CL, Vase T, et al: Cardiovascular risk factors in hematopoietic cell transplantation (HCT) survivors: Role in development of subsequent cardiovascular disease. Blood 120:45054512, 2012. 3. Armenian SH, Sun CL, Shannon T, et al: Incidence and predictors of congestive heart failure following autologous hematopoietic cell transplantation. Blood 118:6023-6029, 2011.

Visit The ASCO Post website at

ASCOPost.com

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

The ASCO Post | NOVEMBER 1, 2013

PAGE 76

JCO Spotlight Head and Neck Cancer

Cabozantinib Improves Disease-Free Survival in Progressive Medullary Thyroid Cancer By Matthew Stenger

abozantinib (Cometriq) is an inhibitor of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2 (VEGFR2), and rearranged during transfection (RET) tyrosine kinases. In a phase III trial reported in Journal of Clinical Oncology, Rossella Elisei, MD, of University of Pisa, Italy, and colleagues found that cabozantinib significantly prolonged progressionfree survival compared with placebo in patients with progressive medullary thyroid cancer.1 This trial provided the basis for U.S. Food and Drug Administration approval of cabozantinib in progressive metastatic medullary thyroid cancer.

Study Details In the trial, 330 patients with documented radiographic progression of metastatic medullary thyroid cancer were randomly assigned 2:1 to oral cabozantinib at 140 mg/d (n = 219) or placebo (n = 111). There was no limit on prior therapy, including exposure to other tyrosine kinase inhibitors. The primary endpoint was progression-free survival. The cabozantinib group and placebo group were generally well matched for age (median, 55 years in both), sex (69% and 63% male), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 56% and 51%), RET mutation status (positive in 46% and 52%, M918Tpositive in 34% and 39%), disease type (sporadic in 87% and 85%), prior anticancer therapy (39% and 43%), prior systemic therapy for medullary thyroid cancer (37% and 42%), ≥ 2 prior systemic therapies (24% and 28%), prior thyroidectomy (92% and 94%), prior tyrosine kinase inhibitor treatment (20% and 22%), number of organs/anatomic locations involved (≥ 2 in 87% of both), and main sites of metastatic disease (eg, lymph nodes in 80% and 78%, liver in 70% and 60%). Cross-over of patients in the placebo group to cabozantinib was not allowed.

Prolonged Progression-Free Survival At the database cutoff date, 45% of patients in the cabozantinib group and 14% of patients in the placebo arm were receiving study treatment. After a median follow-up of 13.9 months, median progression-free survival was 11.2 months in the cabozantinib group vs 4.0 months in the placebo group (hazard ratio [HR] = 0.28, P < .001). Kaplan-Meier estimates of the proportions of patients alive and progression-free at 1 year were 47.3%

Cabozantinib for Medullary Thyroid Cancer ■■ Cabozantinib significantly improved progression-free survival in patients with progressive medullary thyroid cancer, including those with prior tyrosine kinase inhibitor treatment.

■■ No difference in overall survival was observed between cabozantinib and placebo at interim analysis.

■■ Cabozantinib was associated with significant but manageable toxicities. tween the cabozantinib and placebo groups (HR = 0.98, 95% confidence interval = 0.63–1.52). At the interim analysis, 30% of patients in the cabo-

Cabozantinib achieved a statistically significant improvement of [progression-free survival] in patients with progressive metastatic [medullary thyroid cancer] and represents an important new treatment option for patients with this rare disease. —Rossella Elisei, MD, and colleagues

for the cabozantinib group and 7.2% for the placebo group. Progression-free survival was significantly prolonged with cabozantinib in subgroup analyses by age, sex, ECOG performance status, number of prior anticancer regimens, prior tyrosine kinase inhibitor treatment, RET mutation status (positive, unknown, hereditary, sporadic), M918T mutation status (positive, negative), and presence of bone metastases at baseline. The only subgroups for which the hazard ratio was not significant were the RET mutation–negative and M918T mutation status unknown subgroups. The response rate was 28% in the cabozantinib group and 0% in the placebo group, with responses observed irrespective of RET mutation status. An interim analysis of overall survival, performed when 44% of events required for final analysis had occurred, showed no difference be-

zantinib group and 28% in the placebo group had died, with 77% and 80% of deaths being attributed to disease progression.

Toxicities Grade 3 or 4 adverse events occurred in 69% of cabozantinib patients and 33% of placebo patients, with the most frequent in cabozantinib patients being diarrhea (16%), palmar-plantar erythrodysesthesia (13%), and fatigue (9%). Adverse events associated with VEGF pathway inhibition were more common in cabozantinib patients, including grade 3 or 4 hypertension (8.4% vs 0.9%), venous thrombosis (3.7% vs 1.8%), hemorrhage (3.3% vs 0.9%), and gastrointestinal perforation (3.3% vs 0%). Laboratory abnormalities more common in cabozantinib patients included increased AST, increased ALT, increased alkaline phosphatase, hypocalcemia, hypophosphatemia,

hyperbilirubinemia, hypomagnesemia, hypokalemia, hyponatremia, lymphopenia, neutropenia, and thrombocytopenia. No drug-induced severe liver injury was observed. Thyroid-stimulating hormone levels above normal were observed in 57% of cabozantinib patients and 19% of placebo patients. Adverse events led to dose reduction in 79% of cabozantinib patients and 9% of placebo patients, dose interruption in 65% and 17%, and treatment discontinuation in 16% and 8%. Grade 5 adverse events occurred within 30 days of the last dose of study treatment in 7.9% and 7.3% of patients. Serious adverse events occurred in 42% and 23%; those occurring with a frequency ≥ 2% greater in the cabozantinib group consisted of mucosal inflammation (2.8% vs 0%), hypocalcemia (2.8% vs 0%), pulmonary embolism (2.3% vs 0%), and hypertension (2.3% vs 0%). The investigators concluded, “Cabozantinib (140 mg per day) achieved a statistically significant improvement of [progression-free survival] in patients with progressive metastatic [medullary thyroid cancer] and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.” n

Disclosure: The study was supported by Exelixis. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Elisei R, Schlumberger MJ, Müller SP, et al: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. September 3, 2013 (early release online). See commentary on page 77

ASCOPost.com | NOVEMBER 1, 2013

PAGE 77

JCO Spotlight Commentary continued from page 76

Cabozantinib in Medullary Thyroid Cancer: A Landscape-Shaping New Treatment By Mingzhao Xing, MD, PhD

edullary thyroid cancer is derived from parafollicular C cells in the thyroid gland. The disease is sporadic in about 75% of cases and hereditary in the remaining 25%.1 Oncogenic mutations in the gene for tyrosine kinase receptor rearranged during transfection (RET) are driver genetic alterations of medullary thyroid cancer that are seen in 60% to 70% of sporadic cases and almost 100% of hereditary cases. Compared with follicular cell–derived thyroid cancer, medullary thyroid cancer is very rare, accounting for only a few percent of all thyroid malignancies. Nevertheless, medullary thyroid cancer is generally more aggressive than follicular cell–derived thyroid cancer (excluding anaplastic thyroid cancer) and is responsible for a large proportion of thyroid cancer-related mortality. Progressive metastatic medullary thyroid cancer is particularly challenging once the disease becomes surgically inoperable and is the main cause of medullary thyroid cancer–related morbidity and mortality. There have been limited therapeutic options for effective treatment of the disease at this stage. That said, recent developments in the therapeutic use of smallmolecule tyrosine kinase inhibitors have brought unprecedented promise for effective treatment of medullary thyroid cancer. Vandetanib (Caprelsa) was the first tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced medullary thyroid cancer, bringing medical treatment of medullary thyroid cancer into a modern era of molecular targeted therapy.2,3 The recent development of cabozantinib (Cometriq), another tyrosine kinase inhibitor, in the treatment of medullary thyroid cancer has added an exciting Dr. Xing is Professor of Medicine and Oncology, Co-Director of the Johns Hopkins Thyroid Tumor Center, and Chief of the Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore.

new dimension to the current treatment landscape of medullary thyroid cancer by providing a new effective therapeutic option for this cancer.4,5

Cabozantinib Trials Cabozantinib is a triple tyrosine kinase inhibitor known to target three major tyrosine kinases—RET,

the hepatocyte growth factor receptor (MET), and vascular endothelial growth factor receptor 2 continued on page 78

The ASCO Post | NOVEMBER 1, 2013

PAGE 78

JCO Spotlight

Thyroid Cancer continued from page 77

( VEGFR2)—which provides a molecular basis for the strong suppression of metastasis, angiogenesis, and tumor growth observed in preclinical studies.6 Even in the phase I clinical

trial, cabozantinib produced remarkable clinical responses in patients with medullary thyroid cancer.4 The subsequent phase III clinical trial confirmed the therapeutic effects of cabozantinib (140 mg/d orally) in progressive metastatic medullary

thyroid cancer, which prompted an expedited review and approval of this drug by the FDA for the treatment of patients with advanced medullary thyroid cancer.7 The full report of this phase III clinical trial has now been published by Elisei and colleagues.5

This double-blind trial compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic medullary thyroid cancer recruited from 23 countries. The remarkable findings include an estimated median progression-free survival of 11.2 months for cabozantinib vs 4.0 months for placebo (hazard ratio = 0.28, 95% confidence interval = 0.19 to 0.40, P = .001), with progressionfree survival similarly prolonged with cabozantinib across many subgroups; a rate of patients alive and progression-free at 1 year of 47.3% for cabozantinib vs 7.2% for placebo; and a response rate of 28% for cabozantinib vs 0% for placebo. These results unequivocally established the therapeutic effectiveness of cabozantinib for progressive metastatic medullary thyroid cancer. As the overall survival event number had not reached the preset goal at the time of analysis, patient mortality rates cannot be conclusively compared for cabozantinib and placebo at this time. However, with the current remarkable clinical responses, it may be reasonable to be optimistic in expecting a mortality benefit of cabozantinib in medullary thyroid cancer.

Further Considerations It is important to note that in the phase III trial, radiographically documented tumor progression of medullary thyroid cancer was a major criterion for patient recruitment.5 This represents a feature distinct from the trial of vandetanib, in which tumor progression was not a criterion at study entry and, as a result, patients had lessadvanced disease as reflected by the longer median progressionfree survival (19.3 months) in the placebo arm.3 Significant therapeutic effects of cabozantinib have recently been demonstrated in clinical trials in other cancers (such as prostate cancer) at advanced stages.8 Several pivotal clinical trials of cabozantinib are currently ongoing in a large number of cancers.9 Given the positive results in medullary thyroid cancer and prostate cancer, it is hoped that cabozancontinued on page 79

ASCOPost.com | NOVEMBER 1, 2013

PAGE 79

Patient’s Corner

Having Breast Cancer Has Actually Been a Positive Experience I wouldn’t be the nurse I am today if I hadn’t been diagnosed with cancer. By Jodi Harris, LPN, as told to Jo Cavallo

know it sounds strange, but being diagnosed with cancer was one of the best things to have happened to me. I don’t mean to diminish the traumatic experience of hearing the words, “You have breast cancer.” That was over 11 years ago, and I’m still reeling from the diagnosis and its aftereffects. I’m just saying that the experience has made me a bet-

ter person, wife, and mother, and certainly a better nurse caring for patients with cancer. Just before my diagnosis, I had been working in the purchasing department at the Mayo Clinic in Scottsdale, Arizona, but at age 54, I decided that I wanted to go to nursing school. Despite the fact that I work for one of the most prestigious

medical facilities in the world, I hadn’t been vigilant about maintaining routine cancer screenings and had missed several scheduled mammograms. I did, however, participate in our local news station’s Buddy Check program, which encourages breast self-exams with an e-mail alert on the 12th day of each month. It was during one of those breast

sei et al study.5 The potential predictive value of RAS mutation, another common oncogenic genetic alteration in medullary thyroid cancer,10 was not examined. Thus, whether genetic-guided therapy of medullary thyroid cancer using cabozantinib is feasible is an open issue that needs to be addressed in future, perhaps larger, studies. Specific and detailed clinical indications for the use of cabozantinib need to be accurately

in medullary thyroid cancer using combination drug therapies.

self-exams that I felt a lump in my right breast. I knew right away that it was cancer. By then, I was in nursing school and aware from my training that a hard lump like the one I was feeling wasn’t good. After my discovery, things moved very quickly. I had a mammogram the next day, followed by a biopsy of the tumor. continued on page 82

Thyroid Cancer continued from page 78

tinib will prove to be similarly effective in treating these other cancers.

