TAP Vol 5 Issue 4 by Harborside Press LLC

Metastatic Renal Cell Carcinoma 3, 4 | HER2-Positive Breast Cancer

| Managing Cancer Pain

56, 57

VOLUME 5, ISSUE 4

MARCH 1, 2014

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

Genitourinary Cancers Symposium

PREVAIL Trial Shows Enzalutamide to Be a Promising Option for Metastatic Castration-Resistant Prostate Cancer

The Future of Biomedical Research A Conversation With Francis S. Collins, MD, PhD

By Alice Goodman

ncouraging results of the large phase III PREVAIL trial represent another positive milestone for men with metastatic castration-resistant prostate cancer. Enzalutamide (Xtandi) improved overall survival by 29% and reduced the risk of radiographic progression of disease by 81% in men who had not received chemotherapy. An interim analysis of the trial data in 2013 was so favorable that the Independent Data Monitoring Committee halted the trial prematurely and offered all placebo recipients enzalutamide. Complete trial results were reported at the 2014 Genitourinary Cancers Symposium in San Francisco.1

Potential Treatment Standard “In my view, enzalutamide provides clinically meaningful benefit for men with [metastatic castration-resistant prostate cancer]. It is approved by the

FDA in men previously treated with docetaxel, but not yet approved for use prior to docetaxel. If it does get expanded approval for this indication, it is likely to become an important standard option for use in patients with asymptomatic or minimally Tomasz M. Beer, MD symptomatic advanced prostate cancer,” said lead author Tomasz M. Beer, MD, Professor of Medicine and Deputy Director of the Knight Cancer Institute at Oregon Health & Science University, Portland. Between September 2010 and September 2012, PREVAIL included 1,717 patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer who had not received previous chemomotherapy. continued on page 8

Health-Care Policy

Congress Agrees on Repeal of Sustainable Growth Rate By Ronald Piana

he U.S. Congress recently did something rarely seen on Capitol Hill: Leaders from both sides of the aisle agreed on a piece of legislation. On February 6, 2014, the House Energy and Commerce and Ways and Means Committees and the Senate Finance Committee announced its agreement on a bill—the SGR Repeal and Medicare Provider Payment Modernization Act—that would repeal the Medicare sustainable growth rate (SGR) formula, hopefully ending the

year-by-year threat of physician fee cuts that could severely hamper oncologists’ ability to treat their Medicare patients. Funding for the repeal remains to be resolved, and the bill still needs to be approved by both the House and the Senate. For more than a decade, ASCO and other major oncology organizations have lobbied on Capitol Hill for repeal of the SGR. “It’s critical to community oncology practices that Congress fix the broken SGRbased Medicare system and pass real payment It’s critical to community oncology reform—not just to avert another looming SGR cut, practices that Congress fix the broken but because oncology is SGR-based Medicare system and pass way out in front of actually real payment reform—not just to avert implementing payment reform. Congress needs another looming SGR cut, but because to fulfill its responsibility oncology is way out in front of actually and pass a real fix, not duck and simply patch the SGR implementing payment reform. once again,” Ted Okon, —Ted Okon, Executive Director Executive Director of the Community Oncology Alliance

n January, Congress approved a $1 trillion appropriations bill for the rest of fiscal year 2014. While the new bill includes $29.9 billion for the National Institutes of Health (NIH)—$1 billion above FY2013 levels after sequestration—including $4.9 billion for the National Cancer Institute (NCI), it does not restore NIH funding to presequestration spending levels. In addition, the budget leaves the NIH with about 10% less purchasing power in current dollars compared to FY2007. In a wide-ranging interview with The ASCO Post, Francis S. Collins, MD, PhD, Director of the National Institutes of Health, addressed the continued on page 70

Dr. Francis S. Collins is Director of the National Institutes of Health. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage Genitourinary Cancers Symposium �� 3, 4 Gastrointestinal Cancers Symposium ��9, 11, 13, 16 San Antonio Breast Cancer Symposium ��24, 26, 39 American Society of Hematology �� 40, 45 JADPRO Live–Advanced Practitioners �� 50, 51, 60 Direct From ASCO ��32–35 Michael J. Fisch, MD, MPH, on Cancer Pain ��56 Steven T. Rosen, MD, on His New Role at City of Hope �� 67

continued on page 59

Send your comments to editor@ASCOPost.com

A Harborside Press® Publication

The ASCO Post | MARCH 1, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

John A. Fracchia, MD New York Urological Associates

Jamie H. Von Roenn, MD

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Alison Freifeld, MD University of Nebraska Medical Center

Center at Northwestern University Lynn D. Wilson, MD

Associate Editors

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

Joseph S. Bailes, MD Texas Oncology

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

Stanley H. Winokur, MD

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

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

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

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

Robert H. Lurie Comprehensive Cancer

Yale University School of Medicine

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

International Editors

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

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

University of Ibadan, Nigeria

Douglas W. Blayney, MD Stanford University Medical Center

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

Eduardo Cazap, MD, PhD

Philip D. Bonomi, MD Rush University Medical Center

Michael P. Link, MD Stanford University Medical Center

International Union Against Cancer (UICC)

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

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

Nagi El-Saghir, MD

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Mary Gospodarowicz, MD

Robert W. Carlson, MD National Comprehensive Cancer Network

William T. McGivney, PhD Philadelphia, Pennsylvania

Toronto, Ontario, Canada

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

James L. Mulshine, MD Rush University Medical Center

Jacek Jassem, MD

Jay S. Cooper, MD Maimonides Medical Center

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

David Khayat, MD

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Tony Mok, MD

John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado

Clement Adebamowo, BM, ChB (Hons), ScD

Buenos Aires, Argentina

American University of Beirut, Lebanon

Princess Margaret Hospital

Medical University of Gdansk, Poland

Pitie-Salpetriere Hospital, Paris, France

The Chinese University of Hong Kong Shatin, Hong Kong

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Lee S. Schwartzberg, MD University of Tennessee Health Science Center

George D. Demetri, MD Dana-Farber Cancer Institute

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Paul F. Engstrom, MD Fox Chase Cancer Center

Samuel Silver, MD, PhD University of Michigan Health System

Nagahiro Saijo, MD, PhD

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

George W. Sledge, MD Indiana University

Osaka, Japan

Bishoy Morris Faltas, MD Weill Cornell Medical College

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 subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

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

hibited. For permission inquiries, contact permissions@ harborsidepress.com. 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: $271;

Eliezer Robinson, MD

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

National Council for Oncology

Contributing Artist:

Israeli Cancer Association, Haifa, Israel

Portraits by Keith Witmer, Keith Witmer Illustrations.

Kinki University School of Medicine

Disclosure information available at ASCOPost.com.

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

Canada: $397; Individual International: $523; Institutional Domestic: $335; Canada: $461; Institutional International: $587. Single Copy Domestic: $52; Canada: $59; International: $65. Contact subscriptions@harborsidepress.com.

Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com.

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.

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.”

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.

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.

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 | MARCH 1, 2014

PAGE 3

Genitourinary Cancers Symposium Genitourinary Oncology

Cytoreductive Nephrectomy Improves Survival in Metastatic Renal Cell Carcinoma Patients With Longer Life Expectancy By Alice Goodman

rior to the advent of targeted therapy, cytoreductive nephrectomy was associated with a 6-month improvement in overall survival in patients with metastatic renal cell carcinoma. With new and better targeted therapies for the disease, the appropriate use of cytoreductive nephrectomy has been questioned. A new study from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) provides some guidance about which patients with metastatic renal cell carcinoma can expect to have a survival benefit from cytoreductive nephrectomy in the targeted therapy era. Patients with synchronous metastatic renal cell carcinoma who have a life expectancy of 1 year or more appear to have a survival benefit if treated with targeted therapy and cytoreductive nephrectomy, whereas those with a shorter life expectancy will probably have no benefit, according to the IMDC study, which was presented at the 2014 Genitourinary Cancers Symposium in San Francisco.

Patient Selection “Not all patients with metastatic renal cell carcinoma should undergo cy-

toreductive nephrectomy. Patients with longer estimated survival may benefit, but those with four or more risk factors and limited life expectancy should not have this surgery. Of course there may be exceptions to this rule, but this is

Role of Cytoreductive Nephrectomy ■■ Cytoreductive nephrectomy can extend survival in patients with synchronous metastatic renal cell carcinoma treated with targeted therapy. ■■ The surgery offers little survival benefit to patients with shorter life expectancy (ie, < 1 year). ■■ Patients with four or more poor prognostic factors according to IMDC criteria derived little or no benefit from cytoreductive nephrectomy, whereas those with up to three factors had significantly improved survival if they had surgery.

Daniel Y. C. Heng, MD, MPH, FRCPC

an interesting approach to patient selection,” said Daniel Y. C. Heng, MD, MPH, FRCPC, an oncologist at Tom Baker Cancer Centre and Clinical Associate Professor at the University of Calgary, Canada. Two prospective phase III clinical trials are currently evaluating cytoreductive nephrectomy—CARMENA and SURTIME—and results of those should be more definitive than the retrospective analysis that Dr. Heng presented.

The analysis was based on data from consecutive patients treated at 20 international cancer centers with targeted therapy for metastatic renal cell carcinoma (N = 3,245; 2,569 were treated with nephrectomy). After excluding patients who underwent nephrectomy before metastasis occurred, final numbers for the analysis were 982 who had the procedure and 676 who did not. There were more favorable-risk patients in the cytoreductive nephrectomy group (63% vs 45% in the no nephrectomy group). “This is not surprising because of patient selection criteria for surgery, so we have

EXPERT POINT OF VIEW

“C

ytoreductive nephrectomy is routinely used in metastatic renal cell carcinoma, but its use is not as firmly established in the targeted therapy era. And its use is not without

Daniel J. Canter, MD

risk,” said formal discussant of the International Metastatatic Renal Cell Carcinoma Database Consortium (IMDC) trial, Daniel J. Canter, MD, at the Genitourinary Cancers Symposium. Dr. Canter is Vice Chairman of the Urologic Institute of Southeastern Pennsylvania and the Department of Urology of the Einstein Healthcare Network, and Associate Professor at the Fox Chase

Cancer Center, Philadelphia. “Perioperative complications may impact patients’ ability to receive adjuvant or systemic therapy,” he noted. “According to two large studies, the perioperative complication rates range from 26% to 31%, and perioperative mortality is 1.5% to 2.4%.” At Fox Chase, approximately 30% of patients who undergo cytoreductive nephrectomy never receive systemic chemotherapy, usually because of death or rapid disease progression, Dr. Canter continued. “The procedure carries risk and we need to be careful about patient selection,” he emphasized.

Study Strengths Dr. Canter cited two strengths of the study reported by Dr. Heng: It represents the largest cohort undergoing cytoreductive nephrectomy to date, and survival was stratified according to IMDC risk status. Overall survival showed a benefit for

cytoreductive nephrectomy, but there was a selection bias, Dr. Canter continued, because the majority of poor-risk patients do not undergo the procedure. “The take-home message from this study is that we need to make better choices and risk-stratify patients before surgery. Those with zero to three prognostic factors will probably benefit, whereas those with more than three factors will not. By better selection, we can reduce the risk of complications and mortality,” Dr. Canter stated. Another point he made was that perhaps the IMDC criteria–based risk groups should be redefined. “Poor-risk patients are currently defined as having three or more risk factors, but today’s data show that patients with three risk factors have a benefit from [cytoreductive nephrectomy],” he said. “In addition, considering the data on complication rates would be important for future decision-making.” n Disclosure: Dr. Canter reported no potential conflicts of interest.

to adjust results according to baseline characteristics,” Dr. Heng said.

Key Findings In a univariate analysis of overall survival, the cytoreductive nephrectomy group lived longer: 20.6 vs 9.5 months (adjusted hazard ratio = 0.60 [0.52– 0.69], P < .0001). A multifactorial analysis adjusted for IMDC criteria found an incremental benefit of cytoreductive nephrectomy as survival lengthened, but not much benefit with shorter life expectany. IMDC criteria build on Memorial Sloan Kettering Cancer Center criteria and include Karnofsky performance status < 80%, time from diagnosis < 1 year, and results of four lab tests for anemia, hypercalcemia, neutrophilia, and thrombocytosis. The study enrolled insufficient numbers of patients to compare cytoreductive nephrectomy vs no nephrectomy in patients who had all six prognostic factors, but a significant survival benefit was detected in those with 0 to 3 prognostic factors, Dr. Heng said. “If you had one prognostic factor, the difference in median overall survival [favoring cytoreductive nephrectomy] was about 8 months; if you had two factors, the difference was 10 months; and if you had three factors, the difference was 6 months,” Dr. Heng said. n

Disclosure: Dr. Heng is a consultant or advisor for Bayer, Novartis, and Pfizer. For full disclosures of the study authors, visit abstracts. asco.org.

Reference 1. Heng DYC, Rini BI, Beuselinck B, et al: Cytoreductive nephrectomy (CN) in patients with synchronous metastases from renal cell carcinoma: Results from the International Metastatatic Renal Cell Carcinoma Database Consortium (IMDC). Genitourinary Cancers Symposium. Abstract 396. Presented February 1, 2014.

The ASCO Post | MARCH 1, 2014

PAGE 4

Genitourinary Cancers Symposium Genitourinary Oncology

Sequencing Sorafenib and Sunitinib in Either Order Does Not Affect Survival in Metastatic Renal Cell Carcinoma By Alice Goodman

he explosion of new therapies for metastatic renal cell carcinoma is a welcome advance, but studies have not yet defined optimal sequencing of the newer therapies. According to the phase III SWITCH trial, it matters little whether therapy for metastatic renal cell carcinoma begins with sorafenib (Nexavar) and is followed by sunitinib (Sutent) or vice versa. Both sequences achieved comparable progression-free and overall survival, and safety was consistent with previous reports on both drugs. Results of the study were presented at the Genitourinary Cancers Symposium in San Francisco.1 “This is the first randomized, prospective study of first-line sequential therapy with [sorafenib/sunitinib] vs [sunitinib/ sorafenib] for advanced or metastatic renal cell carcinoma. The primary objective of this trial was not met because neither sequence achieved superior total progression-free survival. Overall survival was similar in both arms. Safety profiles were as expected,” said lead author Maurice Stephan Michel, MD, PhD, Medical Director of the Department of Urology at University Hospital Mannheim, Germany.

SWITCH Trial Details SWITCH was a prospective, openlabel, randomized, phase III trial con-

ducted in Germany, Austria, and the Netherlands. Patients (N = 365) with advanced or metastatic renal cell carcinoma who were not suitable candidates for cytokine therapy and had not received prior systemic therapy for advanced disease were randomly assigned 1:1 to first-line therapy with sorafenib or sunitinib; at the time of disease progression or intolerable toxicity, they were transitioned to second-line therapy with sunitinib or sorafenib, respectively. The primary endpoint was total progression-free survival, defined as the time from randomization to confirmed progression or death during second-

Sorafenib/Sunitinib vs Sunitinib/Sorafenib ■■ In metastatic renal cell carcinoma, initiating therapy with sorafenib or sunitinib followed by the opposite drug at disease progression did not have a differential effect on progression-free or overall survival. ■■ An exploratory analysis suggested a possible benefit for the sorafenib/ sunitinib sequence, but this finding should be viewed with caution.

Sloan Kettering Cancer Center criteria, but the sunitinib/sorafenib arm had slightly more favorable-risk patients (39% in the sorafenib/sunitinib arm and 44.8% in the sunitinib/sorafenib arm). At the end of the study, 11% of the

The primary objective of this trial was not met because neither sequence achieved superior total progression-free survival. —Maurice Stephan Michel, MD, PhD

line therapy. At baseline, demographic and disease characteristics were similar for the two treatment arms. Median age was around 64 years, about 75% were male, and about 86% had clear-cell histology. Most patients were classified as intermediate-risk according to Memorial

EXPERT POINT OF VIEW

“W

e have a lot of options for first-line therapy [in renal cell carcinoma] these days. The question is, what do we do with first-line failures?” said Daniel J. Canter, MD, formal discussant of the SWITCH trial at the Genitourinary Cancers Symposium. Dr. Canter is Vice Chairman of the Urologic Institute of Southeastern Pennsylvania and the Department of Urology of the Einstein Healthcare Network, and Associate Professor at the Fox Chase Cancer Center, Philadelphia. “How we select second-line therapies is an area of debate where there is room for improvement,” he noted. “The SWITCH study showed us that switching from sorafenib to sunitinib or vice versa was well tolerated. It didn’t matter which drug was used first. This study was not practice-changing,” Dr. Canter said. “At present, most oncologists in the United States use sunitinib first-line, and only about 2% are using pazopanib [Votrient]. But this may change, and it may be reasonable to use pazopanib followed by sunitinib,” he added. “Globally, we need to figure out the best sequence.” n Disclosure: Dr. Canter reported no potential conflicts of interest.

sunitinib/sorafenib group were still on first-line sunitinib and 9% of the sorafenib/sunitinib group were still on first-line sorafenib. Second-line therapy was delivered to 42% of sunitinib/sorafenib recipients and 57% of sorafenib/sunitinib recipients. By study’s end, 3% and 7%, respectively, were still on second-line therapy.

Key Results No significant difference was observed between the two treatment arms for the primary endpoint of total progression-free survival. Median total progression-free survival was 12.5 months for sorafenib/sunitinib vs 14.9 months for sunitinib/sorafenib (hazard ratio [HR] = 1.01, P = .54). Overall survival was also not significantly different between the two arms. Median overall survival was 31.5 months for sorafenib/sunitinib vs 30.2 months for sunitinib/sorafenib (HR = 0.997, P = .49). Dr. Michel said it would be difficult with current therapies to beat overall survival of more than 30 months. “This is among the longest survival reported

in metastatic renal cell carcinoma,” he stated. An analysis evaluating second-line therapy found a significant difference in disease control rate favoring the sorafenib/sunitinib arm: 48.5% vs 31.6%, respectively (P = .03). However, these results may be biased, Dr. Michel pointed out, as more patients were able to get second-line therapy in the sorafenib/sunitinib arm (56.6% vs 41.5%, respectively; P < .01).

Adverse Effects Side effects after first-line therapy were as expected and differed by drug. Treatment-emergent diarrhea and skin reactions were more common when sorafenib was used as first-line therapy, whereas nausea and stomatitis were more common with first-line sunitinib. Adverse events were generally less frequent during second-line therapy than first-line therapy, which may reflect “survival of the fittest” to reach second-line therapy. Neither drug had any effect on cardiac safety. n

Disclosure: SWITCH was sponsored by the German Cancer Society with a financial grant from Bayer Pharma AG, marketers of sorafenib. Dr. Michel has received honoraria from Astellas Pharma, Bayer, and Novartis. For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Michel MS, Vervenne W, de Santis M, et al: SWITCH: A randomized sequential open-label study to evaluate efficacy and safety of sorafenib/sunitinib versus sunitinib/sorafenib in the treatment of metastatic renal cell carcinoma. 2014 Genitourinary Cancers Symposium. Abstract 393. February 1, 2014.

ASCOPost.com | MARCH 1, 2014

PAGE 5

Genitourinary Cancers Symposium Genitourinary Oncology

Long-Term Safety Data on Radium-223 in Prostate Cancer Reassuring By Alice Goodman

ong-term follow-up of the ALSYMPCA trial showed that radium Ra 223 dichloride (Xofigo) is extremely safe and active in men with castration-resistant prostate cancer and

bone metastases. A snapshot of safety data from about 1.5 years after patients’ final radium-223 injection shows minimal myelosuppression, minimal nonhematologic adverse events, and no reports of acute

Erbitux® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WArNiNG: SEriOuS iNFuSiON rEACtiONS and CArDiOPuLMONArY ArrESt infusion reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European union (Eu)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-Fu) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing information.] iNDiCAtiONS AND uSAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFr-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information] • in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.] Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONtrAiNDiCAtiONS None WArNiNGS AND PrECAutiONS infusion reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] use of Erbitux in Combination With radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

myelogenous leukemia, myelodysplastic syndrome, or primary bone cancer—all adverse events of concern. “These safety data are reassuring and support further evaluation of radium-223

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor receptor (EGFr) Expression and response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADvErSE rEACtiONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). table 1:

incidence of Selected Adverse reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus radiation radiation therapy Alone (n=208) (n=212) body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 16 0 5 0 Chillsa Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc 38 1 24 1 Aspartate Transaminase, highc c Alkaline Phosphatase, high 33 <1 24 0 respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study. Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

in combination with other agents to treat patients with [castration-resistant prostate cancer] and bone metastases,” said Sten Nilsson, MD, PhD, Professor of Oncolocontinued on page 6

The ASCO Post | MARCH 1, 2014

PAGE 6

Genitourinary Cancers Symposium Radium-223 continued from page 5

gy at the Karolinska Institute, Stockholm. Radium-223 is a first-in-class alphaemitting radiopharmaceutical recently approved by the U.S. Food and Drug Administration for treatment of patients with castration-resistant prostate cancer and symptomatic bone metastases, based on

results of the pivotal phase III ALSYMPCA trial. In that study, radium-223 significantly improved overall survival by 3.6 months compared with placebo (P < .001), and the drug was very well tolerated. ALSYMPCA enrolled 921 patients with castration-resistant prostate cancer and at least two symptomatic bone metastases (about two-thirds of pa-

tients had 6–20 bone metastases, and one-third had > 20) and no known visceral metastases. Patients had either received docetaxel or were not candidates for the taxane. They were randomly assigned 2:1 to radium-223

Study Study 2: 2: EU-Approved EU-Approved Cetuximab Cetuximab in in Combination Combination with with Platinum-based Platinum-based Therapy Therapy with with 5-Fluorouracil 5-Fluorouracil —— Study Study 2 used 2 used EU-approved EU-approved cetuximab. cetuximab. Since Since U.S.-licensed U.S.-licensed Erbitux Erbitux (cetuximab) (cetuximab) provides provides approximately approximately 22% 22% higher higher exposure exposure relative relative to to thethe EU-approved EU-approved cetuximab, cetuximab, thethe data data provided provided below below may may underestimate underestimate thethe incidence incidence andand severity severity of adverse of adverse reactions reactions anticipated anticipated with with Erbitux Erbitux forfor thisthis indication. indication. However, However, thethe tolerability tolerability of of thethe recommended recommended dose dose is is supported supported by by safety safety data data from from additional additional studies studies of of Erbitux Erbitux [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in Full in Full Prescribing Prescribing Information]. Information]. Table Table 2 contains 2 contains selected selected adverse adverse reactions reactions in 434 in 434 patients patients with with recurrent recurrent locoregional locoregional disease disease or or metastatic metastatic SCCHN SCCHNreceiving receivingEU-approved EU-approvedcetuximab cetuximabin incombination combinationwith withplatinum-based platinum-basedtherapy therapywith with5-FU 5-FUor or 2 2 platinum-based platinum-based therapy therapy with with 5-FU 5-FU alone alone in Study in Study 2. Cetuximab 2. Cetuximab waswas administered administered at 400 at 400 mg/m mg/m forfor thethe initial initial 2 2 dose, dose, followed followed by by 250250 mg/m mg/m weekly. weekly. Patients Patients received received a median a median of 17 of 17 infusions infusions (range (range 1–89). 1–89). table table 2: 2:

incidence incidence of Selected of Selected Adverse Adverse reactions reactions (≥10%) (≥10%) in Patients in Patients with with recurrent recurrent Locoregional Locoregional Disease Disease or or Metastatic Metastatic SCCHN SCCHN Eu-Approved Eu-Approved Cetuximab Cetuximab Platinum-based Platinum-based plus plus Platinum-based Platinum-based therapy therapy with with therapy therapy with with 5-Fu 5-Fu 5-Fu 5-Fu Alone Alone (n=219) (n=219) (n=215) (n=215) System System Organ Organ Class Class Grades Grades Grades Grades Grades Grades Grades Grades Preferred Preferred Term Term 1–41–4 3 and 3 and 4 4 1–41–4 3 and 3 and 4 4 % of % Patients of Patients EyeEye Disorders Disorders Conjunctivitis Conjunctivitis 10 10 0 0 0 0 0 0 Gastrointestinal Gastrointestinal Disorders Disorders Nausea Nausea 54 54 4 4 47 47 4 4 Diarrhea Diarrhea 26 26 5 5 16 16 1 1 General General Disorders Disorders andand Administration Administration SiteSite Conditions Conditions Pyrexia Pyrexia 22 22 0 0 13 13 1 1 a a 10 10 2 2 <1<1 0 0 Infusion Infusion Reaction Reaction infections infections andand infestations infestations b b 44 44 11 11 27 27 8 8 Infection Infection Metabolism Metabolism andand Nutrition Nutrition Disorders Disorders Anorexia Anorexia 25 25 5 5 14 14 1 1 Hypocalcemia Hypocalcemia 12 12 4 4 5 5 1 1 Hypokalemia Hypokalemia 12 12 7 7 7 7 5 5 Hypomagnesemia Hypomagnesemia 11 11 5 5 5 5 1 1 Skin Skin andand Subcutaneous Subcutaneous tissue tissue Disorders Disorders c c 70 70 9 9 2 2 0 0 Acneiform Acneiform Rash Rash Rash Rash 28 28 5 5 2 2 0 0 Acne Acne 22 22 2 2 0 0 0 0 Dermatitis Dermatitis Acneiform Acneiform 15 15 2 2 0 0 0 0 DryDry SkinSkin 14 14 0 0 <1<1 0 0 Alopecia Alopecia 12 12 0 0 7 7 0 0 a a Infusion Infusion reaction reaction defined defined as as anyany event event of “anaphylactic of “anaphylactic reaction”, reaction”, “hypersensitivity”, “hypersensitivity”, “fever “fever and/or and/or chills”, chills”, “dyspnea”, “dyspnea”, or or b b “pyrexia” “pyrexia” on on thethe firstfirst dayday of dosing. of dosing. Infection Infection – this – this term term excludes excludes sepsis-related sepsis-related events events which which areare presented presented separately. separately. c c Acneiform Acneiform rashrash defined defined as as anyany event event described described as “acne”, as “acne”, “dermatitis “dermatitis acneiform”, acneiform”, “dry“dry skin”, skin”, “exfoliative “exfoliative rash”, rash”, “rash”, “rash”, “rash “rash erythematous”, erythematous”, “rash “rash macular”, macular”, “rash “rash papular”, papular”, or “rash or “rash pustular”. pustular”.Chemotherapy Chemotherapy = cisplatin = cisplatin + 5-fluorouracil + 5-fluorouracil or or carboplatin carboplatin + 5-fluorouracil + 5-fluorouracil ForFor cardiac cardiac disorders, disorders, approximately approximately 9%9% of of subjects subjects in both in both thethe EU-approved EU-approved cetuximab cetuximab plus plus chemotherapy chemotherapy andand chemotherapy-only chemotherapy-only treatment treatment arms arms in Study in Study 2 experienced 2 experienced a cardiac a cardiac event. event. TheThe majority majority of these of these events events occurred occurred in in patients patients who who received received cisplatin/5-FU, cisplatin/5-FU, with with or or without without cetuximab cetuximab as as follows: follows: 11% 11% andand 12% 12% in in patients patients who who received received cisplatin/5-FU cisplatin/5-FU with with or or without without cetuximab, cetuximab, respectively, respectively, andand 6%6% or or 4%4% in patients in patients who who received received carboplatin/5-FU carboplatin/5-FU with with or without or without cetuximab, cetuximab, respectively. respectively. In both In both arms, arms, thethe incidence incidence of cardiovascular of cardiovascular events events waswas higher higher in the in the cisplatin cisplatin with with 5-FU 5-FU containing containing subgroup. subgroup. Death Death attributed attributed to cardiovascular to cardiovascular event event or or sudden sudden death death waswas reported reported in in 3%3% of of thethe patients patients in in thethe cetuximab cetuximab plus plus platinum-based platinum-based therapy therapy with with 5-FU 5-FU armarm andand 2%2% in the in the platinum-based platinum-based chemotherapy chemotherapy with with 5-FU 5-FU alone alone arm. arm. Colorectal Colorectal Cancer Cancer Study Study 4: 4: EU-Approved EU-Approved Cetuximab Cetuximab in in Combination Combination with with FOLFIRI FOLFIRI —— Study Study 4 used 4 used EU-approved EU-approved cetuximab. cetuximab. U.S.-licensed U.S.-licensed Erbitux Erbitux provides provides approximately approximately 22% 22% higher higher exposure exposure to to cetuximab cetuximab relative relative to to thethe EU-approved EU-approved cetuximab. cetuximab. TheThe data data provided provided below below forfor Study Study 4 is4consistent is consistent in incidence in incidence andand severity severity of adverse of adverse reactions reactions with with those those seen seen forfor Erbitux Erbitux in this in this indication. indication. TheThe tolerability tolerability of the of the recommended recommended dose dose is supported is supported by by safety safety data data from from additional additional studies studies of Erbitux of Erbitux [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in Full in Full Prescribing Prescribing Information]. Information]. Table Table3 contains 3 containsselected selectedadverse adversereactions reactionsin in667667patients patientswith withK-Ras K-Rasmutation-negative mutation-negative(wild-type), (wild-type), EGFR-expressing, EGFR-expressing, metastatic metastatic colorectal colorectal cancer cancer receiving receiving EU-approved EU-approved cetuximab cetuximab plus plus FOLFIRI FOLFIRI or or FOLFIRI FOLFIRI alone alone in Study in Study 4 [see 4 [see Warnings Warnings andand Precautions]. Precautions]. Cetuximab Cetuximab waswas administered administered at the at the recommended recommended dose dose andand 2 2 2 2 schedule schedule (400 (400 mg/m mg/m initial initial dose, dose, followed followed by by 250250 mg/m mg/m weekly). weekly). Patients Patients received received a median a median of 26 of 26 infusions infusions (range (range 1–224). 1–224). table table 3: 3:

incidence incidenceof ofSelected SelectedAdverse Adversereactions reactionsOccurring Occurringin in≥10% ≥10%of ofPatients Patientswith withK-Ras K-Ras a a Mutation-negative Mutation-negative (Wild-type) (Wild-type) andand EGFr-expressing, EGFr-expressing, Metastatic Metastatic Colorectal Colorectal Cancer Cancer Eu-Approved Eu-Approved Cetuximab Cetuximab plus plus FOLFiri FOLFiri FOLFiri FOLFiri Alone Alone (n=317) (n=317) (n=350) (n=350) Grades Grades Grades Grades Grades Grades body body System System Grades Grades b b 1–41–4 3 and 3 and 4 4 1–41–4 3 and 3 and 4 4 Preferred Preferred Term Term % of % Patients of Patients blood blood andand Lymphatic Lymphatic System System Disorders Disorders Neutropenia Neutropenia 49 49 31 31 42 42 24 24 EyeEye Disorders Disorders Conjunctivitis Conjunctivitis 18 18 <1<1 3 3 0 0 Gastrointestinal Gastrointestinal Disorders Disorders Diarrhea Diarrhea 66 66 16 16 60 60 10 10 Stomatitis Stomatitis 31 31 3 3 19 19 1 1 Dyspepsia Dyspepsia 16 16 0 0 9 9 0 0 General General Disorders Disorders andand Administration Administration SiteSite Conditions Conditions c c 14 14 2 2 <1<1 0 0 Infusion-related Infusion-related Reaction Reaction Pyrexia Pyrexia 26 26 1 1 14 14 1 1 infections infections andand infestations infestations Paronychia Paronychia 20 20 4 4 <1<1 0 0 investigations investigations Weight Weight Decreased Decreased 15 15 1 1 9 9 1 1 Metabolism Metabolism andand Nutrition Nutrition Disorders Disorders Anorexia Anorexia 30 30 3 3 23 23 2 2 (Continued) (Continued)