Benefit-to-Harm Ratio The adverse effects of cabozantinib, like those of other tyrosine kinase inhibitors, were generally readily manageable in the phase III trial, but some could be potentially serious. Therefore, it is important to respect the principle of individualized

Progressive metastatic medullary thyroid cancer is refractory to conventional treatments and is currently associated with the worst prognosis. With its demonstrated therapeutic value in this challenging group of patients, cabozantinib … is forcefully shaping the landscape of medical treatment for the disease. —Mingzhao Xing, MD, PhD

medicine in the clinical application of cabozantinib in patients with medullary thyroid cancer. While patients with progressive metastatic disease clearly meet the criteria for cabozantinib and may benefit from the treatment, potential serious adverse effects of this drug may outweigh the benefits in patients with indolent stable disease. Use of cabozantinib in such patients may therefore be precluded. The role of RET mutations in medullary thyroid cancer, either sporadic or hereditary, in determining the therapeutic effects of cabozantinib was not firmly established in the Eli-

defined for the best benefit-to-harm ratio in the treatment of patients with medullary thyroid cancer. Also, monotherapy with cabozantinib targets only limited molecular targets and is unlikely to cure medullary thyroid cancer because, as in the case of follicular cell–derived thyroid cancer,11 multiple signaling pathways and molecular mechanisms may be involved in the tumorigenesis and progression of medullary thyroid cancer. As for follicular cell–derived thyroid cancer,12 treatments that may result in cure of the disease may require targeting additional key molecular targets

Therapeutic Milestone Cabozantinib represents another milestone in the development of effective treatments for medullary thyroid cancer. Progressive metastatic medullary thyroid cancer is refractory to conventional treatments and is currently associated with the worst prognosis. With its demonstrated therapeutic value in this challenging group of patients, cabozantinib as a valuable new therapeutic option is forcefully shaping the landscape of medical treatment for the disease. It is exciting to anticipate the new clinical prospects in medullary thyroid cancer to be brought about by this new treatment. It also fills me with great gratitude to think of all those preclinical and clinical investigators who, through their brilliant work and diligent effort in this field, have created this beautiful new landscape for medical treatment of medullary thyroid cancer. n

Disclosure: Dr. Xing receives royalties as a co-inventor on a licensed patent related to the discovery and clinical characterization of BRAF V600E mutation in thyroid cancer. He also receives thyroid cancer research funding support from the National Institutes of Health (R01CA134225 and R01CA113507).

References 1. Roy M, Chen H, Sippel RS: Current understanding and management of medullary thyroid cancer. Oncologist. September 13, 2013 (early release online). 2. Wells SA Jr, Gosnell JE, Gagel RF, et al: Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 28:767-772, 2010. 3. Wells SA Jr, Robinson BG, Gagel RF,

et al: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J Clin Oncol 30:134-141, 2012. 4. Kurzrock R, Sherman SI, Ball DW, et al: Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29:2660-2666, 2011. 5. Elisei R, Schlumberger MJ, Müller SP, et al: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31:3639-3646, 2013. 6. Yakes FM, Chen J, Tan J, et al: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298-2308, 2011. 7. National Cancer Institute: FDA approval for cabozantinib s-malate. Available at http://www.cancer.gov/cancertopics/druginfo/fda-cabozantinib-smalate. Accessed October 9, 2013. 8. Smith DC, Smith MR, Sweeney C, et al: Cabozantinib in patients with advanced prostate cancer: Results of a phase II randomized discontinuation trial. J Clin Oncol 31:412-419, 2013. 9. ClinicalTrials.gov: Studies of cabozantinib. Available at http://clinicaltrials .gov/ct2/results?term=cabozantinib& Search=Search. Accessed October 9, 2013. 10. Agrawal N, Jiao Y, Sausen M, et al: Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab 98:E364-E369, 2013. 11. Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13:184-199, 2013. 12. Xing M, Haugen BR, Schlumberger M: Progress in molecular-based management of differentiated thyroid cancer. Lancet 381:1058-1069, 2013.

Advertisement not displayed in digital edition at advertiserâ&#x20AC;&#x2122;s request

The ASCO Post | NOVEMBER 1, 2013

PAGE 82

Patient’s Corner

Breast Cancer

Celebrating Life

continued from page 79

After I was through with treatment, I never asked—and wasn’t told—if I was in remission or cancer-free. My oncologist advised me to maintain a healthy lifestyle and to have regular follow-up medical visits to monitor late side effects from treatment and to detect any early signs of a cancer

The diagnosis was stage II, triple-negative medullary carcinoma, and several days later I had a lumpectomy. My oncologist then prescribed a 5-month regimen of doxorubicin and cyclophosphamide (4 treatments every 21 days), followed by 30 days of radiation therapy.

recurrence. I knew I never wanted to go through this experience again and vowed to do everything I could to keep the cancer from returning. At the insistence of my oncologist, at age 60, I took up a strenuous fitness program and learned more about eating a healthy diet. I also became even more appreciative of the wonderful

life I have, including a supportive husband, four wonderful daughters, eight terrific grandkids, and fulfilling work, and I enjoy every moment of every day.

Giving Back Going through treatment and its side effects, especially losing my hair, was really tough. We place such

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | NOVEMBER 1, 2013

PAGE 83

Patient’s Corner

importance on our hair, and for me, the loss of my hair was the most dehumanizing aspect of having cancer. But the nurses who cared for me were so kind and encouraging, assuring me every step of the way that my hair would grow back and that I would be healthy again. Their words gave me solace and made me even

more determined to become the best nurse I could be, so I could give that same kindness and encouragement to my patients. In a weird stroke of serendipity, the benefactor who had funded my nursing scholarship was one of the first patients I took care of after getting my license. He and my other pa-

tients with cancer have taught me so much about resilience and resolve, and it is my honor to care for them. Getting a cancer diagnosis and going through treatment took a year out of my life, but it also taught me valuable life lessons about the importance of giving back to people going through a similar experience.

Getting a cancer diagnosis and going through treatment took a year out of my life, but it also taught me valuable life lessons about the importance of giving back to people going through a similar experience. —Jodi Harris, LPN

Advertisement not displayed in digital edition at advertiser’s request

In addition to my work as nurse, I became a volunteer for the American Cancer Society’s Reach to Recovery, Relay for Life, and Making Strides Against Breast Cancer programs, which provide emotional support for women and men diagnosed with breast cancer. As a result, my life is more rewarding than I ever could have imagined. It is the gift cancer gave me. n Jodi Harris, LPN, is a nurse at the Mayo Clinic in Scottsdale, Arizona.

The ASCO Post

Like us on

Facebook facebook.com/TheASCOPost

The ASCO Post | NOVEMBER 1, 2013

PAGE 84

In the Clinic Gastrointestinal Oncology

Nab-Paclitaxel in Metastatic Pancreas Cancer By Matthew Stenger

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

Indication On September 6, paclitaxel protein-bound particles [albuminbound] (nab-paclitaxel, Abraxane) was approved for use in combination with gemcitabine for first-line treatment of patients with metastatic adenocarcinoma of the pancreas.1,2 Approval was based on demonstration of improved overall survival in a multicenter, international, openlabel phase III trial in which 861 patients with metastatic pancreatic cancer were randomly assigned to receive the combination of nab-paclitaxel plus gemcitabine (n = 431) or gemcitabine alone (n = 430).2 Patients had a median age of 63 years (range, 27–88 years, 42% ≥ 65 years), 58% were male, 60% had Karnofsky performance score of 90 or 100, 46% had at least three sites of metastatic disease, and 84% had liver metastases. The primary lesion was located in the pancreatic head in 43% of patients, body in 31%, and tail in 25%. Median overall survival was 8.5 months in the nab-paclitaxel/gemcitabine group vs 6.7 months in the gemcitabine group (hazard ratio [HR] =

OF NOTE Nab-paclitaxel exploits the physiologic transport properties of albumin, potentially avoiding adverse reactions associated with taxanes in conventional preparations and possibly exhibiting increased antitumor activity. 0.72, P < .0001). Progression-free survival was also significantly prolonged n the nab-paclitaxel/gemcitabine group (5.5 vs 3.7 months, HR = 0.69, P < .0001). Objective response rates were 23% vs 7% (P < .0001).

Nab-paclitaxel is a microtubule inhibitor composed of proteinbound paclitaxel particles, a solventfree colloidal suspension of paclitaxel and human serum albumin that exploits the physiologic transport properties of albumin. In addition to potentially avoiding hypersensitivity reactions and adverse reactions associated with taxane solvents in conventional preparations, nab-paclitaxel may exhibit increased antitumor activity by reaching the tumor microenvironment more efficiently than solvent-based paclitaxel via caveolae-mediated transcytosis and by exhibiting preferential uptake by cancer cells.

How It Is Given The recommended dosage of nabpaclitaxel is 125 mg/m2, administered intravenously over 30 to 40 minutes on days 1, 8, and 15 of each 28-day cycle. Gemcitabine is given on days 1, 8, and 15 of each 28-day cycle im-

azole, gemfibrozil, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort). Nab-paclitaxel is contraindicated in patients with absolute neutrophil count < 1,500/µL and in those with severe hypersensitivity reaction to nab-paclitaxel. Patients should undergo frequent monitoring of complete blood count.

Safety Profile Among treated patients in the phase III trial, the median relative dose intensity for gemcitabine was 75% in the nab-paclitaxel/gemcitabine group and 85% in the gemcitabine group, and the median relative dose intensity of nab-paclitaxel was 81%. The most common adverse events of any grade reported at a ≥ 5% higher incidence in the nab-paclitaxel/gemcitabine group included neutropenia (73% vs 58%), fatigue (59% vs 46%), peripheral neuropathy (54% vs 13%), nausea (54% vs 48%), alopecia (50% vs 5%), periph-

Nab-Paclitaxel for Pancreatic Cancer ■■ Nab-paclitaxel (Abraxane) has been approved for use in combination with gemcitabine for first-line treatment of patients with metastatic adenocarcinoma of the pancreas.

■■ The recommended dosage of nab-paclitaxel is 125 mg/m2 IV over 30 to 40

minutes on days 1, 8, and 15 of each 28-day cycle. Gemcitabine is given on days 1, 8, and 15 of each 28-day cycle immediately after nab-paclitaxel.

mediately after nab-paclitaxel. There are recommendations for initial dosing and dose adjustment of nab-paclitaxel and gemcitabine in patients with neutropenia, thrombocytopenia, grade 3 or 4 febrile neutropenia, grade 3 or 4 peripheral neuropathy, grade 2 or 3 cutaneous toxicity, and gastrointestinal toxicity (grade 3 mucositis or diarrhea). No dose adjustment is necessary for patients with mild hepatic impairment, but nab-paclitaxel should be withheld for AST > 10 × upper limit of normal or bilirubin > 5 × upper limit of normal, and the starting dose should be reduced in patients with moderate to severe hepatic impairment. Caution should be used when concomitantly administering nab-paclitaxel with inhibitors or inducers of CYP2C8 or CYP3A4 (eg, ketocon-

eral edema (46% vs 30%), diarrhea (44% vs 24%), and pyrexia (41% vs 28%). The most common grade 3 or higher adverse events in the nab-paclitaxel/gemcitabine group were neutropenia (38% vs 27%), peripheral neuropathy (17% vs 1%), thrombocytopenia (13% vs 9%), asthenia (7% vs 4%), and dehydration (7% vs 2%). The most common serious adverse reactions in nab-paclitaxel/ gemcitabine patients were pyrexia, dehydration, pneumonia, and vomiting. Sepsis was reported in 5% (vs 2%) and pneumonitis was reported in 4% (vs 1%) of patients who received nab-paclitaxel/gemcitabine. Nab-paclitaxel carries boxed warnings against administration in patients with baseline neutrophil counts < 1,500/µL, for frequent

OF NOTE Nab-paclitaxel carries boxed warnings against administration in patients with baseline neutrophil counts < 1,500/µL, for frequent monitoring of peripheral blood cell counts to detect bone marrow suppression, and against substitution of nab-paclitaxel for or with other paclitaxel formulations. monitoring of peripheral blood cell counts to detect bone marrow suppression, and against substitution of nab-paclitaxel for or with other paclitaxel formulations. Nab-paclitaxel also carries warnings/precautions for myelosuppression, sensory neuropathy, sepsis, pneumonitis, severe hypersensitivity reactions (including fatalities), use in hepatic impairment, theoretical risk of viral transmission (due to formulation with albumin derived from human blood), and fetal harm. Women should be advised to avoid becoming pregnant and men should be advised not to father a child while receiving nab-paclitaxel. n References 1. U.S. Food and Drug Administration: Paclitaxel. Available at www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm367613.htm. ® 2. ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) prescribing information, Abraxis BioScience, LLC, September 2013. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2013/021660s037lbl.pdf.

REPORT ADVERSE EVENTS Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

THIS IS WHAT RECURRENT GBM THERAPY CAN LOOK LIKE TODAY NovoTTFTM Therapy delivers efficacy with improved quality of life and fewer treatment-related toxicities1 •

In the Phase III clinical trial of 237 patients with recurrent GBM, the NovoTTF™-100A System demonstrated comparable overall survival (OS) to chemotherapy

•

Patients on the NovoTTF-100A System experienced fewer of the systemic adverse events associated with chemotherapy treatment

•

Most measures of quality of life (QoL), including cognitive and emotional functioning, were improved in NovoTTF-100A System-treated patients compared to chemotherapy-treated patients

Learn more about the NovoTTF-100A System at NovoTTFtherapy.com The NovoTTF-100A System is approved for the treatment of adult patients with recurrent glioblastoma. GBM=Glioblastoma Reference: 1. Instructions for use. NovoTTF-100A System. Novocure; 2012.

For full prescribing information refer to the IFU at NovoTTFtherapy.com

ASCOPost.com | NOVEMBER 1, 2013

Awards

Important Safety Information Indications for Use The NovoTTF™-100A System is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM), following histologically- or radiologically-confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

Innovation Impact Awards Support Efforts to Advance Blood Cancer Research Priorities and Lung Cancer Screening Adoption

Use the NovoTTF-100A System only after receiving training from qualified personnel, such as your doctor, a nurse, or other medical personnel who have completed a training course given by the device manufacturer (Novocure).

elgene Corporation recently announced the two recipients of Celgene’s inaugural Innovation Impact Awards: The Aplastic Anemia & Myelodysplastic Syndromes International Foundation (AA&MDSIF) and the Lung Cancer Alliance. The Innovation Impact Awards program recognizes effective, innovative, and successful initiatives in one of two therapeutic areas: hematology or oncology. According to Celgene, the program aims to recognize the achievements of U.S.-based notfor-profit organizations addressing the needs of patients, caregivers, and health-care providers in today’s challenging health-care environment. Each award winner will receive a $100,000 cash grant and be invited to participate in an Innovation Experience workshop. “We are delighted to announce The Aplastic Anemia & MDS International Foundation and Lung Cancer Alliance as the recipients of our first annual Innovation Impact Awards,” said Joel W. Beetsch, PhD, Vice President of Patient Advocacy at Celgene. “Innovation is at the core of everything we do at Celgene. The Innovation Impact Awards not only recognize the significant contributions of patient and professional organizations to patient treatment and care, but also broaden the impact of the award-winning programs by helping sustain, expand, and replicate those innovative initiatives.”

All servicing procedures must be performed by qualified and trained personnel.

Hematology Award

Contraindications Do not use the NovoTTF-100A System if you have an active implanted medical device, a skull defect (such as, missing bone with no replacement), a shunt, or bullet fragments. Examples of active electronic devices include deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts. Use of the NovoTTF-100A System together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of the NovoTTF-100A System together with skull defects, shunts, or bullet fragments has not been tested and may possibly lead to tissue damage or render the NovoTTF-100A System ineffective. Do not use the NovoTTF-100A System if you are known to be sensitive to conductive hydrogels like the gel used on electrocardiogram (ECG) stickers or transcutaneous electrical nerve stimulation (TENS) electrodes. In this case, skin contact with the gel used with the NovoTTF-100A System may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions

Do not wet the device or transducer arrays. Do not use any parts that do not come with the NovoTTF-100A System Treatment Kit, or that were not sent to you by the device manufacturer or given to you by your doctor. The NovoTTF-100A System commonly causes skin irritation beneath the transducer arrays and in rare cases can lead to headaches, falls, fatigue, muscle twitching or blisters. Please refer to the Instructions For Use NovoTTF-100A System for complete information regarding the device’s indication, contraindications, risks and benefits.

PAGE 86

The Aplastic Anemia & MDS International Foundation received the hematology Innovation Impact Award for the MDS Clinical Research Consortium. AA&MDSIF has historically been very successful in developing research approaches and solutions for patients with these blood disorders where the bone marrow fails to make healthy blood cells. The MDS Clinical Research Consortium will work with prominent U.S. MDS research centers to optimize the research process by articulating pressing basic research questions in MDS and to identify creative, innovative,

and collaborative ways to answer them. AA&MDSIF will help determine the feasibility of each approach and begin design of a major basic research initiative that will be innovative in form, structure, and function.

Oncology Award The Lung Cancer Alliance (LCA) received the oncology Innovation Impact Award for the “National Framework for Excellence in Lung Cancer Screening and Continuum of Care” initiative. LCA convened thought leaders from all fields related to lung cancer in 2012 to devise the National Framework, which has since been adopted by more than 100 medical facilities nationwide and endorsed by numerous professional societies. Funding from the award will help support efforts to educate the at-risk public through an award winning awareness campaign, encouraging more medical facilities to adopt the National Framework and implement its best practices and guidelines, and improving and expanding lung cancer screening. The submissions for this year’s Innovation Impact Awards represented a wide range of approaches to support the hematology and oncology communities. The Aplastic Anemia & MDS International Foundation and Lung Cancer Alliance programs included a high level of innovation, strong vision, and plans to improve patient treatment, care, and survivorship. The competitive Innovation Impact Awards Program was open to U.S.-based not-for-profit patient and professional organizations working in hematology or oncology. Eligible programs were those having demonstrable impact on the lives of patients, family members, caregivers, and/or the medical professionals who provide treatment and care. Those programs had to address a defined challenge faced by the target population. An independent judging panel that included innovation, health-care, and advocacy experts identified the two award recipients from a pool of applicants. For more information about the awards, visit http://www.innovationimpact.com. n

ASCOPost.com | NOVEMBER 1, 2013

PAGE 87

Journal Spotlight Thoracic Oncology

Low-Dose CT Screening Identifies More Early Lung Cancer but Has Lower Positive Predictive Value vs Radiography By Matthew Stenger

esults of the two rounds of annual incidence screening with low-dose computed tomography (CT) vs radiography in the National Lung Screening Trial (NLST) were recently reported by Denise R. Aberle, MD, Professor of Radiology and Bioengineering at the University of California at Los Angeles and national principal investigator for the NLST, and colleagues in The New England Journal of Medicine. Among the findings of the trial is that lowdose CT was more sensitive in detecting early-stage lung cancers but had a lower positive predictive value compared with radiography. The NLST was conducted to determine whether three annual screenings (prevalence round T0 and incidence rounds T1 and T2) with low-dose helical CT can reduce mortality from lung cancer compared with chest radiography in an asymptomatic highrisk population of individuals 55 to 74 years old with a history of at least 30 pack-years of smoking. The current analysis involved findings from the first two incidence screenings (rounds T1 and T2).

In the radiography group, 133 participants were diagnosed with lung cancer, including 65 of 1,482 with positive screening results, 44 of 22,607 with negative screening results, 21 of 2,321 who were not screened, and 3 of 322 ineligible participants with lung cancers diagnosed during the T1 screening year. For the CT vs radiography groups, sensitivity was 94.4% vs 59.6%, specificity was 72.6% vs 94.1%, positive predictive value was 2.4% vs 4.4%, and negative predictive value was 99.9% vs 99.8%.

T2 Screening Round Results At the T2 round, 24,102 (93%) of 25,492 eligible participants under-

Stages of Identified Cancers Among lung cancers of known stage at T1, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group, and

As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. —Denise R. Aberle, MD, and colleagues

T1 Screening Round Results At the T1 round, 24,715 (94%) of 26,285 eligible participants underwent CT screening, with positive results found in 27.9%. Of 26,410 eligible for radiography screening, 24,089 (91%) were screened, with positive results in 6.2%. In the CT group, 186 participants were diagnosed with lung cancer, including 168 of 6,901 participants with positive screening results, 10 of 17,814 with negative screening results, 6 of 1,570 who were not screened at T1, and 2 of 437 ineligible participants with lung cancers that were first diagnosed during the T1 screening year.

with positive screening results, 44 of 22,172 with negative screening results, 18 of 2,764 who were not screened, and 4 of 622 participants who were ineligible for the T2 screening but received a diagnosis of lung cancer during the T2 screening year. For the CT vs radiography groups, sensitivity was 93.0% vs 63.9%, specificity was 83.9% vs 95.3%, positive predictive value was 5.2% vs 6.7%, and negative predictive value was 99.9% vs 99.8%.

went CT screening, with positive results found in 16.8%. Of 26,110 eligible for radiography screening, 23,346 (89%) underwent screening, and positive results were found in 5.0%. In the CT group, 237 participants were diagnosed with cancer, including 211 of 4,054 with positive screening results, 16 of 20,048 with negative screening results, 7 of 1,840 who were not screened at T2, and 3 of 780 ineligible participants with lung cancers diagnosed during the T2 screening year. In the radiography group, 144 participants received a diagnosis of lung cancer, including 78 of 1,174

Low-Dose CT Screening for Lung Cancer ■■ Compared with chest radiography, CT had greater sensitivity, lower

specificity, and lower positive predictive value in the T1 and T2 screening rounds of the National Lung Screening Trial.

■■ Low-dose CT screening resulted in diagnosis of a greater number of earlystage lung cancers and an associated smaller number of late-stage lung cancers.

31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV in the radiography group. The differences in stage distribution between groups persisted at T2. The increase in early-stage lung cancers in the CT group was associated with a decrease in late-stage lung cancers. Over the course of the trial, the incidence of stage IV lung cancer was 138 cases per 100,000 person-years in the CT group vs 204/100,000 personyears in the radiography group (rate ratio = 0.68, 95% confidence interval = 0.57– 0.80).

Relationship of Nodule Size to Cancer Nodule size among patients with lung cancers diagnosed with CT screening at T1 was 4 to 10 mm in diameter in 34.5%, 11 to 20 mm in 44.0%, 21 to 30 mm in 11.9%, and > 30 mm in 4.8%. The positive predictive value for detection of a nodule of any size with CT at T1 was

2.4%, increasing to 58.2% for positive screening results with subsequent biopsy. For nodules 4 to 6 mm in diameter, the positive predictive value at T1 was 0.3%. In the radiography group, the largest nodule or mass observed among 65 lung cancers detected at T1 was 4 to 10 mm in diameter in 13.8%, 11 to 20 mm in 33.8%, 21 to 30 mm in 24.6%, and > 30 mm in 15.4%. The positive predictive value for detection of a nodule of any size at T1 in the radiography group was 4.4%, increasing to 67.4% for positive screening results with subsequent biopsy. In both groups, the positive predictive value for detection of a nodule increased as nodule size increased from 4 to 30 mm. In the radiography group, the positive predictive value for nodules smaller than 4 mm was relatively high; it is unclear whether these nodules corresponded to a lung cancer or prompted follow-up assessments that led to a diagnosis of lung cancer. In both groups, detection of masses larger than 30 mm had a slightly decreased positive predictive value relative to the detection of nodules that were 21 to 30 mm, likely representing interpretation of pneumonia as a positive screening result.

Histology The most common histologic types of lung cancer in both screening groups at both screenings were adenocarcinoma, accounting for 36.6% of cancers in the CT group and 38.2% in the radiography group at T1 and 34.9% and 33.1%, respectively, at T2. Squamous cell carcinoma accounted for 21.0% of cancers in the CT group and 22.9% in the radiography group at T1 and 26.0% and 23.9%, respectively, at T2. In the CT group, lung cancers characterized as bronchioloalveolar cell carcinoma were predominantly diagnosed after a positive screening and accounted for 17.3% and 13.3% of lung cancers detected on positive screening at T1 and T2, respectively. Few bronchioloalveolar cell carcinomas were diagnosed in the radiography group, likely reflecting difficulty in discerning continued on page 88

The ASCO Post | NOVEMBER 1, 2013

PAGE 88

Journal Spotlight

Lung Cancer Screening: Actionable Evidence By James L. Mulshine, MD

his recent paper in The New England Journal of Medicine outlines the details of the clinical outcomes with two incidence screens that were conducted as part of the National Lung Screening Trial (NLST).1 In the wake of the positive review of the U.S. Preventive Services Task Force (USPSTF) draft recommendation, the results of this current report are being subjected to much greater scrutiny as the nation contemplates implementation of the new screening service. What emerges from this analysis is decidedly reassuring.

recall that the NLST protocol did not dictate the precise method of screening management.2 Therefore, these results truly reflect the “community” standard for screening outcomes, which suggests

This very large, complex study was executed in a decisive fashion and provided an unambiguous answer that CT screening for lung cancer can be delivered and can save lives. This result can now be implemented nationally.