Sten Nilsson, MD, PhD

(six injections at 4-week intervals) or placebo. Of 921 patients who underwent randomization, 574 entered 3-year followup (406 for radium-223 and 168 for placebo). Withdrawals from 3-year follow-up totaled 322 (79%) in the

table table 3: 3: incidence incidenceof ofSelected SelectedAdverse Adversereactions reactionsOccurring Occurringin in≥10% ≥10%of ofPatients Patientswith withK-Ras K-Ras a a (Continued) (Continued) Mutation-negative Mutation-negative (Wild-type) (Wild-type) andand EGFr-expressing, EGFr-expressing, Metastatic Metastatic Colorectal Colorectal Cancer Cancer Eu-Approved Eu-Approved Cetuximab Cetuximab plus plus FOLFiri FOLFiri FOLFiri FOLFiri Alone Alone (n=317) (n=317) (n=350) (n=350) Grades Grades Grades Grades Grades Grades body body System System Grades Grades b b 1–41–4 3 and 3 and 4 4 1–41–4 3 and 3 and 4 4 Preferred Preferred Term Term % of % Patients of Patients Skin Skin andand Subcutaneous Subcutaneous tissue tissue Disorders Disorders d d 86 86 18 18 13 13 <1<1 Acne-like Acne-like Rash Rash Rash Rash 44 44 9 9 4 4 0 0 Dermatitis Dermatitis Acneiform Acneiform 26 26 5 5 <1<1 0 0 DryDry Skin Skin 22 22 0 0 4 4 0 0 Acne Acne 14 14 2 2 0 0 0 0 Pruritus Pruritus 14 14 0 0 3 3 0 0 Palmar-plantar Palmar-plantar Erythrodysesthesia Erythrodysesthesia Syndrome Syndrome 19 19 4 4 4 4 <1<1 Skin Skin Fissures Fissures 19 19 2 2 1 1 0 0 a a Adverse Adverse reactions reactions occurring occurring in atin least at least 10% 10% of Erbitux of Erbitux (cetuximab) (cetuximab) combination combination armarm withwith a frequency a frequency at least at least 5%5% greater greater b b c c Adverse reactions reactions were were graded graded using using thethe NCINCI CTC, CTC, V 2.0. V 2.0.Infusion Infusion related related reaction reaction is is thanthan thatthat seen seen in the in the FOLFIRI FOLFIRI arm. arm.Adverse defined defined as any as any event event meeting meeting thethe medical medical concepts concepts of allergy/anaphylaxis of allergy/anaphylaxis at any at any timetime during during thethe clinical clinical study study or any or any event event occurring occurring on the on the firstfirst dayday of dosing of dosing andand meeting meeting thethe medical medical concepts concepts of dyspnea of dyspnea andand fever fever or by or the by the following following events events using using MedDRA MedDRA preferred preferred terms: terms: “acute “acute myocardial myocardial infarction”, infarction”, “angina “angina pectoris”, pectoris”, “angioedema”, “angioedema”, “autonomic “autonomic seizure”, seizure”, “blood “blood pressure pressure abnormal”, abnormal”, “blood “blood pressure pressure decreased”, decreased”, “blood “blood pressure pressure increased”, increased”, “cardiac “cardiac failure”, failure”, “cardiopulmonary “cardiopulmonary failure”, failure”, “cardiovascular “cardiovascular insufficiency”, insufficiency”, “clonus”, “clonus”, “convulsion”, “convulsion”, “coronary “coronary no-reflow no-reflow phenomenon”, phenomenon”, “epilepsy”, “epilepsy”, “hypertension”, “hypertension”, “hypertensive “hypertensive crisis”, crisis”, “hypertensive “hypertensive emergency”, emergency”, “hypotension”, “hypotension”, “infusion “infusion related related reaction”, reaction”, “loss “loss of of consciousness”, consciousness”, “myocardial “myocardial infarction”, infarction”, “myocardial “myocardial ischaemia”, ischaemia”, “prinzmetal “prinzmetal angina”, angina”, “shock”, “shock”, “sudden “sudden death”, death”, “syncope”, “syncope”, or “systolic or “systolic d Acne-like rashrash is defined is defined by by thethe events events using using MedDRA MedDRA preferred preferred terms terms andand included included “acne”, “acne”, “acne “acne hypertension”. hypertension”.d Acne-like pustular”, pustular”, “butterfly “butterfly rash”, rash”, “dermatitis “dermatitis acneiform”, acneiform”, “drug “drug rashrash withwith eosinophilia eosinophilia andand systemic systemic symptoms”, symptoms”, “dry“dry skin”, skin”, “erythema”, “erythema”, “exfoliative “exfoliative rash”, rash”, “folliculitis”, “folliculitis”, “genital “genital rash”, rash”, “mucocutaneous “mucocutaneous rash”, rash”, “pruritus”, “pruritus”, “rash”, “rash”, “rash “rash erythematous”, erythematous”, “rash “rash follicular”, follicular”, “rash “rash generalized”, generalized”, “rash “rash macular”, macular”, “rash “rash maculopapular”, maculopapular”, “rash “rash maculovesicular”, maculovesicular”, “rash “rash morbilliform”, morbilliform”, “rash “rash papular”, papular”, “rash “rash papulosquamous”, papulosquamous”, “rash “rash pruritic”, pruritic”, “rash “rash pustular”, pustular”, “rash “rash rubelliform”, rubelliform”, “rash “rash scarlatiniform”, scarlatiniform”, “rash “rash vesicular”, vesicular”, “skin “skin exfoliation”, exfoliation”, “skin “skin hyperpigmentation”, hyperpigmentation”, “skin “skin plaque”, plaque”, “telangiectasia”, “telangiectasia”, or “xerosis”. or “xerosis”. Erbitux ErbituxMonotherapy Monotherapy——Table Table4 4contains containsselected selectedadverse adversereactions reactionsin in242242patients patientswith withK-Ras K-Ras mutation-negative mutation-negative (wild-type), (wild-type), EGFR-expressing, EGFR-expressing, metastatic metastatic colorectal colorectal cancer cancer who who received received best best supportive supportive care care (BSC) (BSC) alone alone or or with with Erbitux Erbitux in Study in Study 5 [see 5 [see Warnings Warnings andand Precautions]. Precautions]. Erbitux Erbitux waswas administered administered at at thethe 2 2 2 2 recommended recommended dose dose andand schedule schedule (400 (400 mg/m mg/m initial initial dose, dose, followed followed by by 250250 mg/m mg/m weekly). weekly). Patients Patients received received a median a median of 17 of 17 infusions infusions (range (range 1–51). 1–51). table table 4: 4:

incidence incidenceof ofSelected SelectedAdverse Adversereactions reactionsOccurring Occurringin in≥10% ≥10%of ofPatients Patientswith withK-Ras K-Ras Mutation-negative Mutation-negative (Wild-type), (Wild-type), EGFr-expressing, EGFr-expressing, Metastatic Metastatic Colorectal Colorectal Cancer Cancer treated treated with with a a Erbitux Erbitux Monotherapy Monotherapy Erbitux Erbitux plus plus bSC bSC bSC bSC alone alone (n=118) (n=118) (n=124) (n=124) Grades Grades Grades Grades Grades Grades body body System System Grades Grades b b 3 and 3 and 4 4 1–41–4 3 and 3 and 4 4 Preferred Preferred Term Term 1–41–4 % of % Patients of Patients Dermatology/Skin Dermatology/Skin Rash/Desquamation Rash/Desquamation 95 95 16 16 21 21 1 1 DryDry Skin Skin 57 57 0 0 15 15 0 0 Pruritus Pruritus 47 47 2 2 11 11 0 0 Other-Dermatology Other-Dermatology 35 35 0 0 7 7 2 2 NailNail Changes Changes 31 31 0 0 4 4 0 0 Constitutional Constitutional Symptoms Symptoms Fatigue Fatigue 91 91 31 31 79 79 29 29 Fever Fever 25 25 3 3 16 16 0 0 c c 18 18 3 3 0 0 0 0 Infusion Infusion Reactions Reactions Rigors, Rigors, Chills Chills 16 16 1 1 3 3 0 0 Pain Pain Pain-Other Pain-Other 59 59 18 18 37 37 10 10 Headache Headache 38 38 2 2 11 11 0 0 Bone Bone PainPain 15 15 4 4 8 8 2 2 Pulmonary Pulmonary Dyspnea Dyspnea 49 49 16 16 44 44 13 13 Cough Cough 30 30 2 2 19 19 2 2 Gastrointestinal Gastrointestinal Nausea Nausea 64 64 6 6 50 50 6 6 Constipation Constipation 53 53 3 3 38 38 3 3 Diarrhea Diarrhea 42 42 2 2 23 23 2 2 Vomiting Vomiting 40 40 5 5 26 26 5 5 Stomatitis Stomatitis 32 32 1 1 10 10 0 0 Other-Gastrointestinal Other-Gastrointestinal 22 22 12 12 16 16 5 5 Dehydration Dehydration 13 13 5 5 3 3 0 0 Mouth Mouth Dryness Dryness 12 12 0 0 6 6 0 0 Taste Taste Disturbance Disturbance 10 10 0 0 5 5 0 0 infection infection Infection Infection without without neutropenia neutropenia 38 38 11 11 19 19 5 5 Musculoskeletal Musculoskeletal Arthralgia Arthralgia 14 14 3 3 6 6 0 0 Neurology Neurology Neuropathy-sensory Neuropathy-sensory 45 45 1 1 38 38 2 2 Insomnia Insomnia 27 27 0 0 13 13 0 0 Confusion Confusion 18 18 6 6 10 10 2 2 Anxiety Anxiety 14 14 1 1 5 5 1 1 Depression Depression 14 14 0 0 5 5 0 0 a a Adverse Adverse reactions reactions occurring occurring in at in least at least 10% 10% of Erbitux of Erbitux plusplus BSCBSC armarm withwith a frequency a frequency at least at least 5%5% greater greater thanthan thatthat b b c c Adverse Adverse reactions reactions were were graded graded using using thethe NCINCI CTC, CTC, V 2.0. V 2.0. Infusion Infusion reaction reaction is defined is defined as as seen seen in the in the BSCBSC alone alone arm. arm. anyany event event (chills, (chills, rigors, rigors, dyspnea, dyspnea, tachycardia, tachycardia, bronchospasm, bronchospasm, chest chest tightness, tightness, swelling, swelling, urticaria, urticaria, hypotension, hypotension, flushing, flushing, rash, rash, hypertension, hypertension, nausea, nausea, angioedema, angioedema, pain, pain, sweating, sweating, tremors, tremors, shaking, shaking, drug drug fever, fever, or other or other hypersensitivity hypersensitivity reaction) reaction) recorded recorded by the by the investigator investigator as infusion-related. as infusion-related. Erbitux Erbitux in in Combination Combination with with Irinotecan Irinotecan —— TheThe most most frequently frequently reported reported adverse adverse reactions reactions in 354 in 354 patients patients treated treated with with Erbitux Erbitux plus plus irinotecan irinotecan in in clinical clinical trials trials were were acneiform acneiform rash rash (88%), (88%), asthenia/malaise asthenia/malaise (73%), (73%), diarrhea diarrhea (72%), (72%), andand nausea nausea (55%). (55%). TheThe most most common common Grades Grades 3–43–4 adverse adverse reactions reactions included included diarrhea diarrhea (22%), (22%), leukopenia leukopenia (17%), (17%), asthenia/malaise asthenia/malaise (16%), (16%), andand acneiform acneiform rash rash (14%). (14%). immunogenicity: immunogenicity:As Aswith withall alltherapeutic therapeuticproteins, proteins, there thereis ispotential potentialforforimmunogenicity. immunogenicity. Immunogenic Immunogenic responses responses to to cetuximab cetuximab were were assessed assessed using using either either a double a double antigen antigen radiometric radiometric assay assay or or an an ELISA ELISA assay. assay. DueDue to to limitations limitations in in assay assay performance performance andand sampling sampling timing, timing, thethe incidence incidence of of antibody antibody development development in in patients patients receiving receiving Erbitux Erbitux hashas notnot been been adequately adequately determined. determined. Non-neutralizing Non-neutralizing anti-cetuximab anti-cetuximab antibodies antibodies were were detected detected in in 5%5% (49(49 of of 1001) 1001) of of evaluable evaluable patients patients without without apparent apparent effect effect on on thethe safety safety or or antitumor antitumor activity activity of Erbitux. of Erbitux.

1381 13

ASCOPost.com | MARCH 1, 2014

PAGE 7

Genitourinary Cancers Symposium radium-223 group and 144 (86%) in the placebo group. Deaths were the most common reason for withdrawal. Median duration of follow-up was 10.4 months for radium-223 recipients and 7.6 months for placebo recipients. Only 20 patients (16 in the radium-223 group and 4 in the placebo group) completed 3-year follow-up.

Adverse Events The investigators reported only treatment-related adverse events during followup. The incidence of myelosuppression was very low in the radium-223 group during follow-up (< 3%). There were no grade 3/4 nonhematologic treatment-related adverse events for radium-223 except for one pathologic fracture (< 1%).

Data on secondary cancers were reassuring. There were no reports of acute myelogenous leukemia, myelodysplastic syndrome, or primary bone cancer. Five cancers in other organs were reported, two in the radium-223 group and three in placebo patients. “No additional safety issues were reported 1.5 years after patients stopped

Radium-223 in Prostate Cancer ■■ Longer-term safety data on radium-223 show that the radiopharmaceutical has an excellent side-effect profile in patients with castrationresistant prostate cancer. ■■ Radium-223 causes little myelosuppression and few nonhematologic adverse events, and does not increase risk of other primary cancers.