Key Findings As outlined in the discussion in this issue of The ASCO Post, the NLST investigators found a 2.7-fold increase in the detection of lung cancers over the two intervals of screening in the spiral CT arm compared to the chest x-ray arm of the trial, and this finding resulted in a corresponding threefold decrease in the rate of screen-negative (ie, missed) lung cancers. In addition, the efficiency of the screening process improved, reflected in the ratio of suspected cancers to detected cancers, which went from 2.4% of 27.9% to 5.2% of 16.8% across the two screening intervals. Further, the rate of “futile” thoracotomies remained low, at 18.9% and 15.9%, respectively, across the two screening intervals. These outcomes are favorable, although they might be improvable, but Dr. Mulshine is Associate Provost for Research and Director of the Translational Sciences Consortium at Rush Medical College, Chicago.

CT Screening for Lung Cancer continued from page 87

these lesions on planar imaging. Small cell carcinoma was detected with similar frequency in both groups at both screenings, but was more commonly detected in CT partici-

This means that an increased number of cases must be found in a defined cohort at an early stage, and eventually this number would be offset by a correspondingly lower frequency of

—James L. Mulshine, MD

they may be generalizable as national screening is implemented.

False-Positives and Stage Shift The discussion also reviews the critical issue of the definition of a falsepositive nodule. The authors note that the NELSON research group uses a two-step process for interpreting nodule status that initially characterizes noncalcified nodules above a certain size as “indeterminate”; only nodules that show rapid growth are subsequently characterized as positive.3 This approach results in a lower rate of false-positive diagnoses and correspondingly reduces the stress on the screening subjects. Another finding of this study was the emergence of a favorable stage shift.1 For a cancer screening approach to be truly successful, it must advance the diagnosis of detected cancers.

pants with positive results vs those with negative results. The converse was true in the radiography group. The investigators concluded, “Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiogra-

advanced-stage cancer cases found in that cohort. This dynamic was in fact observed in this cohort, with the CT arm showing a higher frequency of curable stage I lung cancer detection and a lower frequency of stage III/IV at both intervals, compared to the x-ray arm. This stage shift is important, as it reflects the potential for increasing curative outcomes with the screening process.

Conclusions These results are consistent with other recent screening reports, and the data in aggregate support the favorable recommendation for national implementation in high-risk individuals aged 55 to 74 years that was recently proposed by the USPSTF.4 Clearly, there is much to do in further improving this service, especially with regard to providing a consistent quality of screening care such as proposed in the

Lung Cancer Alliance’s framework approach.5 The critical issue, however, is that the people of the United States invested a quarter of a billion dollars in the NLST trial. This very large, complex study was executed in a decisive fashion and provided an unambiguous answer that CT screening for lung cancer can be delivered and can save lives. This result can now be implemented nationally. If we execute this complex process and improve mortality outcomes for this most lethal cancer, then the national cancer program will have served its critical role. n Disclosure: Dr. Mulshine reported no potential conflicts of interest.

References 1. Aberle DR, DeMello S, Berg CD, et al: Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 369:920-931, 2013. 2. Aberle D, Adams A, Berg C, et al: Reduced lung-cancer mortality with lowdose computed tomographic screening. N Engl J Med 365:395-409, 2011. 3. van Klaveren R, Oudkerk M, Prokop M, et al: Management of lung nodules detected by volume CT scanning. N Engl J Med 361:2221-2229, 2009. 4. Humphrey LL, Deffebach M, Pappas M, et al: Screening for lung cancer with low-dose computed tomography: A systematic review to update the U.S. Preventive Services Task Force recommendation. Ann Intern Med 159:411-420, 2013. 5. Lung Cancer Alliance: National Framework for Excellence in Lung Cancer Screening and Continuum of Care. Available at http://www.lungcanceralliance. org/get-information/am-i-at-risk/national-framework-for-lung-screening-excellence.html. Accessed October 9, 2013.

phy. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advancedstage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed.” n Disclosure: The study was funded by the

November Is

Lung Cancer Awareness Month.

National Cancer Institute. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Aberle DR, DeMello S, Berg CD, et al: Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 369:920-931, 2013.

See pages 1, 65, 86, and 87 for lung cancer news in The ASCO Post.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 89

Pioneers in Oncology Claudia I. Henschke, PhD, MD, Took a Circuitous Route to Her Groundbreaking Work in Lung Cancer Screening By RonaldPiana

Claudia I. Henschke, PhD, MD

“Once you have tasted flight, you will forever walk the earth with your eyes turned skyward, for there you have been, and there you will always long to return.” —Leonardo da Vinci

ung cancer CT screening may have had no greater advocate than Claudia I. Henschke, PhD, MD. In the face of unrelenting controversy, Dr. Henschke, who is Professor of Radiology, and Head, Lung and Cardiac Screening at Mount Sinai Medical Center in New York, has firmly maintained that certain smokers and former smokers should be offered lowdose computed tomography (CT) scans to detect lung cancer when it is still at a curable stage. After decades of work and intense criticism from skeptics of cancer screening, she was finally vindicated this year, when the U.S. Preventive Services Task Force (USPSTF) recommended low-dose CT scans for certain adults at high risk of having lung cancer.

Early Years Dr. Henschke was born in Berlin. When her father, a scientist, was recruited to work on the U.S. Air Force “Man in Space” project, the Henschke’s immigrated to the United States, landing in Dayton, Ohio, where Dr. Henschke spent her early childhood. After her father completed his service with the Air Force, he became head of radiotherapy at Ohio State University in Columbus. Shortly after, he received an appointment at Memorial Sloan-Kettering Cancer Center in New York. The Henschke family settled in

Forest Hills, New York, where Dr. Henschke attended high school. “Competitive tennis was one of my passions. I was ranked as an amateur back in Ohio. At Forest Hills, my girlfriend was the number 1 ranked player in the East, and I was number 2. We were ranked first in doubles,” said Dr. Henschke. A prodigious student, Dr. Henschke graduated high school at the age of 16 and seized an opportunity to attend the University of Geneva and the University of Munich, where she majored in mathematics and learned French. Competitive tennis and world travels were not enough to sate Dr.

PhD in mathematical statistics and computer science. While doing her graduate work at the University of Georgia, Dr. Henschke worked once again as a private pilot. “Flying was a very important part of me,” she said. However, staying in one place was not yet in the cards for the peripatetic PhD. Newly married, Dr. Henschke swapped Atlanta, Georgia, for Bethesda, Maryland, where her husband had taken an appointment at the National Cancer Institute (NCI). Asked how a tennis-playing pilot with a doctorate in mathematical statistics and computer science made another giant career leap into

I consider the USPSTF’s recent B recommendation for lung cancer screening to be a highlight of my career. It means that Medicare will now cover screening, and people at high risk for lung cancer can finally get screened, no matter what their socioeconomic status. That’s all I ever wanted. —Claudia I. Henschke, PhD, MD

Henschke’s appetite for adventure and challenge. “My father had a seaplane in the Bronx on the Hudson River, and he taught me how to fly. I earned a pilot’s license, an instructor’s license, and a commercial pilot’s license. I was hired as a private pilot by a family from Dallas, so while working for them, I finished my undergraduate studies at Southern Methodist University in Dallas,” explained Dr. Henschke. She added that she also received her master’s degree in mathematical statistics from Southern Methodist, still flying the wealthy family around the country in their twin engine plane.

From Statistics to Oncology To supplement her income, Dr. Henschke took a position at the Graduate Research Center of the Southwest in Dallas. When her professor at the Center was offered an opportunity to head the mathematical statistics and computer sciences department at the University of Georgia, Dr. Henschke followed him there and earned her

oncology, Dr. Henschke responded, “While my husband was at the NCI, I took a position at the Georgetown Medical School’s biostatistics department. I liked statistics, but both of my parents were physicians and my younger sister was finishing medical school. I realized that to do something truly meaningful, I needed to become a medical doctor as well. So I decided to go to medical school. It was an abrupt but firm decision.” In 1974, Dr. Henschke entered Howard University Medical School in Washington, DC, a traditionally African American institution. “Of the three medical schools I applied to—sort of on the spur of the moment—Howard was the only one with an immediate opening. I was the sole white woman in my class, but I never felt out of place—in fact, Howard ended up being a wonderful experience, one that opened my eyes to the challenges that many in underserved communities live with on a daily basis.”

Choosing which oncology field to pursue was not a hand-wringing decision. “Both of my parents were radiotherapists, I always wanted to do research in clinical medicine, and my father told me that radiology offered more opportunity for research than other fields. So, in 1977, I began a residency at Brigham and Women’s Hospital/Harvard Medical School, Boston, which included a 1-year research fellowship. I went into chest radiology because that was my interest at that time,” said Dr. Henschke.

A Seminal Paper In 1983, Dr. Henschke accepted a position as Assistant Attending Radiologist at the Cornell Medical Center in New York. “After being there a while, my chairman gently let me know that it was time for me to begin working on some grants. We organized a multidisciplinary group of physicians and began discussing what kind of exciting projects to do. At the time, we were seeing CT scans of people with incidental pulmonary nodules, and nobody had any idea on what to base their follow-up recommendations for these patients,” she said. The group decided that making clinically relevant recommendations on incidental pulmonary lesions that prevented unnecessary procedures required a good database, which was nonexistent at the time. “As the database idea percolated among the group, my colleague Dr. David Yankelevitz suggested that with my background in statistics, I should evaluate the literature on lung cancer screening,” said Dr. Henschke. Dr. Yankelevitz is Professor of Radiology and a Director, Lung Biopsy Service, at Mount Sinai Medical Center, New York. By chance, an old colleague of Dr. Henschke’s father, who had written early papers on statistical modeling in lung cancer screening, helped her develop a mathematical model to project possible outcomes from CT screening in lung cancer. “It was very exciting,” she said. “We immediately began submitting papers to the NCI, which culminated in a grant to compare CT screening and chest xcontinued on page 90

The ASCO Post | NOVEMBER 1, 2013

PAGE 90

Pioneers in Oncology Claudia I. Henschke, PhD, MD continued from page 89

ray in 1,000 subjects. We developed an optimal approach to evaluate screening for this purpose, called the Early Lung Cancer Action Project (ELCAP), and that is what was reported in The Lancet in 1999.”1 Dr. Henschke said she didn’t fully comprehend the impact of the Lancet paper until her phone began ringing off the hook. “A reporter for The New York Times called me multiple times. She said that her editor kept asking her questions. I remember wondering where the article would be placed in the newspaper, figuring it would be buried in the back section. When I picked up the paper, I was shocked to see the story on the front page,” she said. “Between The Lancet publication and the front-page story in The New York Times, my life sort of exploded into a new direction,” she continued. “Calls were coming in from all over the world. Smokers eager for a new test came out of the woodwork. In fact, a smoking couple came to my office demanding a CT scan. I explained that the study was over, but they said they’d go to Washington and complain. So I jumped through the hospital administration’s hoops and got them screened. Both of them ended up having lung cancer.”

cepted by the medical community. I consider the USPSTF’s recent B recommendation for lung cancer screening to be a highlight of my career. It means that Medicare will now cover screening, and people at high risk for lung cancer can finally get screened, no matter what their socioeconomic status. That’s all I ever wanted.”

The decades-long struggle to have CT screening made available to people at high-risk for lung cancer has consumed most of Dr. Henschke’s career. It still does, giving her little to no time for other passions such as tennis and flying. Although she plans to start hitting the ball around again someday, her passion to fly will be experienced

vicariously, with her eyes turned skyward at planes crossing the sky. n Reference 1. Henschke CI, McCauley DI, Yankelevitz DF, et al: Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 354:99105, 1999.