TheThe incidence incidence of of antibody antibody formation formation is is highly highly dependent dependent on on thethe sensitivity sensitivity andand specificity specificity of of thethe assay. assay. Additionally, Additionally, thethe observed observed incidence incidence of of antibody antibody (including (including neutralizing neutralizing antibody) antibody) positivity positivity in in an an assay assay may may be be influenced influenced by by several several factors factors including including assay assay methodology, methodology, sample sample handling, handling, timing timing of of sample sample collection, collection, concomitant concomitant medications, medications, andand underlying underlying disease. disease. ForFor these these reasons, reasons, comparison comparison of the of the incidence incidence of antibodies of antibodies to Erbitux to Erbitux (cetuximab) (cetuximab) with with thethe incidence incidence of antibodies of antibodies to other to other products products may may be be misleading. misleading. Postmarketing Postmarketing Experience: Experience: TheThe following following adverse adverse reactions reactions have have been been identified identified during during post-approval post-approval useuse of of Erbitux. Erbitux. Because Because these these reactions reactions areare reported reported from from a population a population of uncertain of uncertain size, size, it isit not is not always always possible possible to to reliably reliably estimate estimate their their frequency frequency or establish or establish a causal a causal relationship relationship to drug to drug exposure. exposure. • •Aseptic Aseptic meningitis meningitis • •Mucosal Mucosal inflammation inflammation DruG DruG iNtErACtiONS iNtErACtiONS A drug A drug interaction interaction study study waswas performed performed in which in which Erbitux Erbitux waswas administered administered in combination in combination with with irinotecan. irinotecan. There There waswas no no evidence evidence of any of any pharmacokinetic pharmacokinetic interactions interactions between between Erbitux Erbitux andand irinotecan. irinotecan. uSE uSE iN iN SPECiFiC SPECiFiC POPuLAtiONS POPuLAtiONS Pregnancy: Pregnancy: Pregnancy Pregnancy Category Category C— C— There There areare no no adequate adequate andand well-controlled well-controlled studies studies of Erbitux of Erbitux in pregnant in pregnant women. women. Based Based on on animal animal models, models, EGFR EGFR hashas been been implicated implicated in the in the control control of prenatal of prenatal development development andand may may be be essential essential forfor normal normal organogenesis, organogenesis, proliferation, proliferation, andand differentiation differentiation in the in the developing developing embryo. embryo. Human Human IgGIgG is is known known to cross to cross thethe placental placental barrier; barrier; therefore, therefore, Erbitux Erbitux may may be be transmitted transmitted from from thethe mother mother to the to the developing developing fetus, fetus, andand hashas thethe potential potential to cause to cause fetal fetal harm harm when when administered administered to pregnant to pregnant women. women. Erbitux Erbitux should should be be used used during during pregnancy pregnancy only only if the if the potential potential benefit benefit justifies justifies thethe potential potential riskrisk to the to the fetus. fetus. Pregnant Pregnant cynomolgus cynomolgus monkeys monkeys were were treated treated weekly weekly with with 0.40.4 to to 4 times 4 times thethe recommended recommended human human dose dose of of cetuximab cetuximab (based (based on on body body surface surface area) area) during during thethe period period of of organogenesis organogenesis (gestation (gestation dayday [GD] [GD] 20–48). 20–48). Cetuximab Cetuximab waswas detected detected in in thethe amniotic amniotic fluid fluid andand in in thethe serum serum of of embryos embryos from from treated treated dams dams at at GDGD 49.49. NoNo fetal fetal malformations malformations or or other other teratogenic teratogenic effects effects occurred occurred in in offspring. offspring. However, However, significant significant increases increases in in embryolethality embryolethality andand abortions abortions occurred occurred at doses at doses of approximately of approximately 1.61.6 to 4totimes 4 times thethe recommended recommended human human dose dose of cetuximab of cetuximab (based (based on on total total body body surface surface area). area). Nursing Nursing Mothers: Mothers: It isIt not is not known known whether whether Erbitux Erbitux is secreted is secreted in human in human milk. milk. IgGIgG antibodies, antibodies, such such as as Erbitux, Erbitux, cancan be be excreted excreted in human in human milk. milk. Because Because many many drugs drugs areare excreted excreted in human in human milk milk andand because because of the of the potential potential forfor serious serious adverse adverse reactions reactions in nursing in nursing infants infants from from Erbitux, Erbitux, a decision a decision should should be be made made whether whether to discontinue to discontinue nursing nursing or or to discontinue to discontinue thethe drug, drug, taking taking intointo account account thethe importance importance of the of the drug drug to the to the mother. mother. If nursing If nursing is is interrupted, interrupted, based based on on thethe mean mean half-life half-life of of cetuximab cetuximab [see [see Clinical Clinical Pharmacology Pharmacology (12.3) (12.3) in in FullFull Prescribing Prescribing Information], Information], nursing nursing should should notnot be be resumed resumed earlier earlier than than 60 60 days days following following thethe lastlast dose dose of Erbitux. of Erbitux. Pediatric Pediatric use: use: TheThe safety safety andand effectiveness effectiveness of of Erbitux Erbitux in in pediatric pediatric patients patients have have notnot been been established. established. TheThepharmacokinetics pharmacokineticsof ofcetuximab, cetuximab,in incombination combinationwith withirinotecan, irinotecan,were wereevaluated evaluatedin inpediatric pediatric patients patientswith withrefractory refractorysolid solidtumors tumorsin inan anopen-label, open-label,single-arm, single-arm,dose-finding dose-findingstudy. study.Erbitux Erbituxwaswas 2 2 , to, to 27 27 patients patients ranging ranging from from 1 to 1 to 12 12 years years old;old; andand administered administered once-weekly, once-weekly, at at doses doses up up to to 250250 mg/m mg/m in in 19 19 patients patients ranging ranging from from 13 13 to to 18 18 years years old.old. NoNo new new safety safety signals signals were were identified identified in in pediatric pediatric patients. patients. TheThepharmacokinetic pharmacokineticprofiles profilesof ofcetuximab cetuximabbetween betweenthethetwotwoageagegroups groupswere weresimilar similarat atthethe75 75andand 2 2 single single dose dose levels. levels. TheThe volume volume of of thethe distribution distribution appeared appeared to to be be independent independent of of dose dose andand 150150 mg/m mg/m 2 2 2 2 . Following . Followinga single a singledose doseof of250250mg/m mg/m , the , thegeometric geometric approximated approximatedthethevascular vascularspace spaceof of2–32–3L/mL/m (CV%) (CV%) value value waswas 17.7 17.7 mg•h/mL mg•h/mL (34%) (34%) in in thethe younger younger ageage group group (1–12 (1–12 years, years, n=9) n=9) andand mean mean AUC AUC 0-inf0-inf 13.4 13.4 mg•h/mL mg•h/mL (38%) (38%) in in thethe adolescent adolescent group group (13–18 (13–18 years, years, n=6). n=6). TheThe mean mean half-life half-life of of cetuximab cetuximab waswas 110110 hours hours (range (range 69 69 to to 188188 hours) hours) forfor thethe younger younger ageage group, group, andand 82 82 hours hours (range (range 55 55 to to 117117 hours) hours) forfor thethe adolescent adolescent ageage group. group.

3810101_0207501_UpTheAnti_ROB_v3_M.indd 10101_0207501_UpTheAnti_ROB_v3_M.indd 3 3

Geriatric Geriatric use: use: Of Of thethe 1662 1662 patients patients who who received received Erbitux Erbitux (cetuximab) (cetuximab) with with irinotecan, irinotecan, FOLFIRI FOLFIRI or or Erbitux Erbitux monotherapy in in sixsix studies of of advanced colorectal cancer, 588588 patients were 65 65 years of of ageage or or older. NoNo monotherapy studies advanced colorectal cancer, patients were years older. overall differences in safety or efficacy were observed between these patients andand younger patients. overall differences in safety or efficacy were observed between these patients younger patients. Clinical Clinical studies studies of Erbitux of Erbitux conducted conducted in patients in patients with with head head andand neck neck cancer cancer diddid notnot include include sufficient sufficient number number of of subjects aged 65 65 andand over to determine whether they respond differently from younger subjects. subjects aged over to determine whether they respond differently from younger subjects. OvErDOSAGE OvErDOSAGE 2 2 in in oneone patient. patient. NoNo adverse adverse events events were were TheThe maximum single dose of of Erbitux administered is 1000 mg/m maximum single dose Erbitux administered is 1000 mg/m reported reported forfor thisthis patient. patient. NONCLiNiCAL NONCLiNiCAL tOxiCOLOGY tOxiCOLOGY Carcinogenesis, Carcinogenesis, Mutagenesis, Mutagenesis, impairment impairment of of Fertility: Fertility: Long-term Long-term animal animal studies studies have have notnot been been performed performed to to testtest cetuximab cetuximab forfor carcinogenic carcinogenic potential, potential, andand no no mutagenic mutagenic or or clastogenic clastogenic potential potential of of cetuximab cetuximab waswas observed observed in in thethe Salmonella-Escherichia Salmonella-Escherichia colicoli (Ames) (Ames) assay assay or or in in thethe in in vivovivo ratrat micronucleus micronucleus test. test. Menstrual Menstrual cyclicity cyclicity waswas impaired impaired in female in female cynomolgus cynomolgus monkeys monkeys receiving receiving weekly weekly doses doses of of 0.40.4 to to 4 times 4 times thethe human human dose doseof ofcetuximab cetuximab(based (basedon ontotal totalbody bodysurface surfacearea). area). Cetuximab-treated Cetuximab-treatedanimals animalsexhibited exhibitedincreased increased incidences incidences of of irregular irregular or or absent absent cycles, cycles, as as compared compared to to control control animals. animals. These These effects effects were were initially initially noted noted beginning beginning week week 25 25 of of cetuximab cetuximab treatment treatment andand continued continued through through thethe 6-week 6-week recovery recovery period. period. In In thisthis same same study, study, there there were were no no effects effects of of cetuximab cetuximab treatment treatment on on measured measured male male fertility fertility parameters parameters (ie,(ie, serum serum testosterone testosterone levels levels andand analysis analysis of sperm of sperm counts, counts, viability, viability, andand motility) motility) as as compared compared to control to control male male monkeys. monkeys. It isIt not is not known known if cetuximab if cetuximab cancan impair impair fertility fertility in humans. in humans. Animal Animal Pharmacology Pharmacology and/or and/or toxicology: toxicology: In cynomolgus In cynomolgus monkeys, monkeys, cetuximab, cetuximab, when when administered administered at doses at doses of of approximately approximately 0.40.4 to to 4 times 4 times thethe weekly weekly human human exposure exposure (based (based on on total total body body surface surface area), area), resulted resulted in in dermatologic dermatologic findings, findings, including including inflammation inflammation at the at the injection injection sitesite andand desquamation desquamation of the of the external external integument. integument. At At thethe highest highest dose dose level, level, thethe epithelial epithelial mucosa mucosa of of thethe nasal nasal passage, passage, esophagus, esophagus, andand tongue tongue were were similarly similarly affected, affected, andand degenerative degenerative changes changes in in thethe renal renal tubular tubular epithelium epithelium occurred. occurred. Deaths Deaths duedue to to sepsis sepsis were were observed observed in 50% in 50% (5/10) (5/10) of of thethe animals animals at at thethe highest highest dose dose level level beginning beginning after after approximately approximately 13 13 weeks weeks of of treatment. treatment. PAtiENt PAtiENt COuNSELiNG COuNSELiNG iNFOrMAtiON iNFOrMAtiON Advise Advise patients: patients: • •To To report report signs signs andand symptoms symptoms of infusion of infusion reactions reactions such such as as fever, fever, chills, chills, or breathing or breathing problems. problems. • •Of Of thethe potential potential risks risks of of using using Erbitux Erbitux during during pregnancy pregnancy or or nursing nursing andand of of thethe need need to to useuse adequate adequate contraception contraception in both in both males males andand females females during during andand forfor 6 months 6 months following following thethe lastlast dose dose of Erbitux of Erbitux therapy. therapy. • •That That nursing nursing is not is not recommended recommended during, during, andand forfor 2 months 2 months following following thethe lastlast dose dose of Erbitux of Erbitux therapy. therapy. • •To To limit limit sunsun exposure exposure (use (use sunscreen, sunscreen, wear wear hats) hats) while while receiving receiving andand forfor 2 months 2 months following following thethe lastlast dose dose of Erbitux. of Erbitux.

treatment,” Dr. Nilsson reported. n Disclosure: Dr. Nilsson is a consultant or advisor for Algeta. For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Nilsson S, Vogelzang NJ, Sartor AO, et al: 1.5-year post-treatment follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer and bone metastases from the phase 3 ALSYMPCA study. Genitourinary Cancers Symposium. Abstract 9. Presented January 30, 2014.

EXPERT POINT OF VIEW

® ® is aisregistered a registered trademark trademark of ImClone of ImClone LLCLLC a wholly-owned a wholly-owned subsidiary subsidiary of Eli of Eli LillyLilly andand Company. Company. Erbitux Erbitux Manufactured Manufactured by by ImClone ImClone LLCLLC a wholly-owned a wholly-owned subsidiary subsidiary of Eli of Eli LillyLilly andand Company, Company, Branchburg, Branchburg, NJNJ 08876 08876 USA USA Distributed Distributed andand marketed marketed by by Bristol-Myers Bristol-Myers Squibb Squibb Company, Company, Princeton, Princeton, NJNJ 08543 08543 USA USA Co-marketed Co-marketed by by Eli Eli LillyLilly andand Company, Company, Indianapolis, Indianapolis, IN 46285 IN 46285 USA USA

Copyright Copyright ©© 2004–2013 2004–2013 ImClone ImClone LLCLLC a wholly-owned a wholly-owned subsidiary subsidiary of Eli of Eli LillyLilly andand Company, Company, andand Bristol-Myers Bristol-Myers Squibb Squibb Company. Company. All All rights rights reserved. reserved. 1236886B3 1236886B3

RevRev August August 2013 2013 693US13PBS02201 693US13PBS02201

Michael J. Morris, MD

ommenting on the ALSYMPCA follow-up study presented at the Genitourinary Cancers Symposium, Michael J. Morris, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said that radium-223 was a very effective and safe drug, but its actual target and mechanism of action are not well understood. He contrasted this drug with orteronel, a drug for which the mechanism of action is well understood but that did not extend survival in patients with hormone-refractory prostate cancer. Dr. Morris said that there are several issues that remain to be resolved with radium-223: the optimal dose, the number of doses, how to combine and sequence radium-223 with

8/22/13 8/22/133:54 3:54 PMPM

continued on page 8

The ASCO Post | MARCH 1, 2014

PAGE 8

Genitourinary Cancers Symposium Enzalutamide continued from page 1

They were randomly assigned to receive enzalutamide at 160 mg/d or placebo. For the coprimary endpoints of the trial, enzalutamide reduced the risk of death by 29% (hazard ratio [HR] = 0.706, P < .0001), and reduced the risk of radiographic progression by 81% (HR = 0.86, P < .0001). Overall response rate according to imaging of soft-tissue disease was 59% with enzalutamide (20% complete

this arm, he continued. Enzalutamide was well tolerated after 17 months of treatment, with the most common side effects (seen in ≥ 20% of patients) being fatigue (36% of enzalutamide patients, 26% of placebo patients), constipation (22% and 27%, respectively), back pain (27% and 22%), and joint pain (20% and 16%). Any adverse event was reported by 97% of the enzalutamide group and 93% of placebo patients. Grade 3 or higher adverse events were reported in 43% of the

We have two active drugs [abiraterone and enzalutamide] for [metastatic prostate cancer] patients. My hope is that our future studies will further define which patients benefit from which approach. —Tomasz M. Beer, MD

responses and 39% partial responses) vs 5% in the placebo group (P < .0001). Importantly, enzalutamide delayed the need for chemotherapy by a median of 17 months: Median time to chemotherapy was 28 months in the enzalutamide group vs 10.8 months in the placebo arm, representing a significant 65% reduction (HR = 0.35, P < .0001). “This is important from a pragmatic perspective. Many men don’t want to take chemotherapy, especially if they are asymptomatic or mildly symptomatic,” Dr. Beer commented.

Subgroup Analysis Eleven percent of men enrolled in PREVAIL had visceral metastases. These men are typically excluded from clinical trials in this patient population. A post hoc subgroup survival analysis of progression-free and overall survival showed that the hazard ratio for patients with visceral disease is generally similar to the overall population. “Results in the subgroup analysis for visceral disease were not discordant with the rest of the study results,” Dr. Beer said. The safety observation period was three times longer with enzalutamide vs placebo, reflecting longer duration of treatment in

Expert Point of View continued from page 7

other agents, identifying response biomarkers, and understanding the target.

Note of Caution Maha H. Hussain, MD, FACP, FASCO, Professor of Medicine and Urology at the University of Michigan Comprehensive Cancer Center, Ann Arbor, said that the safety of radium 223 was reassuring.

enzalutamide group vs 37% of the placebo group. About 6% of patients in both arms discontinued treatment due to adverse events, reflecting good tolerability.

Abiraterone or Enzalutamide? Dr. Beer said that both abiraterone (Zytiga) and enzalutamide have shown benefit in docetaxel-naive patients with metastatic disease, but at present there are no head-to-head comparisons to guide treatment selection. “This study did not compare the two drugs head-to-head, so I won’t try to compare results of trials,” commented Dr. Beer. “But there are some noteworthy differences between trials of the two drugs. For example, PREVAIL included 11% of men with visceral metastasis, while these patients were excluded from the abiraterone trial.”

EXPERT POINT OF VIEW

harles Ryan, MD, moderator of the press conference at the Genitourinary Cancers Symposium where the PREVAIL trial data were discussed, emphasized that this study breaks new ground for enzalutamide (Xtandi) in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. “The interim analysis showed benefit in this patient group, and this is an important study in our field to be sure,” noted Dr. Ryan, who is Professor of Charles Ryan, MD Clinical Medicine and Urology, and Program Leader, Genitourinary Medical Oncology at the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco. Dr. Ryan said that about 50,000 men in the United States each year would fall into the category of asymptomatic or mildly symptomatic metastatic castrationresistant prostate cancer. “Most patients with advanced disease will encounter resistant disease in their lifetime,” he continued. “The average survival for these men is less than 3 years. This study is important from the perspective of patients not yet treated with chemotherapy. It may expand the regulatory approval of enzalutamide.” Dr. Ryan noted that less than 50% of men with metastatic castration-resistant prostate cancer actually receive chemotherapy. “Approval [for predocetaxel treatment] would open up treatment options for men who previously had fewer options,” he stated. n Disclosure: Dr. Ryan reported no potential conflicts of interest.

He cited the following practical considerations: Abiraterone requires steroid coadministration whereas enzalutamide does not; abiraterone therapy entails dietary restrictions, whereas enzalutamide therapy does not. “These subtle differences may play a role in clinical decision-making for individual patients,” Dr. Beer continued. “I won’t make a blanket statement. We have two active drugs for patients. My hope is that our future studies will further define which patients benefit from which approach. For now, we have encouraging

Enzalutamide in Metastatic Prostate Cancer ■■ Enzalutamide, an oral androgen receptor inhibitor, prolonged overall survival, progression-free survival, and time to chemotherapy initiation in men with chemotherapy-naive, asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. ■■ Dramatic improvements in these endpoints led to premature stopping of the trial. ■■ Future trials will determine the optimal use of this drug.

“One of the concerns with radiopharmaceuticals is long-term effects. The data from ALSYMPCA is reassuring regarding the safety of radium-223 in terms of bone marrow function and leukemias. This drug is likely to move forward to earlier stages of the disease, where long-term side effects become even more important,” she said. Nevertheless, Dr. Hussain sounded a note of caution: “Even though radium-223 appears to be safe to combine

results for both drugs and we will treat patients by making decisions one at a time,” Dr. Beer stated. Further studies comparing these treatments and sequencing them are needed, as well as studies earlier in the disease process, Dr. Beer noted. He added that the drugs will be studied in sequence and in combination and in earlier stages of disease. “We will see a continued evolution of how these drugs are used,” Dr. Beer predicted. n

Disclosure: Dr. Beer has received research funding from Astellas Pharma, Cougar Biotechnology, Janssen Biotech, and Medivation. For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Beer TM, Armstrong AJ, Sternberg, CN, et al: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Genitourinary Cancers Symposium. Abstract LBA1. Presented January 30, 2014.

careful in monitoring patients. For example, take the case of mitoxantrone, a drug that appeared to be safe in patients with metastatic castration-resistant prostate cancer, however, when tested earlier in the course of disease, was associated with acute myelogenous leukemia.” n Maha H. Hussain, MD, FACP, FASCO

with other therapies and to use earlier in the course of disease, we still have to be

Disclosure: Dr. Hussain is the lead investigator for an upcoming trial of radium-223. Dr. Morris reported no potential conflicts of interest.

ASCOPost.com | MARCH 1, 2014

PAGE 9

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Irinotecan Drug-Eluting Beads Improve Outcomes in Colorectal Cancer Patients With Liver Metastases By Caroline Helwick

rinotecan drug-eluting beads (DEBIRI) given simultaneously with FOLFOX (leucovorin, fluorouracil, oxaliplatin) and bevacizumab (Avastin) in patients with unresectable colorectal liver metastasis improved response rates, increased resectability, and prolonged hepatic progression–free survival in a study

FOLFOX and bevacizumab as a firstline treatment for unresectable colorectal liver metastasis. The drug-eluting beads are a proprietary product that contains 100 mg of irinotecan in the form of 100- to 300-micron beads that are administered via infusion into the hepatic artery. The study included 70 patients with

Simultaneous [modified] FOLFOX6 with bevacizumab and hepatic arterial irinotecan drug-eluting beads is safe, without causing chemotherapy delivery delays and without increasing chemotherapy toxicity. —Robert C.G. Martin, MD, PhD

reported at the 2014 Gastrointestinal Cancers Symposium in San Francisco, by Robert C.G. Martin, MD, PhD, Sam and Lolita Weakley Professor and  Director of Surgical Oncology at the University of Louisville in Kentucky.1

Less Toxic Option “Reports have demonstrated the activity of combining both irinotecan and oxaliplatin into a FOLFOXIRI [ FOLFOX/irinotecan] therapy. An option to gain similar benefits and less toxicity would be to administer the irinotecan through a hepatic arterial approach,” Dr. Martin explained. The study assessed the maximal response and adverse event rates of irinotecan drug-eluting beads with

metachronous and synchronous colorectal liver metastases, who were randomly assigned to modified FOLFOX6 plus bevacizumab (n = 30) or modified FOLFOX6, bevacizumab, and DEBIRI (FOLFOXDEBIRI, n = 40). FOLFOX/bevacizumab and the drug-eluting beads were generally administered on alternate weeks. All 40 patients in the experimental arm received at least one infusion of DEBIRI, 37 received two, 18 received three, 13 received four, 4 received five, and 3 received six infusions. The primary endpoints were response rates and adverse events. Secondary endpoints were conversion to resection and progression-free survival. Patients in each arm received a median number of eight chemotherapy cycles.

EXPERT POINT OF VIEW

elanie B. Thomas, MD, Associate Director of Clinical Investigations and the Grace E. DeWolff Chair of Medical Oncology at the Medical University of South Carolina in Charleston, commented on the findings by Martin et al for The ASCO Post. “I think this study is exciting,” she said. “They were thorough about image assessment, and this alone will be informative. By traditional RECIST Melanie B. Thomas, MD criteria the DEBIRI didn’t show an improvement, but by other imaging assessments it did. They also had a high rate of downstaging for surgery. While the study was too small to look for statistical significance, these are very positive and encouraging findings.” n Disclosure: Dr. Thomas reported no potential conflicts of interest.

High Response Rates The overall response rate was significantly higher with FOLFOXDEBIRI than with FOLFOX/bevacizumab. By modified RECIST criteria, responses were observed in 79% vs 54%, respectively, at 2 months; 91% vs 59% at 4 months; 83% vs 64% at 6 months; 54% vs 27% at 9 months; and 50% vs 24% at 12 months. These differences were statistically significant; however, differences in response by standard RECIST 1.1 criteria were not. Dr. Martin explained that standard RECIST 1.1 assessment depends upon the diameter of the tumor, whereas modified RECIST does not. “The challenge with this, using any hepatic arterial therapy, is that the diameter of liver tumors doesn’t change much, but you do see tumors go from hypervascular to partially vascular,” he said in an interview with The ASCO Post. “So by standard RECIST, we don’t see much tumor change, ie, response, but we do see stable disease. By modified RECIST, we showed a statistically significant improvement in both overall response and target response.”

‘Great Downsizing’ With FOLFOXDEBIRI, significantly more patients were downsized to resectability (35% vs 16%, P = .05), and in this group, median progression-free survival was improved from 7.6 months in the control arm to 15.3 months with FOLFOXDEBIRI. “The enhanced response rate led to great downsizing to resection and subsequent improvement in hepatic progression–free survival,” Dr. Martin noted. Overall progression-free survival, however, was not improved in the experimental arm, whose median progressionfree survival was 12 months, compared with 15 months for FOLFOX alone (P = .18). Dr. Martin said that due to the size of the study and limited follow-up, statistically significant differences in these

endpoints would not be expected. “Simultaneous [modified] FOLFOX6 with bevacizumab and hepatic arterial irinotecan drug-eluting beads is safe, without causing chemotherapy delivery delays and without increasing chemotherapy toxicity,” Dr. Martin said. There were 144 grade 3/4 adverse events in 32 patients on the DEBIRI arm and 36 among 18 patients in the control arm. Serious adverse events numbered 57 and 15, respectively, which was significantly higher for the DEBIRI arm (P = .03). Chemotherapyrelated adverse events numbered 38 and 21, respectively (P = .08).

Keys to Effectiveness “Simultaneous FOLFOXDEBIRI leads to improved overall response rates, improved hepatic progression–free survival [not statistically significant], and more durable overall progression-free survival in patients downsized to resection,” Dr. Martin concluded. He suggested that the “keys to effectiveness and expansion” will be to define patients with liver-dominant disease, to maintain proper DEBIRI techniques and dosing, to collaborate with medical oncologists, and to follow an appropriate treatment strategy that follows up in the reevaluation for surgical resection. Dr. Martin indicated that a phase III trial would need to stratify patients according to KRAS status and include cetuximab (Erbitux) and bevacizumab. n Disclosure: Dr. Martin has a consulting or advisory role with Biocompatibles International.

Reference 1. Martin RCG, Scoggins CR, Rilling WS, et al: Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liverlimited metastasis. 2014 Gastrointestinal Cancers Symposium. Abstract 174. Presented January 17, 2014.

Irinotecan Drug-Eluting Beads in Colorectal Cancer ■■ In a randomized controlled trial of patients with unresectable, liver-limited colorectal cancer metastases, irinotecan drug-eluting beads given with FOLFOX and bevacizumab improved response rates. ■■ Hepatic progression–free survival was also improved, as was the ability to downsize tumors for resection.

(dabrafenib) 50 mg, 75 mg capsules

For more information, visit TAFINLARHCP.com TAFINLAR is a registered trademark of the GlaxoSmithKline group of companies. ©2013 GlaxoSmithKline group of companies. All rights reserved. Printed in USA. TAF015R0 May 2013

ASCOPost.com | MARCH 1, 2014

PAGE 11

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Biomarker-Defined Subgroup Benefits From Novel Approach to Advanced Hepatocellular Carcinoma By Caroline Helwick

romising efficacy in advanced hepatocellular carcinoma patients was reported for a novel transforming growth factor–beta receptor type 1 (TGF-β1) kinase inhibitor, LY2157299 monohydrate, at the 2014 Gastrointestinal Cancers Symposium

Sandrine Faivre, MD, PhD

in San Francisco.1 In particular, patients with moderate to poorly differentiated tumors that overexpressed alpha-fetoprotein had improved time to progression and overall survival, suggesting alpha-fetoprotein may serve as a biomarker for this compound, reported Sandrine Faivre, MD, PhD, a medical oncologist at the Hôpital Beaujon in Clichy, France. “LY2157299 displays a suitable safety profile for patients with ChildPugh stage A or B7 hepatocellular carcinoma,” Dr. Faivre reported.

Why Target TGF-β1? “TGF-β signaling is associated with progression in hepatocellular carcinoma,” she noted. TGF-β has a role in modulating E-cadherin, [alpha-fetoprotein], and T regulatory cells. LY2157299 is a TGF-β receptor 1 kinase inhibitor that has antitumor activity in various hepatocellular carcinoma models, and has demonstrated a favorable toxicity profile in patients with glioma. In the current study, inhibition of TGF-β1 receptor by LY2157299 was associated with pharmacodynamic effects, resulting in decreased alphafetoprotein, TGF-β1, and E-cadherin serum levels. The study enrolled 109 patients with advanced hepatocellular carcinoma who had disease progression on or were ineligible to receive sorafenib (Nexavar), who

had received only one prior systemic regimen, and who had elevated alphafetoprotein levels (a population with enriched TGF-β signaling). Patients with Child-Pugh stage A or B7 hepatocellular carcinoma were randomly assigned to receive LY2157299 monohydrate, administered for 14 days of a 28-day cycle in doses of either 160 or 300 mg/d. The doses yielded similar safety and activity results, with 300 mg/d achieving a better drug exposure. By RECIST criteria, approximately one-third of the patients achieved stable disease, but the pharmacodynamic effects on three prespecified potential biomarkers were more impressive, she reported. A > 20% reduction from baseline alphafetoprotein was observed in 24%; a > 20% reduction in TFG- β1 was observed in 53% (and in 72% of alpha-fetoprotein responders); and a > 20% reduction in Ecadherin was observed in 43% (including 36% of alpha-fetoprotein responders).

Robust Results For the whole population, the median time to progression was 2.8 months and median overall survival

Targeting TFG-β in Hepatocellular Carcinoma ■■ LY2157299 monohydrate, a TFG-β1 receptor kinase inhibitor, improved time to progression and overall survival in a subset of patients with advanced hepatocellular carcinoma. ■■ While the drug was not particularly active in the unselected population, patients whose levels of alpha-fetoprotein were reduced > 20% with treatment had a significant improvement in time to progression and overall survival, compared to patients lacking such a response.

was 8.3 months, and there were no differences between the two dose levels. In contrast, for “alpha-fetoprotein responders”—ie, the 24% of patients with > 20% reduction in alpha-fetoprotein baseline levels—outcomes were much improved, she reported. For alpha-fetoprotein responders, median time to progression was 4.3 months, vs 1.5 months for nonresponders (P < .0001), and median overall survival was 21.4 vs 6.8 months, respectively (P < .0006). “A proportion of patients with an [alpha-fetoprotein] response showed very sustained disease control and long overall survival,” she added. Interestingly, when analyzed according to baseline alpha-fetoprotein

EXPERT POINT OF VIEW

osep M. Llovet, MD, Professor of Medicine at Mount Sinai Hospital, New York, commented on the findings reported by Faivre et al for The ASCO Post. “This is the first time a TGF-β inhibitor has been clinically tested in hepatocellular carcinoma, and the drug has a good safety profile. But this is a phase II single-arm study, not randomized,” he cautioned. Josep M. Llovet, MD He suggested that while the results were encouraging, the patient population needs to be better defined, and this extends to patients enrolled on future phase III studies. He noted that in the unselected population, the drug appears to have no benefit. “We need a biomarker that can predict response,” he said. “[Alphafetoprotein] levels at baseline are not good predictors of response. It’s the patients who have decreased [alpha-fetoprotein] with treatment [who are likely to benefit]. We need a baseline biomarker.” n

Disclosure: Dr. Llovet has served as a consultant for Bristol-Myers Squibb and has received honoraria from Bayer Pharmaceuticals and Bristol-Myers Squibb.

levels, response rates to treatment were not different between those with elevated alpha-fetoprotein (≥ 200 ng/mL) or normal alpha-fetoprotein (< 200 ng/mL). “High baseline [alpha-fetoprotein] remained prognostic for poor outcomes,” she noted. Among this group of 74 patients, median time to progression was 12 weeks and median overall survival was 30 weeks. Among patients with alpha-fetoprotein < 200 ng/mL at baseline, however, responders had at least a 70% reduction in risk for both progression and death, vs nonresponders.