Tumor lines of defense merit closer examination

Early Lung Cancer Action Project Building on the success of the first lung cancer screening trial, Dr. Henschke and her colleagues updated their approach and began accruing patients for another screening trial, which would offer only low-dose CT screening. “In October 1999, we also began the New York–ELCAP and then the International–ELCAP (I-ELCAP), which held international meetings every 6 months to discuss how to refine our lung cancer screening methods and data collection. We are now approaching our 29th International Conference,” said Dr. Henschke. Dr. Henschke is proud that I-ELCAP was the seed for valuable international collaboration and consensus-building on the issue of lung cancer screening, given that prior to her work, early detection in lung cancer was never a priority in the research and regulatory world. “I never dreamed that it would take close to 15 years for lung cancer screening with low-dose CT to be ac-

References: 1. Batist G, Wu JH, Spatz A, et al. Resistance to cancer treatment: the role of somatic genetic events and the challenges for targeted therapies. Front Pharmacol. 2011;2:59. doi:10.3389/fphar.2011.00059. 2. Verheul HMW, Pinedo HM. Clinical implications of drug resistance. In: Pinedo HM, Giaccone G, eds. Drug Resistance in the Treatment of Cancer. Cambridge, United Kingdom: Cambridge University Press; 1998:199-231. In: Sikora K, ed. Cancer: Clinical Science in Practice. 3. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615-627. 4. Morin PJ. Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat. 2003;6(4):169-172. 5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. 6. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324-1337. 7. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432(7015):307-315. 8. Evan G, Littlewood T. A matter of life and cell death. Science. 1998;281(5381):1317-1322. 9. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest. 2008;118(6):1979-1990. 10. Zoubeidi A, Gleave M. Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol. 2012;44(10):1646-1656. 11. So A, Hadaschik B, Sowery R, Gleave M. The role of stress proteins in prostate cancer. Curr Genomics. 2007;8(4):252-261. 12. Jäättelä M, Wissing D. Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection. J Exp Med. 1993;177(1):231-236. 13. Wilson MR, Easterbrook-Smith SB. Clusterin is a secreted mammalian chaperone. Trends Biochem Sci. 2000;25(3):95-98. 14. Gleave M, Miyake H, Zangemeister-Wittke U, Jansen B. Antisense therapy: current status in prostate cancer and other malignancies. Cancer Metastasis Rev. 2002;21(1):79-92. 15. Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene. 2003;22(47):7414-7430. 16. Zoubeidi A, Ettinger S, Beraldi E, et al. Clusterin facilitates COMMD1 and I-κB degradation to enhance NF-κB activity in prostate cancer cells. Mol Cancer Res. 2010;8(1):119-130. 17. Sensibar JA, Sutkowski DM, Raffo A, et al. Prevention of cell death induced by tumor necrosis factor α in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). Cancer Res. 1995;55(11):2431-2437. 18. Hassan MK, Watari H, Han Y, et al. Clusterin is a potential molecular predictor for ovarian cancer patient’s survival: targeting clusterin improves response to paclitaxel. J Exp Clin Cancer Res. 2011;30:113. 19. July LV, Beraldi E, So A, et al. Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther. 2004;3(3):223-232. 20. Miyake H, Nelson C, Rennie PS, Gleave ME. Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 2000;60(1):170-176.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 91

Announcements

CancerCare Launches New Edition of Financial Resource Guide for People With Cancer

ancerCare recently announced the launch of a new edition of A Helping Hand: The Resource Guide for People With Cancer, Financial Edition, a reference guide to assist patients with can-

cer and their families in navigating the financial resources available to them. A Helping Hand is a comprehensive handbook featuring up-to-date contact information and descriptions for hun-

dreds of national and regional organizations offering financial help to people with cancer. The new edition also provides valuable tips patients and caregivers can use to manage finances and easily

Cytoprotective proteins and the evasion of apoptosis

Clusterin may promote cancer resistance in multiple ways

Resistance is a fundamental challenge in all forms of cancer and at all stages of disease.1 Its primary clinical manifestation is tumor progression.2 Resistance may result from changes in the tumor microenvironment, genetic factors, or cellular mechanics.3,4 In almost 50% of cases, intrinsic resistance is present before treatment begins, and resistance will be acquired in a large number of the remaining cases.2

Research suggests that stress-induced clusterin contributes to cancer’s ability to resist apoptosis by:

Avoiding apoptosis is a fundamental biologic capability acquired by cancer to enable its growth, survival, and resistance.5-9 Mechanisms such as upregulation of cytoprotective proteins, including HSP27, HSP70, and HSP90, have evolved to protect cells against environmental stress.3,10-12 Clusterin, possibly the first identified secreted chaperone protein, is one such molecule.13 While secretory clusterin is involved in many normal biologic processes, its overexpression has been implicated in a wide variety of cancers.10,14 It is thought that clusterin contributes to both cancer cell survival and resistance by disrupting important cell death pathways, thus protecting the cancer cell from apoptosis.5-10,15-21

• Inhibiting proapoptotic signaling through interaction with surface proteins (eg, receptors) on stressed cells10,22,23 • Inhibiting the proapoptotic protein Bax to prevent its activation of the intrinsic pathway through the mitochondria24 • Promoting cell survival by enhancing activity of NF-κB transcriptional activity16 • Inhibiting endoplasmic reticulum stress and the aggregation of proteins to maintain protein homeostasis and prevent apoptosis10,22,25-27 In studies, clusterin expression has also been notably associated with poor prognosis, advanced stage of cancer, higher tumor grade, and invasion and metastasis.18,20,28-35

Join us on the journey at exploremerit.com Teva Oncology is committed to exploring the latest insights into tumor dynamics and resistance.

21. Hoeller C, Pratscher B, Thallinger C, et al. Clusterin regulates drug-resistance in melanoma cells. J Invest Dermatol. 2005;124(6):1300-1307. 22. Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res. 2010;16(4):1088-1093. 23. Carver JA, Rekas A, Thorn DC, Wilson MR. Small heat-shock proteins and clusterin: intra- and extracellular molecular chaperones with a common mechanism of action and function? IUBMB Life. 2003;55(12):661-668. 24. Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005;7(9):909-915. 25. Poon S, Easterbrook-Smith SB, Rybchyn MS, Carver JA, Wilson MR. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000;39(51):15953-15960. 26. Nizard P, Tetley S, Le Dréan Y, et al. Stress-induced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic. 2007;8(5):554-565. 27. Li N, Zoubeidi A, Beraldi E, Gleave ME. GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer [published online ahead of print June 11, 2012]. Oncogene. doi:10.1038/onc.2012.212. 28. Miyake H, Gleave M, Kamidono S, Hara I. Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology. 2002;59(1):150-154. 29. Redondo M, Villar E, Torres-Muñoz J, Tellez T, Morell M, Petito CK. Overexpression of clusterin in human breast carcinoma. Am J Pathol. 2000;157(2):393-399. 30. Hazzaa SM, Elashry OM, Afifi IK. Clusterin as a diagnostic and prognostic marker for transitional cell carcinoma of the bladder. Pathol Oncol Res. 2010;16(1):101-109. 31. Ekici S, Eroglu A, Dogan Ekici AI, Türkeri L. Clusterin immunoreactivity as a predictive factor for progression of non-muscle-invasive bladder carcinoma. Urol Int. 2011;86(1):31-35. 32. Pucci S, Bonanno E, Pichiorri F, Angeloni C, Spagnoli LG. Modulation of different clusterin isoforms in human colon tumorigenesis. Oncogene. 2004;23(13):2298-2304. 33. Shannan B, Seifert M, Leskov K, et al. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 2006;13(1):12-19. 34. Yang GF, Li XM, Xie D. Overexpression of clusterin in ovarian cancer is correlated with impaired survival. Int J Gynecol Cancer. 2009;19(8):1342-1346. 35. Steinberg J, Oyasu R, Lang S, et al. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin Cancer Res. 1997;3(10):1707-1711. ©2013 Teva Pharmaceutical Industries Ltd. All rights reserved. ONC-40235 August 2013.

access support in their local community.

Roadmap to Guide Patients and Families “Even with insurance, most people are unprepared for the out-of-pocket expenses that accompany cancer. These can include copayments and medications for side effects, as well as costs for transportation to and from treatment and childcare,” said CancerCare Director of Patient Assistance Programs Jane Levy, MSW, LCSW-R. “Finding help with the expenses of daily living can be overwhelming. A Helping Hand is a roadmap that guides patients and their families to organizations that can best address their unique needs,” Ms. Levy said. The new edition provides valuable tips patients and caregivers can use to manage finances and easily access support in their local community. Health-care professionals can also rely on A Helping Hand for accurate information about which services can directly benefit their patients. Copies of A Helping Hand may be ordered fee of charge for anyone interested by visiting www.cancercare.org/publications. n

New Editor-inChief Named for Molecular Cancer Therapeutics

he American Association for Cancer Research (AACR) recently announced the appointment of Napoleone Ferrara, MD, to Editor-in-Chief of the journal Molecular Cancer Therapeutics. Dr. Ferrara presently serves as

Napoleone Ferrara, MD

Professor of Pathology and Senior Deputy Director for Basic Sciences at the Moores Cancer Center in the University of California San Diego Medical Center, and his team focuses on investigating mechanisms of tumor angiogenesis. n

The ASCO Post | NOVEMBER 1, 2013

PAGE 92

2013-2014 Oncology Meetings November Graft vs Host Disease National Symposium November 1 • Independence, Ohio For more information: www. cowdenfoundation.org/ gvhd-home/ Washington State Medical Oncology Society Fall 2013 Oncology Conference November 1 • Seattle, Washington For more information: www.wsmos.org Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org

Georgia Society of Clinical Oncology 4th Annual Winship Gastrointestinal Cancers Symposium November 2 • Atlanta, Georgia For more information: http:// www.gasco.us/meetings-topic. php?meetingid=92 EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu

Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences

Massachusetts Society of Clinical Oncologists Annual Meeting November 7 • Boston, Massachusetts For more information: www.massoncologists.org

2013-2014

SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013 SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013 Markers in Cancer 2013: A Joint Meeting by ASCO, EORTC, and NCI November 7-9 • Brussels, Belgium For more information: www. markersincancer.eu

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences

Shades of Autumn days getting shorter the unopened rose buds …

The Arizona Clinical Oncology Society Fall Membership Conference: Clinical Advances and Payment Challenges in Oncology Care November 8 • Phoenix, Arizona For more information: www.tacos-oncology.com

Fall color viewing here and there the sky … leaves leaves … not one left on our maple

Missouri Oncology Society Fall Membership Conference November 8 • St. Louis, Missouri For more information: www.accccancer.org/ossn_network/MO/ MOevents.asp

seasonal affective disorder pumpkin festival lifts my mood

Haiku and illustration by Jyothirmai Gubili

Jyothirmai Gubili is an editor with the Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center in New York.

Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro

Society for Immunotherapy of Cancer (SITC) 28th Annual Meeting November 8-10 • National Harbor, Maryland For more information: www. sitcancer.org/2013 New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences Florida Society of Clinical Oncology Fall Session November 9-10 • Jacksonville, Florida For more information: www.flasco.org Rocky Mountain Oncology Society Educational Symposium November 14 • Greenwood Village, Colorado For more information: www.rmos-colorado.com Academy of Oncology Nurse Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference Iowa Oncology Society Fall Membership Conference November 15 • West Des Moines, Iowa For more information: www.ios-iowa.com Oregon Society of Medical Oncology Fall 2013 Oncology Conference November 15 • West Des Moines, Iowa For more information: www.osmo.org Hawaii Society of Clinical Oncology Fall Membership Conference November 16 • Honolulu, Hawaii For more information: www.hsco-hawaii.com 1st Indian Cancer Congress 2013 November 21-24 • Delhi, India For more information: www.indiancancercongress2013. org

ASCOPost.com | NOVEMBER 1, 2013

PAGE 93

2013-2014 Oncology Meetings African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December Sixth AACR International Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved December 6-9 • Atlanta, Georgia For more information: www.aacr.org 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org

Third International Gastrointestinal Cancers Conference December 13-15 • Antalya, Turkey For more information: www.igicc2013.org

European Society for Medical Oncology Sarcoma and GIST 2014 February 18-19 • Milan, Italy For more information: www.esmo.org

ELCC 2014 European Lung Cancer Conference March 26-29 • Genèva, Switzerland For more information: www.esmo.org/ Conferences/ELCC-2014-Lung-Cancer

January 2014

Multidisciplinary Head and Neck Cancer Symposium February 20-22 • Scottsdale, Arizona For more information: www.headandnecksymposium.org

ACCC 40th Annual National Meeting March 31-April 2 • Arlington, Virginia For more information: www.accccancer.org/meetings/AM2014.asp

AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer January 6-9 • San Diego, California For more information: www.aacr.org 2014 Gastrointestinal Cancers Symposium January 16-18 • San Francisco, California For more information: www.gicasym.org 10th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 18 • Orlando, Florida For more information: www.flasco.org/events?eventId=7103 10&EventViewMode=EventDetails JADPRO Live January 24-26 • St. Petersburg, Florida For more information: www.advancedpractitioner.com/ jadprolive

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org Current Controversies in the Multi-Disciplinary Management of Locally Advanced Non Small Cell Lung Cancer December 12-13 • St. Louis, Missouri For more information: https://cme. wustl.edu/lungcancer/

2013-2014

Clinical and Multidisciplinary Hematology and Oncology 2014: The 11th Annual Review January 24-26 • Scottsdale, Arizona For more information: www.mayo. edu/cme/internal-medicine-andsubspecialties-2014s431

February APOS 11th Annual Conference February 13-15 • Tampa, Florida For more information: www.apossociety.org/apos2014/

March 31st Annual Miami Breast Cancer Conference® March 6-9 • Miami Beach, Florida For more information: www. gotoper.com/conferences/mbcc/ meetings/31st-Annual-Miami-BreastCancer-Conference Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer Center March 7-10 • New York, New York For more information: www.mskcc. org/hemoncreviewcourse NCCN 19th Annual Conference: Advancing the Standard of Cancer Care™ March 13–15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp 7th Annual Interdisciplinary Prostate Cancer Congress™ March 15 • New York, New York For more information: www.gotoper.com/conferences/ ipcc/meetings/7th-AnnualInterdisciplinary-Prostate-CancerCongress