Biomarker Is Key Dr. Faivre acknowledged the 8-month overall survival for the whole population is on par with the median overall survival for placebo arms in other studies, but she emphasized that the benefit will most likely be limited to a biomarker-defined subgroup. “Using [alpha-fetoprotein] monitoring, we showed the subset of patients who benefited from this treatment. Probably the majority of the others will not benefit from this approach,” she commented. n

Disclosure: Dr. Faivre has received honoraria and research funding from Lilly. For full disclosures of the study authors, visit meetinglibrary.asco.org.

Reference 1. Faivre SJ, Santoro A, Kelley RK, et al: A phase 2 study of a novel transforming growth factor-beta receptor I kinase inhibitor, LY2157299 monohydrate, in patients with advanced hepatocellular carcinoma. 2014 Gastrointestinal Cancers Symposium. Abstract LBA173. Presented January 17, 2014.

Because your patients have different needs… …Amgen supports a broad range of access programs INDEPENDENT CO-PAY FOUNDATIONS Amgen Assist can check the current funding status at different independent foundations for your office

MEDICARE

UNINSURED

COMMERCIALLY INSURED

THE SAFETY NET FOUNDATION The Safety Net Foundation provides products at no cost to eligible uninsured and underinsured patients THE NEULASTA/NEUPOGEN FIRST STEP™ PROGRAM The NEULASTA/NEUPOGEN FIRST STEP™ Program helps reduce out-of-pocket (OOP) costs for all eligible commercially insured patients. Go to www.amgenfirststep.com for program eligibility and limitations

NEULASTA/NEUPOGEN FIRST STEP™ PROGRAM For more information regarding these programs, please call 1-888-4ASSIST or visit AmgenAssistOnline.com To enroll your patient into the Amgen FIRST STEP™ Co-pay Coupon Program call 1-888-65-STEP1 (1-888-657-8371) or visit amgenfirststep.com. The NEULASTA/NEUPOGEN FIRST STEP™ Program MasterCard is issued by The Bancorp Bank pursuant to license by MasterCard International and this card may not be used everywhere Debit MasterCard is accepted. No cash or ATM access. MasterCard is a registered trademark of MasterCard International Incorporated. The Bancorp Bank; Member FDIC.

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

ASCOPost.com | MARCH 1, 2014

PAGE 13

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Capecitabine Acceptable in Neoadjuvant Rectal Cancer Setting By Caroline Helwick

s neoadjuvant therapy for rectal cancer, infusional fluorouracil (5-FU) and oral capecitabine achieve similar outcomes, and the addition of oxaliplatin confers no additional benefit, according to the mature results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial, which were presented at the 2014 Gastrointestinal Cancers Symposium in San Francisco.1 “Because the use of oral capecitabine avoids the need for central venous catheters and ambulatory infusions pumps, it can be considered a new standard of care in this setting,” said Carmen J. Allegra, MD, Professor of Medicine and Chief of Hematology/Oncology at the University of Florida, Gainesville. He further commented to The ASCO Post on the importance of having data confirming the lack of benefit with oxaliplatin. “I think while many physicians are already using capecitabine, many are also using a lot of oxaliplatin, and they have been doing it without data. Now we have negative data,” he said.

Study Details NSABP R-04 compared 5-FU and capecitabine combined with pelvic radiation therapy preoperatively in 1,608

patients with stage II or III rectal cancer, and evaluated whether the addition of oxaliplatin would improve outcomes. Patients were randomly assigned to one of four treatment arms, each of which included radiation. Chemotherapy regimens were assigned in a 2×2 design: continuous-infusion 5-FU (225 mg/m2 for

at the 2011 ASCO Annual Meeting, were that capecitabine and preoperative radiation achieved rates similar to continuous infusional 5-FU for surgical downstaging, sphincter-sparing surgery, and pathologic complete response rates, and the addition of oxaliplatin did not improve outcomes.2

This study establishes capecitabine as a standard of care in the preoperative rectal cancer setting. —Carmen J. Allegra, MD

5 days per week) with or without oxaliplatin (50 mg/m2 per week for 5 weeks), or capecitabine (825 mg/m2 twice daily for 5 days per week) with or without oxaliplatin (50 mg/m2 per week for 5 weeks). The primary endpoint of local-regional tumor control included local-regional tumor recurrence, complete surgical resection (> R0), and no surgery. The preliminary findings, presented

Role of Capecitabine in Rectal Cancer ■■ NSABP R-04 found that capecitabine achieved outcomes similar to those seen with infusional 5-FU in the neoadjuvant treatment of rectal cancer. ■■ Rates of local-regional tumor control, the primary endpoint, were similar— approximately 88% in each arm. ■■ Pathologic complete response, disease-free survival, and overall survival rates were also similar. ■■ The addition of oxaliplatin did not increase benefit but did increase toxicity.

Outcomes Similar in Both Arms The study found no significant differences in local-regional tumor control, disease-free survival, or overall survival between regimens for the comparison of 5-FU and capecitabine, and the comparison of oxaliplatin vs no oxaliplatin, Dr. Allegra reported. “Clearly, there was no difference in the use of either fluoropyrimidine or the use, or nonuse, of oxaliplatin,” he said. An analysis of the primary endpoint showed that 3-year rates of localregional tumor control ranged from 87.4% to 88.2%. At 3 years, the rates of local-regional recurrence among patients who had an R0 resection ranged from 2% to 4% for patients with stage II disease, and from 4% to 11% for those with stage III disease. By 5 years, distant metastases devel-

oped in 16% of stage II patients and 26% of stage III patients. About 80% of each arm were alive 5 years after surgery. From 84% to 97% of patients received more than 80% of the optimal chemotherapy dose in combination with preoperative radiotherapy. Adverse event rates were similar for 5-FU and capecitabine. “The addition of oxaliplatin provided no improvement in outcomes but did add significant toxicity,” including more grade 3/4 diarrhea (P < .0001), he reported. Dr. Allegra noted that capecitabine is more expensive than 5-FU; however, it also costs more to maintain a port and administer the infusion. “This study establishes capecitabine as a standard of care in the preoperative rectal cancer setting,” he concluded. The study also has a large qualityof-life component, and results from this are expected in 2015. n

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

References 1. Allegra CJ, Yothers G, O’Connell MJ, et al: Neoadjuvant therapy for rectal cancer: Mature results from NSABP protocol R-04. 2014 Gastrointestinal Cancers Symposium. Abstract 390. Presented January 18, 2014. 2. Roh MS, Yothers GA, O’Connell MJ, et al: The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. 2011 ASCO Annual Meeting. Abstract 3503. Presented June 4, 2011.

Don’t Miss These Important Reports in This Issue of The ASCO Post Francis S. Collins, MD, PhD, on Biomedical Research see page 1

Daniel J. Canter, MD, on Metastatic Renal Cell Carcinoma see page 3

Maha Hussain, MD, on Metastatic Prostate Cancer see page 8

Debu Tripathy, MD, on HER2-Positive Breast Cancer see page 25

Michael J. Fisch, MD, MPH, on Managing Cancer Pain see page 56

Steven T. Rosen, MD, on His New Position at City of Hope see page 67

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | MARCH 1, 2014

PAGE 14

Issues in Oncology

U.S. Government Accountability Office Issues Report on Drug Shortages

he U.S. Government Accountability Office (GAO) recently issued a report evaluating drug shortages and the associated public health threats, including prolonged duration of a disease, permanent injury, and death.1 This report follows a recommendation by GAO in 2011 that the U.S. Food and Drug Administration (FDA) enhance its ability to respond to shortages. In the recently released report, GAO has reviewed trends in drug shortages, effects on patients and providers, causes, and FDA progress in addressing shortages. GAO has recommended that FDA strengthen its internal controls over its drug shortage data, and that the Agency conduct periodic analyses to routinely and systematically assess drug shortage information to proactively identify drug shortage risk factors.

risks of drug shortages. In response to the GAO report, ASCO has issued a statement in support of strengthening the FDA’s current capacity to monitor the adequacy of the nation’s drug supply for the benefit

of people with cancer and other conditions (see sidebar on page 15). n Reference 1. U.S. Government Accountability Office: Drug shortages: Public

health threat continues, despite efforts to help ensure product availability. Report GAO-14-194, published February 10, 2014. Available at www.gao .gov/products/GAO-14-194. Accessed February 11, 2014.

Findings According to the GAO report, there is a high number of drug shortages, and although new drug shortages declined in 2012, the total number of shortages active during a given year has increased since 2007. This includes both new shortages reported and ongoing shortages that began in a prior year. Many shortages are of generic sterile injectable drugs and result from a manufacturer halting or slowing production to address quality problems, triggering a supply disruption. In other cases, manufacturers have a limited ability to respond to supply disruptions due to constrained manufacturing capacity. Quality and economic issues also were reported to be factors causing drug shortages. The report noted that although shortages have persisted, FDA has prevented more potential shortages in the last 2 years by improving its responsiveness and implementing recommendations made by GAO in 2011. FDA has also developed procedures to enhance coordination between headquarters and field staff. However, according to the GAO report, shortcomings in its management of drug shortage data are inconsistent with internal control standards. For example, FDA has not created policies or procedures governing the management of the data and does not perform routine quality checks on its data. In addition, FDA has not conducted routine analyses of the data to proactively identify and evaluate the

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | MARCH 1, 2014

PAGE 15

Issues in Oncology

ASCO Supports Reinforcing FDA Capacity to Monitor Nation’s Drug Supply ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FASCO, Issues Statement

“T

he GAO report identifies production lapses due to quality

problems and constrained manufacturing capacity as being the central

causes of the widespread incidence and persistence of drug shortages.

Advertisement not displayed in digital edition at advertiser’s request

“The report also emphasizes that the FDA has made significant progress in preventing shortages by improving its responsiveness to emergent supply chain disruptions in the past 2 years. However, the GAO report determines that current FDA efforts to prevent and resolve shortages suffer from lapses in data availability and quality that

ASCO remains alarmed about the high number of drug shortages and supports strengthening the FDA’s current capacity to monitor the adequacy of the nation’s drug supply. —Richard L. Schilsky, MD, FACP, FASCO

prevent FDA from improving its response to drug shortages. These shortcomings hinder the FDA’s ability to understand the causes of specific shortages and proactively develop strategies to prevent them from occurring. “ASCO remains alarmed about the high number of drug shortages, particularly of sterile injectable chemotherapy and supportive care products, and supports strengthening the FDA’s current capacity to monitor the adequacy of the nation’s drug supply for the benefit of people with cancer and other conditions.” n

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication

The ASCO Post | MARCH 1, 2014

PAGE 16

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

GI Symposium Presentations Include Important Updates in Treatment and Prognosis of Pancreatic and Colorectal Cancers By Caroline Helwick

ore than 650 studies were presented at the 2014 Gastrointestinal Cancers Symposium, which attracted a multidisciplinary group of more than 3,500 medical, surgical, and radiation oncologists and gastroenterologists. The following briefs highlight a handful of noteworthy studies from the meeting.

Updated Survival Outcome in MPACT An updated analysis of the MPACT trial (cutoff, May 2013) upheld the overall survival benefit of nab-paclitaxel (Abraxane) plus gemcitabine,

David Goldstein, MD

vs gemcitabine alone, in metastatic pancreatic adenocarcinoma.1 Median overall survival was 8.7 months with the combination and 6.6 months with gemcitabine alone (hazard ratio [HR] = 0.72; P < .0001), and the 24-month overall survival rate was 10% vs 5%, respectively, according to David Goldstein, MD, Senior Staff Specialist in the Department of Medical Oncology at Prince of Wales Hospital in Sydney, Australia. In the updated model, cancer antigen (CA) 19-9 was a significant predictor of overall survival and the number of metastatic sites was no longer significant. Treatment with nab-paclitaxel plus gemcitabine appeared to reduce the negative effect of CA 19-9 as a prognostic factor, he said. “Longer follow-up demonstrated a median overall survival difference of 2.1 months and identification of patients surviving at least 3 years (4%) in the nab-paclitaxel plus gemcitabine

arm,” Dr. Goldstein said. “We believe nab-paclitaxel is an important option for patients with metastatic pancreatic cancer, with the potential for longterm survivors.”

es II, III, and IV disease (P = .013) and between local/regional disease and metastatic disease (P < .001). At a cutoff of at least two circulating tumor cells per 2 mL of blood, sensitivity was 68.8%, specificity was 96%, and positive predictive value was 92.3%. Circulating tumor cells were more discriminatory than CA 19-9 levels, Dr. Ankeny added. “[Circulating tumor cells] show promise as a biomarker at the time of disease presentation that could be used for pretreatment staging,” he suggested.

Circulating Tumor Cells in Pancreatic Cancer Diagnosis

Systemic Inflammation and Colorectal Cancer Outcomes

Circulating tumor cells can aid in the diagnosis of pancreatic ductal adenocarcinoma and can identify patients with metastases at presentation, according to a prospective analysis from the University of California, Los Angeles.2 Researchers evaluated 61 consecutive patients suspected of having pancreatic cancer, or recently diagnosed with it but untreated. They examined 2 mL of blood for the presence and number of circulating tumor cells using NanoVelcro technology enhanced by anti-EpCAM enrichment. Of the 61 patients, 41 had cancer and 20 had nonmalignant pathology on tissue biopsy. “We were able to discriminate between pancreatic ductal adenocarcinoma and non-adenocarcinoma diseases using [circulating tumor cell] presence as a marker,” said Jacob S. Ankeny, MD, a resident in the Department of Surgery, University of California, Los Angeles. Seven patients with presumed stage II disease were found to have metastatic disease at surgery. In five of these patients, the presence of at least two circulating tumor cells was detected, he added. The investigators found that circulating tumor cell enumeration could be used to discriminate between stag-

Immune response impacts metastatic colorectal cancer tumor biology. Local inflammation with high-density tumor infiltrating lymphocytes is associated with good prognosis, while systemic inflammation, assessed by a neutrophil-lymphocyte ratio > 5, is associated with a poor prognosis. It is believed that a reduction in tumor burden (such as through surgical resection) might, in turn, reduce the level of tumor-promoting cytokines (ie, interleukin-6) that lead to systemic inflammation; in particular, reversal of a neutrophil-lymphocyte ratio > 5 (to ≤ 5) might improve patient survival. Australian investigators explored this concept in 156 patients after primary resection for de novo metastatic colorectal cancer. This group’s median overall survival was 18.3 months.3 While there was a trend toward worse survival for those with a neutrophillymphocyte ratio > 5 at diagnosis (HR = 1.3; P = .15), postoperative neutrophil-lymphocyte ratio was a more impressive marker. Patients with a postoperative neutrophil-lymphocyte ratio > 5 had a statistically significantly worse survival (HR = 2.37; P < .001) than those with a neutrophil-lymphocyte ratio ≤ 5, Primary resection resulted in reversal of neutrophil-lymphocyte ratio > 5 in 56% of patients, and this conveyed a significant survival advantage over persistence of neutrophil-lymphocyte ratio > 5 (HR = 0.53; P = .012). In fact, survival for patients with reversal of neutrophillymphocyte ratio > 5 was similar to those who had neutrophil-lymphocyte

Jacob S. Ankeny, MD

New Data in Pancreatic Cancers ■■ Updated analysis of MPACT upheld the overall survival improvement found with nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer. ■■ The presence of circulating tumor cells accurately distinguished between pancreatic cancer and benign conditions, and helped stage disease.

ratio ≤ 5 preoperatively, reported Philip V. Tran, MD, Director of Medical Imaging at the Western Hospital in Footscray, Australia. Patients with the reversal of this potential biomarker of inflammation tended to have larger primary tumors but low metastatic burden (based on maximal diameter of largest metastasis).

Early Tumor Shrinkage and Deep Response The importance of achieving an early response to treatment for metastatic colorectal cancer was confirmed in an Italian study in which early tumor shrinkage predicted improved progression-free survival, postprogression survival, and overall survival after chemotherapy plus bevacizumab (Avastin).4 Deepness of response also correlated significantly with these outcomes, reported Chiara Cremolini, MD, a medical oncologist at the Santa Chiara Hospital in Pisa, Italy. Early tumor shrinkage was defined as the relative change in the sum of the longest diameters of RECIST target lesions at week 8, compared to baseline, with a cutoff value of 20%. Deepness of response was the relative change in the sum of the longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of nontarget lesions, compared to baseline.

Chiara Cremolini, MD

The data came from the TRIBE study, which randomized 508 patients to FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) plus bevacizumab or FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, irinotecan) plus bevacizumab. Median progression-free survival was significantly improved with FOLFOXIRI/bevacizumab (P = .003), and significantly more of these patients achieved an early response (64% vs 51%, P =

ASCOPost.com | MARCH 1, 2014

PAGE 17

Gastrointestinal Cancers Symposium .006), and a higher extent of deepness of response (P = .0009) compared to the FOLFIRI/bevacizumab arm. With the arms combined, both early tumor shrinkage and deepness of response predicted progression-free survival, postprogression survival, and overall survival. Median progression-free survival was 12.7 months in patients achieving early tumor shrinkage and 10 months in those without (HR = 0.66, P < .0001). Median postprogression survival was 17.1 vs 10.7 months, respectively (HR = 0.64, P = .0005). Median overall survival was 35.8 vs 22.4 months, respectively (HR = 0.54, P < .0001), Dr. Cremolini reported. Deepness of response greater than the median was associated with a median overall survival of 36.8 months, vs 21.3 months without (HR = 0.47; P < .0001). Moreover, for the first time, a significant correlation of the deepness of response with progression-free survival was demonstrated (HR = 0.61 [0.49–0.73], P < .0001). “Both [early tumor shrinkage] and deepness of response correlate with progression-free survival, postprogression survival, and overall survival, irrespective of the treatment arm,” Dr. Cremolini said. “These data confirm the importance of achieving an early response in metastatic colorectal cancer and the value of both early tumor shrinkage and deepness of response as determinants of long-term outcomes and potential endpoints for clinical trials.”

Induction vs Adjuvant Chemotherapy in Rectal Cancer The randomized phase II Spanish

GCR-3 trial, involving 108 patients, evaluated the efficacy and toxicity of two strategies in locally advanced rectal cancer. Arm A received chemotherapy plus radiotherapy, followed by surgery and four more cycles of postoperative adjuvant CAPOX (capecitabine and oxaliplatin), and arm B received CAPOX followed by chemoradiation and surgery. The study previously showed that the induction approach (arm B) allowed most patients to receive planned treatment, with less toxicity, and no compromise in pathologic complete response and complete resection rates. Investigators reported an updated analysis at a median follow-up of 5 years.5 At 5 years, disease-free survival was 64.3% in arm A and 62.1% in arm B (P = .85) and overall survival was 77.9% and 74.7%, respectively (P = .64).

New Data in Colorectal Cancers ■■ Reduction in systemic inflammation after primary resection, as measured by the neutrophil-leukocyte ratio, was significantly associated with improved survival in patients with metastatic colorectal cancer. ■■ Early tumor shrinkage and deepness of response correlated with progression-free survival, postprogression survival, and overall survival after chemotherapy plus bevacizumab in metastatic colorectal cancer patients. ■■ For the treatment of locally advanced rectal cancer, induction chemotherapy prior to chemoradiation was toxicity sparing, compared to adjuvant chemotherapy, but clinical outcomes were similar between the arms, in 5-year follow-up of the Spanish GCR-3 trial.

tion arm. “The induction approach, however, achieved a better toxicity profile and allowed for greater exposure to systemic therapy, without affect compliance to chemoradiation,” reported Carlos Fernandez-Martos, MD, a medical oncologist at Fundacion Instituto Valenciano de Oncologia in Spain. n Disclosure: Dr. Goldstein is a consultant or advisor for and has received research funding from Celgene. Drs. Ankeny, Tran, Cremolini, and Fernandez-Martos reported no potential conflicts of interest. For full disclosures from the study authors, visit meetinglibrary.asco. org.

Carlos Fernandez-Martos, MD

Local recurrences after macroscopically complete resection of the primary tumor occurred in 2.1% of patients randomly assigned to arm A and in 1.9% of patients randomly assigned to induction chemotherapy. The cumulative incidence of distant metastases at 5 years in the intentionto-treat population was 21.1% in the adjuvant arm and 23.2% in the induc-

References 1. Goldstein D, El-Maraghi RH, Hammel P, et al: Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. 2014 Gastrointestinal Cancers Symposium. Abstract 178. Presented January 17, 2014. 2. Ankeny JS, Hou S, Lin M, et al: Pancreatic circulating tumor cells as a diagnostic adjunct in pancreatic cancer. 2014

Gastrointestinal Cancers Symposium. Abstract 175. Presented January 17, 2014. 3. Tran PV, Sinnathamby M, Wong H-L, et al: Are the survival benefits associated with primary resection in de novo metastatic colorectal cancer mediated by reversal of systemic inflammation? 2014 Gastrointestinal Cancers Symposium. Abstract 464. Presented January 18, 2014. 4. Cremolini C, Loupakis F, Lonardi S, et al: Early tumor shrinkage and deepness of response to predict progressionfree, postprogression and overall survival: Results from the phase III TRIBE trial. 2014 Gastrointestinal Cancers Symposium. Abstract 521. Presented January 18, 2014. 5. Fernandez-Martos C, Pericay C, Aparicio J, et al: Chemoradiation (CRT) followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant CRT and surgery for locally advanced rectal cancer: Results of the Spanish GCR-3 randomized phase II trial after a median follow-up of 5 years. 2014 Gastrointestinal Cancers Symposium. Abstract 383. Presented January 18, 2014.

Contact The ASCO Post Advertising

Editorial Correspondence

Rates, reprints, or supplements

Editorial Office

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

Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

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

Rights & Permissions e-mail: Permissions@harborsidepress.com

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

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

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

100%

Patients, %

80%

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

60% 40% 20% 0%

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

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

ORR 29.2% (n=33)

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

POMALYST + low-dose dex (N=113)

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

Study design: A Phase 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 | MARCH 1, 2014

PAGE 22

News

ASCO Applauds CVS Caremark’s Move to Stop Selling Tobacco

VS Caremark recently announced that it will stop selling cigarettes and other tobacco products at its more than 7,600 CVS/pharmacy stores across the United States by October 1, 2014, making CVS/pharmacy the first national pharmacy chain to take this

step in support of the health and wellbeing of its patients and customers. In response, ASCO President Clifford A. Hudis, MD, FACP, has issued the following statement: “CVS Caremark should be commended for its courageous decision to 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

stop selling tobacco products in all of its pharmacy stores. The oncology community is extremely grateful that CVS Caremark recognized that support for tobacco use has no place in any healthcare facility and took action. We hope this is an inspirational example of corpoToxicity

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

rate responsibility for others to follow. “Tobacco use is the leading preventable cause of cancer in the world and also worsens the prognosis of people already diagnosed with many types of cancer. Overall, tobacco kills more than 480,000 Americans each year, and (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 | MARCH 1, 2014

PAGE 23

News

more than 4 million people worldwide, shortening smokers’ lives, on average, by more than 7 years. “We urge all pharmacies and other businesses that still sell tobacco products to follow CVS Caremark’s lead.” “Ending the sale of cigarettes and tobacco products at CVS/pharmacy is the right thing for us to do for our customers • 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

and our company to help people on their path to better health,” said Larry J. M erlo, President and CEO, CVS Caremark. “Put simply, the sale of tobacco products is inconsistent with our purpose.” CVS Caremark’s decision to stop selling tobacco products is consistent with the positions taken by the American Medical Association, American Heart (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)]

Association, American Cancer Society, American Lung Association, and American Pharmacists Association, which have all publicly opposed tobacco sales in retail outlets with pharmacies. The company estimates that it will lose approximately $2 billion in revenues on an annual basis from the tobacco shopper. n 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.

The ASCO Post | MARCH 1, 2014

PAGE 24

San Antonio Breast Cancer Symposium Breast Cancer

HER2-Positive Breast Cancer Patients With Small Tumors Benefit From Low-Toxicity Regimen By Caroline Helwick

here may be a benefit for treating small HER2-positive tumors—a breast cancer subset for whom treatment

recommendations have not been established but for whom there is still risk of recurrence—and this can be done with

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

little toxicity, according to a multicenter study presented at the 2013 San Antonio Breast Cancer Symposium.1 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

“Smaller, HER2-positive, node-negative breast cancers are thought to have a sufficiently high chance of recurring that many doctors have offered patients a combination of chemotherapy and trastuzumab [Herceptin] to reduce that risk,” said senior author Eric P. Winer, MD, Chief of the Division of Women’s Cancers in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, Boston. “But, as this approach had not been tested in many women with smaller tumors, we have lacked a standard approach to preventing recurrence in this group.” That may be largely because previous studies of chemotherapy plus anti-HER2 treatment for node-negative patients have included few subjects with tumors measuring < 2 cm and virtually none with tumors ≤ 1 cm, a group for whom treatment has been debated. The findings of the current study offer, for the first time, a set of standard treatment guidelines for recurrence prevention in this group of patients, according to Dr. Winer.

APT Trial The Adjuvant Paclitaxel and Trastuzumab (APT) study of 406 women with HER2-positive, node-negative tumors ≤ 3 cm was presented at the San Antonio Breast Cancer Symposium by Sara M. Tolaney, MD, MPH, a medical oncologist at Dana-Farber Cancer Institute, who explained the need to balance risks and benefits in a group of patients who will likely derive a small absolute treatment benefit. “In balancing the risks and benefits

Adjuvant Therapy in Stage I Breast Cancer ■■ Women with HER2-positive, node-negative breast cancer tumors ≤ 3 cm appeared to derive benefit from adjuvant treatment with weekly paclitaxel plus trastuzumab. ■■ Treatment of these small tumors has been debated; while very small (T1a) tumors probably would still not warrant treatment, the study confirms that treatment with a low-toxicity regimen (lacking doxorubicin) benefits many patients.

ASCOPost.com | MARCH 1, 2014

PAGE 25

San Antonio Breast Cancer Symposium of treatment, the development of regimens with lower degrees of toxicity is particularly important for this patient population,” she said. The investigators, therefore, designed a more tolerable chemotherapy regimen than is often given. Patients received only paclitaxel at 80 mg/m2 plus trastuzumab at 2 mg/kg weekly for 12 weeks, fol-

(P < .0001). By hormone receptor status, disease-free survival rates were 98.5% in receptor-positive patients and 99.2% in receptor-negative patients. The recurrence-free survival rate (invasive locoregional recurrence, distant recurrence, death from breast cancer) was 99.2%, Dr. Tolaney reported. Few adverse events were noted.

The development of effective targeted therapies provides the opportunity not only to improve outcomes, but to back off toxicity by limiting some of the chemotherapy. The challenge now is to determine in whom a completely chemotherapyfree regimen might be a possibility.

“This doesn’t mean that every single patient with node-negative HER2positive disease has to be treated with trastuzumab and chemotherapy, and there are patients with T1a tumors who almost certainly should not be treated systemically,” he said in an interview with The ASCO Post. The T1a population accounted for 20% of subjects, while 9% had relatively large T2 tumors. “This was not just a population of patients with tumors less than 1 cm, and in spite of that, the outcome was very favorable,” he noted. “We think that for most women with stage I HER2-positive breast cancer, trastuzumab plus paclitaxel is an entirely reasonable, and certainly appealing, regimen because of its low-toxicity profile,” he maintained.

Key Findings After a median follow-up of 3.6 years, only 10 of 406 patients experienced a recurrence or death, accounting for 2.5% of the population. There were only four local/regional recurrences (0.9%).

Sarah M. Tolaney, MD, MPH

Study patients developed three new contralateral primary breast cancers (0.7%), all HER2-negative, and two distant recurrences (0.5%). Disease-free survival at 3 years was 98.7%

Only two patients (0.5%) developed symptomatic congestive heart failure, and both cases resolved after discontinuation of trastuzumab. Asymptomatic declines in left-ventricular ejection fraction were observed in 13 patients (3.2%), and 11 patients were able to resume trastuzumab after a treatment interruption. Dr. Tolaney acknowledged that the study has limitations. It was a singlearm, nonrandomized trial, and about 20% of enrolled patients had T1a tumors that already have a very favorable prognosis. Also, two-thirds had hormone receptor–positive tumors, and this may be associated with late recurrences. Nevertheless, she suggested that paclitaxel plus trastuzumab can be considered “a reasonable and appealing approach for the majority of patients with stage I HER2-positive breast cancer.”

Practice-Changing Results Dr. Winer suggested that the results were practice-changing. For this population, the paclitaxel/trastuzumab doublet “should be considered one of the standard strategies for recurrence prevention,” he said.

Disclosure: Dr. Winer receives research funding from Genentech. Dr. Tolaney reported no potential conflicts of interest.

Reference 1. Tolaney SM, Barry WT, Dang CT, et al: A phase II study of adjuvant paclitaxel and trastuzumab (APT) trial for node-negative, HER2-positive breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 11, 2013.

EXPERT POINT OF VIEW

—Eric P. Winer, MD

lowed by 9 months of trastuzumab alone at 6 mg/kg every 3 weeks. The study was a nonrandomized prospective trial to define the outcomes in a uniformly treated cohort based on the fact that “a prospective randomized trial of trastuzumabbased therapy is likely not feasible,” Dr. Tolaney said.

The APT study also “speaks to a larger point,” he said, “and that is the development of effective targeted therapies provides the opportunity not only to improve outcomes, but to back off toxicity by limiting some of the chemotherapy. The challenge now is to determine in whom a completely chemotherapy-free regimen might be a possibility.” n

ebu Tripathy, MD, Professor of Medicine, Co-Leader of the Women’s Cancer Program, and the Priscilla and Art Ulene Chair in Women’s Cancer at the University of Southern California Norris Cancer Center, Los Angeles, commented on the APT study for The ASCO Post. “In treating early-stage HER2-positive breast cancer, we know that chemotherapy plus trastuzumab [Herceptin] lowers the risk of recurrence. Debu Tripathy, MD But when the risk itself is very low for small nodenegative tumors, the question is, at what point is it not worth it, because there are side effects,” he said. Dr. Tripathy noted that most trastuzumab trials included tumors less than 1 or 2 cm, “so we don’t know much about the benefit of treatment in those situations.” Even studies attempting to estimate benefit are not felt to be very accurate, he said.