JANUARY 24–26, 2014

Renaissance Vinoy St. Petersburg • St. Petersburg, FL

Chair: Pamela Hallquist Viale • Co-Chairs: Sandra E. Kurtin and Wendy H. Vogel

advancedpractitioner.com/jadprolive

April ESTRO 33 April 4-8 • Vienna, Austria For more information: www.estro. org/congresses-meetings/items/ estro-33 American Association for Cancer Research Annual Meeting April 5-9 • San Diego, California For more information: www.aacr.org 15th Annual Meeting of the American Society of Breast Surgeons April 30-May 4 • Las Vegas, Nevada For more information: www. breastsurgeons.org/index.php

May Oncology Nursing Society 39th Annual Congress May 1-4 • Anaheim, California For more information: www.ons.org ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http:// am.asco.org

EARN UP TO

11CE

CREDITS/ CONTACT HOURS For nurses, physician assistants, and pharmacists

NP FOR YO s AND UR PA s

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

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

100%

Patients, %

80%

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

60% 40% 20% 0%

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

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

ORR 29.2% (n=33)

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

POMALYST + low-dose dex (N=113)

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

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

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

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

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

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

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

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

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

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

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious

adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported

Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

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

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

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

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

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

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

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

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

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

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

The ASCO Post | NOVEMBER 1, 2013

PAGE 98

Awards

Association of Community Cancer Centers’ 2013 Innovator Award Recipients Announced

en cancer programs that have developed pioneering solutions to address the challenges of treating cancer patients have received the Association of Community Cancer Centers’ (ACCC)

2013 Innovator Awards. Established in 2011, ACCC’s Innovator Awards are sponsored by GE Healthcare. The award recipients presented the details and outcomes of their programs at the ACCC

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

National Oncology Conference held recently in Boston. “Both ACCC and GE Healthcare are proud to honor programs that are enhancing community cancer care

Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

through progressive, patient-focused tools and strategies,” said Virginia T. Vaitones, MSW, OSW-C, ACCC President and oncology social worker at Pen Bay Medical Center in Rockport,

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

ASCOPost.com | NOVEMBER 1, 2013

PAGE 99

Awards

Maine. “They will provide inspiration and spark new innovations for all of us working in cancer care.”

Innovator Award Recipients

Virginia T. Vaitones, MSW, OSW-C

• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

Avera McKennan Hospital and University Health Center, Avera Cancer Institute, Sioux Falls, South Dakota. Rural chemotherapy. Avera Can-

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

cer Institute created a process to unify chemotherapy administration standards across 45 sites. Within 9 months of launching the initiative, compliance across all sites that administer chemotherapy was achieved. Baton Rouge General Medical Center, Pennington Cancer Center, Baton Rouge, Louisiana. Disaster

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

charts provide informational security net for patients. Taking lessons learned from Hurricane Katrina, the radiation oncology treatment team at Pennington Cancer Center, located just outside of New Orleans, developed an emergency chart system—a portable electronic medical record that provides patients continued on page 100

The ASCO Post | NOVEMBER 1, 2013

PAGE 100

Awards

ACCC Innovator Awards with their “must-have” documents in a universal format. The George Washington University, GW Cancer Institute, Washington, DC. Catalyzing patient-centered care to exceed new accreditation standards. This innovator has developed a program

that helps patients navigate their cancer treatment. Lay navigators work with a social worker and nurse navigators to guide patients from screening through treatment and into survivorship care. Gibbs Cancer Center & Research Institute, Spartanburg, South Carolina. Integration of palliative care into a medical oncology practice. This quality

8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

continued from page 99

improvement initiative integrated a halfday supportive care clinic into the medical oncology practice, expanding palliative care services beyond the inpatient setting. Methodist Healthcare System, Methodist Cancer Center, San Antonio, Texas. Emergent care for oncology patients via the VIP (very immunocompromised patient) program. The VIP

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

Program quickly evaluates and treats oncology patients in the emergency department. A VIP Kit educates patients on when to report to the emergency department and improves coordination of care with community-based physicians. St. Luke’s Mountain States Tumor Institute (MSTI), Boise, Idaho. Improving oncology genetic counseling. MSTI addressed two barriers to genetic counseling, access to qualified genetic specialists and patient identification, through a two-pronged approach—telehealth and weekly chart review. The result is improved convenience and access, cost savings, and improved quality. Temple University Hospital, Temple Cancer Program, Philadelphia. Creating transparency with an electronic dosimetry whiteboard. An electronic dosimetry “whiteboard” that centrally displays the status of every case increased transparency and communication and identified potential bottlenecks, allowing the staff to make process changes. The whiteboard led to improved patient satisfaction and employee morale. Texas Health Harris Methodist Hospital, Fort Worth, Klabzuba Cancer Center, Fort Worth, Texas. Community/corporate collaborations for mobile health outreach. Klabzuba Cancer Center adapted their mobile mammography clinics to provide additional services including cancer, cardiovascular, and bone density screenings, pelvic and clinical breast examinations, and patient education. The mobile units remove barriers to care access. University of Texas Southwestern Medical Center, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas. CancerGene Connect—Creating a virtual genetic counseling environment. University of Texas Simmons Cancer Center has developed CancerGene Connect, a patient-driven online genetic risk assessment program. Using CancerGene Connect cuts evaluation and documentation time in half and expands the program without increasing staff or compromising patient care. Winship Cancer Institute, Emory University, Atlanta. Implementation of a community-based program for cancer survivors and caregivers. Winship Cancer Institute implemented the community-based “Winship at the Y” program in collaboration with the YMCA of Metro Atlanta’s The Coach Approach©. In the first 9 months of the program, almost 100 survivors and caregivers were referred for enrollment. For further details, visit www.accccancer.org/innovator. n

ASCOPost.com | NOVEMBER 1, 2013

PAGE 101

In the News Breast Cancer

Better Risk Communication Strategies Needed to Ensure Decision to Have Contralateral Prophylactic Mastectomy Is Evidence-Based By Charlotte Bath

verestimating the risk that cancer in one breast will affect the other breast may cause many young women with breast cancer to choose contralateral prophylactic mastectomy even though most know it does not clearly improve survival. In a survey of 123 women who were diagnosed with cancer in one breast and chose to have a bilateral mastectomy, only 18% responded that women with breast cancer who undergo contralateral prophylactic mastectomy live longer, but when rating factors that were extremely or very important factors in their own decision to have contralateral prophylactic mastectomy, 98% indicated a desire to reduce their risk of contralateral breast cancer and 94% a desire to improve survival. Peace of mind was also considered extremely or very important by 95% of women responding. The survey results were published in the Annals of Internal Medicine1 and reported by

It is interesting that at a time when we are seeing fewer second cancers because of the use of adjuvant hormonal therapy and when radiation is very effective after a lumpectomy in preventing a recurrence in the initial breast, that this is the time when we are now seeing this uptick in bilateral mastectomies. —Eric P. Winer, MD

major news and medical media. “By raising awareness of the extent to which people seem to misperceive their risks, these data may to some degree affect clinical practice,” study coauthor Eric P. Winer, MD, said in an interview with The ASCO Post. “If doctors are aware of this, they can proactively address it.” Dr. Winer is Chief of

Expect Questions About Contralateral Prophylactic Mastectomy: Carefully Review Risks and Alternatives

hysicians were considered the most important source of information about contralateral prophylactic mastectomy in a survey of 123 women who were diagnosed with cancer in one breast and chose to have the contralateral procedure. While 80% of the women reported that they spoke with their physicians to at least some extent about the reasons for having contralateral prophylactic mastectomy, only 51% reported that their physicians discussed the reasons not to have the surgery. The survey also found that many women overestimate their risk for cancer in the unaffected breast.

Risk Perception “Knowing that there is this tendency for people to misperceive risk, I think it becomes that much more important for physicians to very carefully go over the risks and problems associated with additional surgery and carefully go through the potential benefits,” Eric P. Winer, MD, told The ASCO Post in an interview discussing the survey results. Dr. Winer is coauthor of an article in the Annals of Internal Medicine detailing the survey results. He is also Chief of the Division of Women’s Cancers and Director of the Breast Oncology Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School in Boston. He pointed out that that most of those surveyed said they were satisfied with their decisions and that 90% reported they would definitely choose contralateral prophylactic mastectomy if they had to make the choice again. “So it is not as if they are making these decisions and then most of them were regretting it. But we want to make sure that people are making informed decisions,” Dr. Winer stressed. “Even if it is just a few patients out of 100 who might choose something differently, we want to give them the opportunity to do so by understanding what they are really facing.” n

the Division of Women’s Cancers and Director of the Breast Oncology Center at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School in Boston. Proactively addressing the issue could include fully explaining to patients and families the low risks of developing contralateral breast cancer in most women (those without BRCA1 or BRCA2 mutations), as well as the risks and possible adverse effects of additional surgery and breast reconstruction.

Misperception of Risk The survey results indicate that women who are not at increased risk for contralateral breast cancer because of genetic mutations overestimate the actual risk, “estimating that a median of 10 women out of 100 would develop contralateral breast cancer without contralateral prophylactic mastectomy within 5 years, which exceeds the actual risk of approximately 2% to 4% over 5 years,” the study authors reported. Women with mutations of BRCA1 (18% of patients surveyed) or BRCA2 (7%) more accurately perceived their risk for contralateral breast cancer, estimating that a median of 20 women out of 100 would develop contralateral breast cancer without contralateral prophylactic mastectomy within 5 years. A recent study cited by the authors found a 10-year cumulative risk of 24% to 31% among young women with a family history of breast cancer and a BRCA1 or BRCA2 mutation.2 Dr. Winer said that the more accurate perceived risk among the gene

mutation carriers could be attributed to “the benefits of meeting with a genetic counselor, because most of them do. Maybe it is the benefit of having a little more information out there, and by ‘out there’ I mean both on the Internet and from friends and family about the real risks that they face.”

Competing Risk The greatest risk for young women with breast cancer is from systemic recurrence and death from their initial breast cancer, and contralateral prophylactic mastectomy is not likely to alter this competing risk. The misperception among many women about breast cancer risk “points to a need for better risk communication strategies in an effort to ensure that treatment decision-making is truly evidencebased while remaining patient-centered,” the study authors concluded. For a woman with a known BRCA1 or BRCA2 mutation, “particularly if it is someone who has a low risk of dying from her initial breast cancer, having the other breast removed is an entirely rational thing to do,” Dr. Winer said. “The conversation that is hard is when someone has a very high-risk initial cancer and you are dealing with the fact that there is a huge competing risk that the woman will unfortunately have a recurrence and ultimately die from her first cancer, making anything you do on the other side much less relevant. That is a hard conversation and it is one that people have a hard time understanding at times,” he noted. “The way I usually explain it is, the main event at the moment is the cancer you have. Let us get through this,” Dr. Winer continued. “Let’s see how you do over the next several years, and then we will, if necessary, address your concerns about your other breast.”

Overall Satisfaction High The women completing the survey were diagnosed with breast cancer at age 40 or younger and were participants in an ongoing prospective cohort study to explore biologic, medical, and quality-of-life issues specific to young women. They received surveys continued on page 102

The ASCO Post | NOVEMBER 1, 2013

PAGE 102

In the News

Contralateral Prophylactic Mastectomy continued from page 101

twice a year for the first 3 years after diagnosis and then annually for an additional 7 years. Women who reported a bilateral mastectomy on any survey within 1 year after diagnosis received the supplementary contralateral pro-

phylactic mastectomy questionnaire with 23 items related to decision-making, knowledge, risk perceptions, and worry about breast cancer. “Overall satisfaction with the decision was high: 80% of women were extremely confident in their decision to have [contralateral prophylactic mastectomy], and 90% of respon-

dents would have definitely chosen [contralateral prophylactic mastectomy] if deciding again,” according to the study report.

Some Outcomes Worse Than Expected Despite the high overall rate of satisfaction with contralateral prophy-

Partner with ASCO to provide dynamic educational courses and resources to your Oncology Fellows!

lactic mastectomy, several outcomes were worse than expected. These included a higher number of surgeries or procedures than expected, reported by 33% of those responding. In addition, 28% reported that numbness or tingling in the chest was worse than expected, 42% reported that their sense of sexuality was worse than they expected after surgery, and 31% reported being more self-conscious about their appearance than expected. Problems such as numbness and tingling, “to a large extent are things people have to live with. A lot of that is a result of axillary surgery rather than breast surgery,” Dr. Winer said. “I think it is really difficult to know whether the problems people cite related to sexuality are attributable to having had bilateral mastectomies. We wouldn’t for a second say that this is causal,” he added.

Appearance Issues

ASCO’s Education Essentials for Oncology Fellows (EEOF) A unique package of ASCO content has been designed and priced specially for Oncology Training Programs.

Basic Package

Premium Package

Provides access to all ASCO Virtual Meetings, eLearning courses, ASCO Flashcards™ (excludes ASCO-SEP), and the Achieving Career Success eBook

Includes all content in the Basic Package plus all ASCO-SEP, 3rd Edition resources (print book/eBook, Online Question Bank, and ASCO Flashcards™

Access is offered to your Fellows on a yearly basis, July 1st through July 31st of the following year.

Learn More university.asco.org/EEOF

“I generally tell patients that when you choose to have reconstruction, it is like adding another medical problem to your list of medical problems, because you either are moving some piece of your body where is wasn’t intended to be, or you are going to have an implant. And while implants are safe, we know that they can at times need to be replaced. Particularly in women who are going to need postmastectomy radiation, which is done quite frequently when patients have positive lymph nodes, the implant can lead to fibrosis and the cosmetic appearance is not necessarily going to be particularly good,” Dr. Winer explained. Even for women considering a single mastectomy in the breast with cancer, “if a woman can have a lumpectomy, and I know that even if she has a mastectomy, she is going to wind up getting radiation or there is a high chance of it, I try to talk her out of having a mastectomy,” Dr. Winer said, because of the effect of the radiation on the appearance of the reconstructed breast. “Another procedure that is done with a fair amount of frequency these days,” Dr. Winer said, “and that should be fully explained to those considering it, is a nipple-sparing mastectomy. The entire breast is removed except for the nipple, the areola complex, with the idea is that it looks a little bit more natural,” Dr. Winer commented. continued on page 103

ASCOPost.com | NOVEMBER 1, 2013

PAGE 103

Letters to the Editor Dermatologic Oncology

Intralesional Cytokine Therapy in Cutaneous Melanoma: A Call for Clinical Trials

utaneous melanomas are mostly an immunogenic group of tumors, but they are also heterogeneous. Therefore, therapeutic specificity and autogenetic approaches are essential to secure beneficial results. The objective of sentinel lymph node biopsy, at the time of diagnosis, is to identify patients with early regional lymph node metastases to initiate early adjuvant therapy after lymphadenectomy. At the present time, surgical excision of the primary site with or without regional lymph node dissection followed by systemic administration of allogeneic material did not result in major survival benefits. Postoperative systemic adjuvant therapy has resulted in some benefit, but the fact remains that over 60% of patients develop recurrences and metastases and over 50% die of their disease in the first 5 years.

Variety of Approaches Patients with dermal and subdermal metastases offer an excellent opportunity to evaluate the effects of intralesional therapy in cutaneous melanoma. Historically, several approaches had been utilized in the management of in-transit metastases with limited success. These included repeated local excisions, hyperthermic isolated limb perfusion with melphalan with or without tumor

Contralateral Prophylactic Mastectomy continued from page 102

“But it is an insensate nipple. And it doesn’t always stay looking quite the same way once you remove all the breast tissue” and the nipple is on the reconstructed breast.

‘Bit of a Disconnect’ “There is a little bit of a disconnect in the responses to the survey in that the majority of people recognized that having a contralateral prophylactic mastectomy would not improve their survival, and yet still over 90% of the people cited improvement in survival as a reason for doing this,” Dr. Winer acknowledged. “This discordance suggests some degree of cognitive dissonance,” Dr. Winer and coauthors wrote in the

necrosis factor, limb infusion with a variety of agents, laser therapy, intralesional injection of various chemotherapeutic and biologic agents, gene therapy, and as a final resort, radiation therapy and systemic therapy. In addition, intralesional therapy with either of two cytokines— namely, granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine)1 and interleukin-2 (IL-2, Proleukin)2—each gave promising results, but they were never used sequentially or in combination. Intralesional therapy with GM-CSF can increase the number and activation of dendritic cells,3 which are very efficient antigen-presenting cells that are capable of processing tumor antigens and crosstalk to lymphocytes. On the other hand, IL-2 administration can stimulate and activate tumor-infiltrating lymphocytes, which can result in the induction of cytotoxic T cells. Therefore, we felt that sequential intralesional administration of intralesional GM-CSF followed by IL-2 might complement one another, using the patient’s own tumor as a source for tumor antigens. In an exploratory study in patients with dermal and subdermal metastatic melanoma,

we explored the use of intra lesional therapy with low-dose GMCSF (500 µg once weekly). In case of failure to obtain a complete response in 4 to 6 weeks, IL-2 was substituted (18 million IU/wk).4 The results revealed that such intralesional therapy was well tolerated without major side effects. Complete responses were obtained in patients with small lesions ranging in size from a few mm up to 1 cm regardless of whether these were primary, satellite, or in-transit metastases. However, none of the large sclerotic lesions responded to intralesional therapy with either cytokine. The complete responses were noted clinically and confirmed pathologically by rebiopsy of some of the injected sites at 6 to 8 weeks after cessation of the therapy, and showed absence of tumor cells and no mononuclear cell infiltrates. Of note, two patients in whom prior treatment failed (relatively high doses of systemic adjuvant therapy with GM-CSF at 125 µg/m2/d for 14 consecutive days followed by IL-2 at 9 million IU/m2/d for 4 days, repeated every 28 days for 2 years) had a complete response to intralesional therapy—one to GM-CSF and the other to IL-2 after failure of GM-CSF therapy. This suggested that intralesional therapy could be

more effective than systemic administration of the same cytokines. The overall survival of the responders varied from 31 to 48 months to date. When both cytokines were administered preoperatively in the primary melanoma, 1 week before surgery, the resected tissues gave us a chance to evaluate the early effects of intralesional therapy. The pathology examination of the resected tissues showed complete tumor necrosis with massive pigmented histiocytes at the primary and the satellite. At the same time, the histiocytes were also noted in the regional lymph nodes. Immunohistochemical studies showed overexpression of various immune cells at the injection sites and the lymph nodes. This approach is supported by a recent report showing that the number of tumor-infiltrating lymphocytes in the primary melanoma is an independent predictor of sentinel lymph node status and patient survival.5 Whether the activation of these cells at the tumor sites could be established by IL-2 alone remains unclear; in theory, it may require the presence of antigenpresenting cells to process the tumor antigens. Intralesional therapy can induce in vivo tumor-specific autoimmunity, regardless of tumor anti-

study report. “Most women acknowledge that [contralateral prophylactic mastectomy] does not improve survival, but anxiety and fear of recurrence probably influence women during the decision-making process, leading them to identify their desire to extend life and prevent metastatic disease as among the most important reasons for having [contralateral prophylactic mastectomy],” they said. “The apparent discordance between patient perceptions and realistic expectations provides a teachable opportunity for physicians treating newly diagnosed patients with breast cancer,” Pamela R. Portschy, MD, and Todd M. Tuttle, MD, MS, of the University of Minnesota, Minneapolis, wrote in an accompanying editiorial.3 They also called on physicians to communicate the actual risk for con-

tralateral breast cancer and the complications and alternatives to contralateral prophylactic mastectomy. “With improved patient education, perhaps the [contralateral prophylactic mastectomy] trends in the United States will plateau or be reversed,” they wrote. According to the study report, contralateral prophylactic mastectomy rates “have increased dramatically among women treated for early-stage breast cancer in the United States,” from 4% to 6% in the late 1990s to between 11% and 25%. “It is interesting,” Dr. Winer said, “that at a time when we are seeing fewer second cancers because of the use of adjuvant hormonal therapy and when radiation is very effective after a lumpectomy in preventing a recurrence in the initial breast, that this is

the time when we are now seeing this uptick in bilateral mastectomies.” n

Exploratory Study

continued on page 104

References 1. Rosenberg SM, Tracy MS, Meyer ME, et al: Perceptions, knowledge, and satisfaction with contralateral prophylactic mastectomy among young women with breast cancer. Ann Intern Med 159:373381, 2013. 2. Reiner AS, John EM, Brooks JD, et al: Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: A report from the Women’s Environmental Cancer and Radiation Epidemiology Study. J Clin Oncol 31:433439, 2013. 3. Portschy PR, Tuttle TM: Contralateral prophylactic mastectomy: Perceptions versus reality. Ann Intern Med 159:428429, 2013.

The ASCO Post | NOVEMBER 1, 2013

PAGE 104

Letters to the Editor

Intralesional Cytokine Therapy continued from page 103

genic and genetic profiles, and can overcome tumor heterogeneity.

Conclusions Intralesional therapy is less expensive and more effective than other approaches to cutaneous melanoma. These observations open up new possibilities for clinical trials. The strategy could be used to standardize the management of in-transit metastases and to initiate new approaches to adjuvant therapy in highrisk melanoma patients. n —E. George Elias, MD, PhD University of Maryland at St. Joseph Medical Center Baltimore, Maryland

Disclosure: Dr. Elias reported potential conflicts of interest.

References 1. Vaquerano JE, Cadbury P, Treseler P, et al: Regression of in-transit melanoma of the scalp with intralesional recom-

binant human granulocyte-macrophage colony-stimulating factor. Arch Dermatol 135:1276-1277, 1999. 2. Weide B, Derhovanessian E, Pflugfelder A, et al: High response rate after intratumoral treatment with interleukin-2: Results from a phase 2 study of 51 patients with metastasized melanoma. Cancer 116:4139-4146, 2010.

3. Nasi ML, Lieberman P, Busam KJ, et al: Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic melanoma recruits dendritic cells. Cytokines Cell Mol Ther 5:139-144, 1999. 4. Elias EG, Sharma BK: Targeting melanoma sites in vivo can induce com-

plete tumor ablation and prolong patient survival: An exploratory study. J Cancer Sci Ther 5:244-248, 2013. 5. Azimi F, Scolyer RA, Rumcheva P, et al: Tumor infiltrating lymphocytes grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30:2678-2683, 2012.

What if you could help the immune system respond to cancer cells? PD-L1 expression helps tumor cells evade the immune system programmed death-ligand 1 (PD-L1), which binds to the PD-1 and B7.1 receptors on Tumor expression of

The ASCO Post

T cells, deactivates T-cell–mediated cytotoxicity. This inhibits the immune

Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

system and allows the tumor to continue to grow.1 Nearly all cancer types show increased expression of PD-L1.2

PD-1

Inactivated T cell

PD-L1 TCR

B7.1

MHC

Tumor cell

PD-L1 Write to The ASCO Post at editor@ASCOPost.com. Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307-314. 3. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol. 2012;13:1129-1132.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 105

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Calcium Channel Blockers Linked to Increased Risk of Lobular/Ductal Breast Cancer

Women who are currently using calcium channel blockers and have been doing so for 10 or more years are at increased risk of the two most common histologic types of breast cancer, invasive ductal carcinoma and invasive

lobular carcinoma, according to a population-based case control study. “While some studies have suggested a positive association between [calcium channel blocker] use and breast cancer risk, this is the first study to observe that

Blocking PD-L1 may restore the body’s adaptive immune response Genentech is investigating the strategy of inhibiting the interaction between tumor-expressed PD-L1 and its receptors on T cells; blocking this interaction may restore the body’s adaptive immune system to respond to cancer cells.1 Research is also under way to validate PD-L1 as a potential biomarker for cancer immunotherapy.3

Activated T cell

B7.1

TCR

MHC

Tumor cell death

PD-1

Explore the role of cancer immunotherapy and PD-L1 inhibition at ResearchCancerImmunotherapy.com

long-term current use of [calcium channel blockers] in particular [is] associated with breast cancer risk,” the authors wrote in JAMA Internal Medicine.

Major Findings “Overall, current, former, and shortterm use of antihypertensive were not associated with risk of either [invasive ductal carcinoma] or [invasive lobular carcinoma],” reported Christopher I. Li, MD, PhD, and colleagues from Fred Hutchinson Cancer Center in Seattle. “In examining duration effects for current users, we found an increased risk only in relation to use of [calcium channel blockers] for 10 years or longer.” An increased risk was observed for both invasive ductal carcinoma (odds ratio [OR] = 2.4, 95% confidence interval [CI] = 1.2–4.9; P = .04 for trend) and [invasive lobular carcinoma] (OR = 2.6, 95% CI = 1.3–5.3; P = .01 for trend). The relationship did not vary appreciably according to estrogen-receptor status or type of calcium channel blocker (shortacting vs long-acting, dihydropyridines vs nondihydropyridines). The women participating in the study were aged 55 to 74 years and included 880 diagnosed with invasive ductal carcinoma, 1,027 diagnosed with invasive lobular carcinoma, and 856 controls. The women with breast cancer were “somewhat more likely to have a first-degree family history of breast cancer, to be current alcohol users, and to be current smokers,” the researchers noted The study found “some indication” that the current use of angiotensin converting enzyme inhibitors for 10 years or longer was associated with reduced risks of invasive ductal carcinoma and invasive lobular carcinoma. Since the authors could cite no other studies reporting this relationship, and the risk estimate for invasive ductal carcinoma “was within the limits of chance,” they advised that the finding “needs to be interpreted cautiously.” Diuretics, beta-blockers, and angiotensin II antagonists were not associated with risk. The investigators called for further research to confirm the association between breast cancer and calcium channel blockers. They stated that quantification of the potential relationships between antihypertensive agents and breast cancer risk may aid clinical decision-making about selection of antihypertensive agents. continued on page 106

The ASCO Post | NOVEMBER 1, 2013

PAGE 106

In the Literature

Emerging Clinical Data continued from page 105

‘First-Rate Study’

In an accompanying editorial, atricia F. Coogan, ScD, of the Slone P Epidemiology Center at Boston University, stated, “the data make a convincing case that the hypothesis that long-term [calcium channel blocker] use increases the risk of breast cancer is worthy of being pursued. The data are persuasive because this was a first-rate study.” If the two- to threefold increase in breast cancer among long-term calcium channel blocker users is confirmed, longterm use of these agents “would take its place as one of the major modifiable risk factors for breast cancer,” she added. Postmonitoring surveillance of medications vis observational studies “is a crucial public health function and should now be applied to the question of longterm [calcium channel blocker] use and breast cancer risk,” she concluded. Li CI, et al: JAMA Intern Med 173:1629-1637, 2013. Coogan PF: JAMA Intern Med 173:1637-1638, 2013.

LEUKEMIA Front-Line Treatment Strategies to Achieve LongTerm Control of CLL Combined With Optimal Quality of Life “The management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine [Treanda], and the monoclonal

antibodies alemtuzumab [Campath], rituximab [Rituxan], and ofatumumab [Arzerra]), and many more drugs are in advanced clinical development to be approved for the treatment of CLL,” Michael Hallek, MD, of the Center for Integrated Oncology, University of Cologne, Germany, wrote in Blood. “In addition, the extreme heterogeneity of the clinical course as well as our improved ability for foreseeing the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, and a very aggressive course with high-risk leukemia,” Dr. Hallek commented. “On this background it becomes increasingly challenging to select the right treatment strategy for each condition.”

Three Options Dr. Hallek outlined three options using current treatment modalities to achieve long-term control of CLL with optimal quality of life: 1. Combine three, four, or more of the best agents in a simultaneous short-term treatment (up to 6 months) aimed at achieving minimal residual disease complete remissions lasting longer than the remissions achieved so far. For example, such an approach could combine the best currently available chemotherapies with antibodies and with kinase inhibitors or Bcl-2 antagonists, Dr. Hallek suggested. He cautioned, however, that these combinations would need to be compared against the current standard, rituximab plus fludarabine/cyclophosphamide

(FCR), and results would not be available for a few years. “Moreover, such a treatment strategy will not be without toxicity and therefore be tolerated only by patients with good physical fitness.” 2. Use sequential monotherapies of new or old agents, giving each agent until maximal response was achieved. “After a long-lasting response, treatment could be repeated with the same agent, whereas alternative agents would be used in case of short remissions,” Dr. Hallek wrote. “This strategy might be applied in elderly or non-fit patients (‘slow go’), where the goal of treatment is symptom control rather than disease control.” 3. Combine the best agents “in a sequence that tailors the treatment according to the initial tumor load and the response to therapy,” Dr. Hallek suggested. “The goal of this strategy would be “to prevent the outgrowth of adverse leukemic subclones and to minimize the use of chemotherapy, thereby reducing the risk for secondary mutations of the CLL clone(s) and for secondary malignancies that are frequent and prognostically unfavorable events in CLL. For this treatment approach, I propose the term ‘sequential TTT (triple T)’ (tailored, targeted, total eradication of MRD),” Dr. Hallek stated. All currently available options would be used in a nonaggressive, nontoxic manner, with an aim of completely eliminating or controlling the malignant clone. The triple T therapy, according to Dr. Hallek, would be available for fit and unfit patients because of its limited toxicity and could be given in an outpatient setting. Using current treatment options in a tailored and response-adjusted manner could also save money and resources, he noted. The proposed sequenced strategy, which still needs to be validated by clinical research, might consist of debulking, induction, and then maintenance. Hallek M: Blood. September 24, 2013 (early release online).

PALLIATIVE RADIOTHERAPY Inequality in Delivery of Palliative Radiotherapy Among Black Patients With Cancer and Elderly With Comorbidities

An analysis of data from more than 51,000 patients with stage IV cancer shows “significant inequality” in the delivery of palliative radiotherapy among the elderly, patients with comorbidity, and black patients with

prostate and colorectal cancer, reported James D. Murphy, MD, MS, and colleagues from Stanford University School of Medicine and the University of California, in the Journal of Oncology Practice. The Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database was used to identify patients with the four most commonly diagnosed cancers in the United States: breast, prostate, non–small cell lung, and colorectal cancers. The patients were diagnosed between 2000 and 2007 and observed through 2009. Among the 51,610 patients identified, 21,279 (41%) received palliative radiotherapy; 54% of patients with lung cancer, 42% of patients with breast cancer, 40% of patients with prostate cancer, and 12% of patients with colorectal cancers. “Across all disease sites, multivariate analysis showed that older patients (P < .001) and those with high comorbidity scores (P < .001) were less likely to receive palliative [radiotherapy],” the investigators found. Older persons also had slightly shorter courses of radiation, an average of 1.3 days shorter for every 10 years older (P < .001). “Black patients with prostate cancer were 20% less likely (P < .001), and black patients with colorectal cancer were 28% less likely (P < .001), than white patients to receive palliative [radiotherapy],” the researchers reported. No significant differences between black and white patients were noted for breast or lung cancer. There were higher rates of palliative radiotherapy for lung, breast, and prostate cancer in higher socioeconomic classes and among people who were married. “The use of palliative [radiotherapy] decreased slightly over time for lung cancer and remained relatively stable for breast, prostate, and colorectal cancers,” the investigators reported. The authors also observed that a significant proportion of patients received radiotherapy shortly before death. “Specifically, 23% of patients with lung cancer died within 2 weeks of completing palliative [radiotherapy], followed by those with colorectal (12%), breast (12%), and prostate cancers (8%).” Other significant predictors (P < .05) of death within 2 weeks of radiotherapy included increased age, increased comorbidity, and male sex. n Murphy JD, et al: J Oncol Pract 9:e220-e227, 2013.

ASCOPost.com | NOVEMBER 1, 2013

PAGE 107

Perspective

Sequestration

not only has our government reduced research today, it may have destroyed our best opportunity for a better future for our loved ones, our future generations, and ourselves. Furthermore, once money has been

continued from page 1

Budget Control Act of 2011. (Table 1 below shows early estimates of the cuts involved; Congress has since made modest changes to reduce the sequester, but the bigger outlook still holds.)

$8 billion in 2023 without the sequestration and then would get a 10% increase (or $800 million) starting that year, after the insult of sequestration it would get a $600 million increase that year because it will

We all have a personal stake in this. Certainly, all physicians (and especially oncologists) understand the need to keep the research pipeline going so that we may have newer and better medications with which to treat our patients.

Act of Violence Across-the-board cutting of budgets for the National Institutes of Health (NIH), National Science Foundation, Centers for Disease Control and Prevention, Food and Drug Administration, and so many others constitutes the single greatest act of violence against present and future generations that a U.S. Congress has ever committed. Essentially, the cleaver against research is a weapon of mass destruction. How many lives will be lost or debilitated by disease with the wanton act of not using a surgical blade to cut rather than a cleaver? Indiscriminant cutting is an act of legislative malpractice. Not only are critical projects left to lie fallow, but young scientists who might have the secrets of tomorrow’s cures are discouraged, rejected, or simply driven to leave basic and clinical research. Thus,

—Richard J. Boxer, MD, FACS

removed from the flow toward improved health, the money will never be replaced at the same level. If there is a reduction of $2 billion for 10 years, there will never be a quick infusion of $20 billion. Once the money spigot gets restarted, it will increase slowly at a percentage of the budget of the previous year. If the National Cancer Institute (NCI) would have had a budget of

have had its budget cut to $6 billion. Thus, the pain and destructive force of sequestration is prolonged well into the future. Moreover, these $1.7 billion cuts are not being imposed on medical research that has been on a runaway path of consumption. These cuts come after a decade of nearly a 20% decline in real dollars after inflation has been taken into account.

Table 1: Estimated R&D Cuts Under Balanced Sequestration, FY 2013–2017 (budget authority in millions of constant 2012 dollars) 2013

2014

2015

2016

2017

Total Cut

5-yr Percent

Department of Defense

–6,928

–6,818

–6,696

–6,585

–6,495

–3,3524

–9.1%

HHS

–2,528

–2,429

–2,333

–2,241

–2,155

–11,685

–7.6%

NIH

–2,439

–2,343

–2,251

–2,162

–2,079

–11,274

–7.6%

Department of Energy

–972

–944

–916

–889

–865

–4,585

–8.2%

National Science Foundation

–456

–438

–421

–404

–388

–2,106

–7.6%

NASA

–763

–733

–704

–676

–650

–3,527

–7.6%

Department of Agriculture

–189

–182

–175

–168

–161

–875

–7.6%

Department of Commerce

–103

–98

–95

–91

–87

–474

–7.6%

Department of the Interior

–65

–62

–60

–57

–55

–299

–7.6%

Environemntal Protection Agency

–46

–44

–43

–41

–39

–213

–7.6%

Homeland Security

–50

–48

–46

–44

–43

–232

–7.6%

Total R&D Cut

–12,099

–11,796

–11,488

–11,196

–10,939

–57,519

–8.4%

Source: AAAS estimates of R&D, based on Congressional Budget Office and Office of Management and Budget (OMB) analyses of the Budget Control Act. Constant dollar conversions based on OMB’s gross domestic product deflators from the fiscal year 2013 budget. HHS = Department of Health and Human Services; NASA = National Aeronautics and Space Administration; NIH = National Institutes of Health; R&D = research and development. Reprinted, with permission, from the American Association for the Advancement of Science (AAAS) R&D Budget and Policy Program. Available at www. aaas.org/spp/rd/fy2013/SeqSum.pdf.

Significant Consequences Allow me to list just a few of the ramifications of our government’s actions (or inactions). Compared to 2012, beginning in 2013 and continuing as far as the eye can see: ■■ The NCI will receive $30 million less annually. ■■ Approximately 700 fewer competitive research project grants will be awarded annually by the NIH. ■■ Approximately 750 (~5%) fewer new patients will be admitted annually to the NIH Clinical Center. NIH drives job creation and economic growth. NIH research funding directly supports hundreds of thousands of American jobs and serves as a foundation for the medical innovation sector, which employs 1 million U.S. citizens. Cuts to NIH funding will have an economic impact in communities throughout the United States. For every six applications submitted to the NIH, only one will be funded.

Personal Stake We all have a personal stake in this. Certainly, all physicians (and especially oncologists) understand the need to keep the research pipeline going so that we may have newer and better medications with which to treat our patients. All of us have experienced a personal or loved one’s benefit from clinical or basic science research. Whether it is because of a 70% reduction in cardiac disease due to improved therapy (eg, development of statins), or millions of Americans living with a history of cancer, or reduced infectious disease rates due to improved vaccines or antibiotics, we all have a vested interest in funding research. I am alive—thanks to a bone marrow transplant many years ago—because of the basic and clinical research performed and the volunteers who came before me and subjected themselves to risks with the questionable reward of research. If it were not for that research funded by the NIH, I wouldn’t be here to advocate for it today. The stakes could not be higher. We must advocate for our patients, for our loved ones, for our grandchildren. We must stand for common sense. n

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

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

An ongoing commitment to access and support ASSISTANCE FOR PATIENTS WHO NEED SUPPORT WITH AFINITOR ® (everolimus) TABLETS

With the AFINITOR Co-Pay Card, eligible commercial patients pay a maximum co-pay of $25* Use convenient samples to support treatment start

Visit www.AFINITOR.com to learn more

*The AFINITOR $25 Co-Pay Card is not valid for prescriptions for which payment may be made in whole or in part under federal or state healthcare programs, including, but not limited to, Medicare or Medicaid. The Co-Pay Card is available through your physician or at www.AFINITOR.com. This program will expire June 30, 2014.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

2/13

AFI-1060010