Absence of Doxorubicin Since this is a small population of patients who have a favorable outcome, and since accruing HER2-positive patients to a placebo arm would be impossible, a properly powered randomized trial was out of the question. Instead, Dr. Winer and his team designed a single-arm study to define outcomes in a uniformly treated patient cohort, without a comparator but with an appreciation of the expected rate of events in such a population. The weekly paclitaxel was standard treatment, but the omission of doxorubicin was not. “Did the absence of doxorubicin affect outcomes? We don’t know, but the number of events is low enough that it really doesn’t matter. The outcomes surpassed their expectations,” Dr. Tripathy ponted out, concluding that the research points to “a treatment option—a ‘niche regimen’—for these smaller tumors.” n

Disclosure: Dr. Tripathy’s institution (University of Southern California) receives funding from Genentech/Roche for clinical research.

Delivered to your inbox every weekday evening. Visit ASCOPost.com to learn more.

The ASCO Post | MARCH 1, 2014

PAGE 26

San Antonio Breast Cancer Symposium Breast Cancer

Innovative I-SPY 2 Trial Yields First Results in Triple-Negative Breast Cancer By Caroline Helwick

n innovative approach to streamlining the testing of novel agents in breast cancer has yielded some of its first results, which were reported at the 2013 San Antonio Breast Cancer Symposium.1

Adaptive Trial Design The veliparib/carboplatin plus standard neoadjuvant therapy regimen is currently one of seven experimental treatments evaluated to date in the multidrug I-SPY 2 trial, which uses an adaptive design based on biomarker subtypes to eval-

Hope S. Rugo, MD

uate novel agents in the neoadjuvant setting. The objective of the novel approach is to speed up and therefore revolutionalize the way that oncology drugs are tested and approved, said Hope S. Rugo, MD, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. The strategy involves the evaluation of drugs in small study populations, using advanced statistical techniques that promptly cull potential winners from losers. Experimental regimens can “graduate” in at least one of 10 possible signatures defined by hormone receptor status, HER2 status, and MammaPrint. This propels the drugs into phase III trials. Veliparib is the first drug to complete testing in the innovative study.

I-SPY 2 is a new way of getting new drugs into clinical testing more rapidly. This is very important as our number of novel treatment options expands. —Peter Ravdin, MD, PhD

“Our goal is to identify and graduate regimens that have at least an 85% Bayesian predictive probability of success in [future] 300-patient biomarker-linked phase III neoadjuvant trials,” she said. Peter Ravdin, MD, PhD, Breast Cancer Researcher and Biostatistician, San Antonio, Texas, and Co-Director of the symposium, and moderator of the press conference where the results were presented, commented, “I-SPY 2 is a new way of getting new drugs into clinical testing more rapidly. This is very important as our number of novel treatment options expands.”

Benefit From Veliparib/ Carboplatin In a study of 71 patients, veliparib/ carboplatin, added to standard neoadjuvant chemotherapy, produced a pathologic complete response rate of 52%, and thus the novel agent “graduated” with the triple-negative signature, which is the subset recommended for this regimen’s subsequent development, said Dr. Rugo. In other “signatures,” the combination was predicted to be far less successful. For example, for the hormone receptor–positive/HER2-negative group, the estimated pathologic complete response rate was 14% for the combination and 19% for controls, she said.

“The I-SPY 2 standing trial mechanism efficiently evaluates agents and combinations in biomarker-defined patient subsets,” Dr. Rugo said. “This adaptive trial successfully identified a biomarker signature/drug pair for veliparib/carboplatin on the basis of a modest number of patients.”

Simultaneous Testing of Many Drugs I-SPY 2 is sponsored by the Biomarkers Consortium, which represents 20 sites across the United States and Canada, and the trial is the work of over 100 investigators and advocates. Laura J. Esserman, MD, MBA, Professor of Surgery and Ra-

principal investigator is Donald A. Berry, PhD, Professor in the Department of Biostatistics at The University of Texas MD Anderson Cancer Center, Houston. Dr. Esserman emphasized the value of the study design. “The trial enables many drugs to be tested simultaneously, and it shows that many collaborators can work together and get faster results,” she told The ASCO Post. “The idea is to let the

Donald A. Berry, PhD

phase II trial be the screening trial, and to move forward the drugs with the biggest signals. We believe the right path forward is to do this as one trial. We want to make the process seamless.” The phase III testing of veliparib will be powered for event-free survival. In addition to veliparib, Dr. Esserman noted, neratinib has also graduated from the I-SPY 2 trial, and findings for the neratinib-containing regimen will be presented at the upcoming Annual Meeting of the American Association for Cancer Research in April. n

Disclosure: Drs. Essserman, Berry, Rugo, and Ravdin reported no potential conflicts of interest. Laura J. Esserman, MD, MBA

diology and Director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco, Comprehensive Cancer Center is the co–principal investigator for I-SPY 2, and the other co–

References 1. 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. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013.

Exercise Program Reduces Aromatase Inhibitor–Associated Joint Pain By Alice Goodman

mid studies of novel targeted therapies, genetic analyses of tumors, and new ways to approach the treatment of breast cancer, a low-tech study presented at the 2013 San Antonio Breast Cancer Symposium found that a yearlong exercise program reduced joint pain associated with aromatase inhibitors in breast cancer survivors.1 This is the first study to examine the impact of exercise vs usual care on the side effects of aromatase inhibitors.

The finding that exercise reduces joint pain could improve adherence to aromatase inhibitor therapy, improve quality of life, and reduce breast cancer recurrence and mortality risk, said the authors.

Poor Adherence Common “[Aromatase inhibitors] are standard of care for hormone receptor–positive breast cancer, but numerous studies show that the side effects lead to poor adherence and drug discontinuation. Approximately

20% of women discontinue [aromatase inhibitors], and 40% don’t take the medications as prescribed. Arthralgias are reported in up to 50% of women within 6 months of starting [aromatase inhibitor] therapy,” said lead author Melinda L. Irwin, PhD, MPH, Associate Professor at the Yale School of Public Health and CoLeader of Cancer Prevention and Control at the Yale Cancer Center, New Haven, Connecticut. “Many women report joint pain before starting an [aromatase inhibi-

tor], and the pain gets worse [while they’re on the aromatase inhibitor],” she added. “Our study showed that the better the adherence to exercise, the less joint pain the person experienced. The more research findings we have, the more likely clinicians will be to refer patients to exercise,” Dr. Irwin added. “We’ve known for a long time that exercise is beneficial in breast cancer survivors, yet there aren’t many programs that continued on page 27

ASCOPost.com | MARCH 1, 2014

PAGE 27

San Antonio Breast Cancer Symposium Exercise and Joint Pain continued from page 26

patients can be referred to. Most medical oncologists haven’t focused on prescribing or recommending exercise, and the overall prevalence of exercise, especially strength-training, is low in breast cancer survivors,” stated co-author Jennifer A. Ligibel, MD, Assistant Professor of

domly assigned to a yearlong program of exercise or usual care. The exercise program, based upon the standard exercise recommendations from the U.S. Surgeon General, entailed twice-weekly supervised sessions that included six common strength-training exercises and 2.5 hours per week of moderateintensity aerobic exercise. Patients as-

Our study showed that the better the adherence to exercise, the less joint pain the person experienced. The more research findings we have, the more likely clinicians will be to refer patients to exercise. —Melinda L. Irwin, PhD, MPH

Medicine, Harvard Medical School and Dana-Farber Cancer Center.

Study Details The HOPE study enrolled 121 women with stage I to IIIC hormone receptor–positive breast cancer who were taking aromatase inhibitors for an average of 1.5 years and experiencing at least mild arthralgias. Women were ran-

signed to usual care were provided with written information and physical activity recommendations and monitored with monthly phone calls to assess aromatase inhibitor adherence. Usual care patients were also offered a visit with an exercise trainer at the end of the study. Pain was measured on the Brief Pain Inventory (BPI) scale of 0 to 10, where a score of 3 to 4 signified mild pain; 5 to 7,

Exercise, Joint Pain, and Aromatase Inhibitor Adherence ■■ A yearlong exercise program reduced joint pain and improved exercise capacity in breast cancer survivors taking aromatase inhibitors. ■■ These findings support the importance of exercise in improving adherence to aromatase inhibitor therapy and thereby reducing breast cancer recurrence and associated mortality. ■■ Clinicians should encourage their patients with hormone receptor–positive breast cancer taking aromatase inhibitors to exercise.

moderate pain; and 8 to 10, severe pain, with 10 signifying the most severe pain. Women entering the study had a mean BPI score of 6. Women assigned to exercise were able to increase their exercise by about 110 minutes per week compared with the usual care group (P = .0001). Seventy percent of women assigned to the exercise program attended all of the twice-weekly strength-training sessions. Patients in the exercise program significantly increased their cardiorespiratory fitness (P = .0013) and reduced their body weight (P = .026) compared with those receiving usual care. Over 12 months, patients assigned to exercise experienced a 30% decrease in worst pain, a 20% decrease in pain severity, and a 20% decrease in the amount of interference pain caused in daily ac-

EXPERT POINT OF VIEW

ommenting on the results of the HOPE Study presented at the 2013 San Antonio Breast Cancer Sym-

[aromatase inhibitors], the measures tested in this study may also impact long-term patient outcome,” Dr. Arteaga said. He moderated a press conference where these data were discussed.

Potential Clinical Significance Kerry S. Courneya, PhD, Professor and Canada Research Chair in Physical Activity and Cancer, University of Alberta, Edmonton, weighed in on the study as well. Dr. Courneya Carlos L. Arteaga, MD

posium, Carlos L. Arteaga, MD, said, “We all know that this is the right thing to do. This important study provides us with new guidelines and a structure so that patients find it easier to follow the recommendation of programmed exercise when taking aromatase inhibitors.” Dr. Arteaga is Director of the Breast Cancer Program at VanderbiltIngram Cancer Center, Co-Chair of the San Antonio meeting, and President-Elect of the American Association for Cancer Research (AACR). “Even more important, by impacting adherence to treatment with

hibitors and one of the first to include women experiencing mild to moderate pain prior to starting the exercise program,” he said. “The finding that women experiencing aromatase inhibitor–related pain were able to adhere to the exercise program and experience benefits related to their pain is significant from a quality of life and health perspective. If these improvements in pain and functioning were to translate into improved

If these improvements in pain and functioning were to translate into improved aromatase inhibitor adherence and even improved outcomes, the clinical significance would be substantial. —Kerry S. Courneya, PhD

has published studies on the benefits of exercise in cancer patients. “This is an important study. It is one of the first to focus on breast cancer survivors taking aromatase in-

aromatase inhibitor adherence and even improved outcomes, the clinical significance would be substantial.” n Disclosure: Drs. Arteaga and Courneya reported no potential conflicts of interest.

Jennifer A. Ligibel, MD

tivities, whereas those assigned to usual care experience about a 5% increase in these three parameters (P < .05 for all three comparisons).

Dose-Response Relationship Morever, a dose-response relationship was seen with exercise. That is, the more adherent patients had more improvement in joint pain. “Even some exercise improved outcomes,” Dr. Irwin pointed out. “Women assigned to exercise who only adhered some of the time experienced a 15% improvement in joint pain. Exercise makes activities easier to perform, and therefore people experience less pain,” she said. “Exercise has the potential to improve [aromatase inhibitor] adherence and quality of life. Improvement in joint pain with exercise in this study has been shown to be better than with glucosamine, vitamin D, and acupuncture in other studies,” Dr. Irwin said. The study was based on women who had free gym memberships, which made it easier for them to participate. Only five women dropped out of the exercise program. Dr. Irwin noted that there are a growing number of free exercise programs for cancer survivors, but these are typically available in larger cities and metropolitan areas. n

Disclosure: Drs. Irwin and Ligibel reported no potential conflicts of interest.

Reference 1. Irwin ML, Cartmel B, Gross C, et al: Randomized trial of exercise vs usual care on aromatase inhibitor-associated arthralgias in women with breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S3-03. Presented December 12, 2013.

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

0.4

(95% CI: 6.0-7.2)

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.

T:14”

B:14.25”

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, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration

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

DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

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. © 2014 Celgene Corporation 01/14 US-ABR130068a(1)

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) Levels Bilirubin Levels ABRAXANE Dosea Pancreatic c 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 75 600 2nd dose reduction If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine < 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. Cycle Day Day 1 Day 8

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 1; No dose reduction Grade 3 or 4 resume at 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 or diarrhea lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In 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%. 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 gemcitabinetreated 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 Gemcitabine ABRAXANE(125 mg/m2)/Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

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

Gemcitabine (N=402)

System Organ Class

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

General disorders and administration site conditions

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%)

Gastrointestinal disorders

Skin and subcutaneous tissue disorders Nervous system disorders

Metabolism and nutrition disorders Respiratory, thoracic and mediastinal disorders

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%)

Alopecia

212 (50%)

6 (1%)

21 (5%)

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%) 3 (1%)

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

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%)

Hypokalemia

52 (12%)

18 (4%)

28 (7%)

6 (1%)

Cough

72 (17%)

30 (7%)

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%) 1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

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%)

Psychiatric disorders

Depression

51 (12%)

1 (<1%)

24 (6%)

T:14”

B:14.25”

S:13”

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, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history. Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site

10 16

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. 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. 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. 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. 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. 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_BSv007 10_2013

The ASCO Post | MARCH 1, 2014

PAGE 32

Philanthropy Spotlight

Direct From ASCO

Amplifying the Signal: Foundation Donor Takes His Advocacy Into the Twittersphere

ichael A. Thompson, MD, PhD, a Medical Oncologist for Aurora Cancer Care and the Medical Director of Early Cancer Research at Aurora Health Care in Wisconsin, has become something of an expert on the Conquer Cancer Foundation. It began in 2006, when he received a Conquer Cancer Foundation of

form had during the Arab Spring movement, which was going on at that time and which exemplified one of Twitter’s great virtues. According to Dr. Thompson, “[With Twitter], it’s not just the people in power. Anyone can have a voice.” Their discussions led to an intriguing question: “If [Twitter] was go-

[With Twitter], it’s not just the people in power. Anyone can have a voice…. What if we could use that for the power of good in oncology? —Michael A. Thompson, MD, PhD

ASCO Young Investigator Award, and accelerated through his participation in the 2012–2013 ASCO Leadership Development Program, when he and group of colleagues focused on the Foundation for their culminating project. “I learned about how integral the Conquer Cancer Foundation is to how ASCO operates,” Dr. Thompson said, “The Conquer Cancer Foundation is a huge part of ASCO, and I think people still don’t understand how it integrates with ASCO. The Foundation needs funding to keep up all the activities it supports—ASCO membership fees don’t pay for everything.” Over the course of the Leadership Development Program project, Dr. Thompson became a Conquer Cancer Foundation donor, and has since become a strong advocate for the Foundation. He’s even brought his advocacy online via the Twitter social media platform, helping to “amplify the signal” for the Conquer Cancer Foundation and raise awareness about its vision of a world free from the fear of cancer.

Twitter and Oncology Dr. Thompson (@mtmdphd on Twitter) first became active on Twitter in 2010 with the guidance of friend and colleague Michael J. Fisch, MD, MPH (@fischmd) of The University of Texas MD Anderson Cancer Center. They discussed Twitter at length, particularly given the impact that the social media plat-

ing beyond this kind of trivial thing where people were posting pictures of their food, and you could take down a dictatorial, well-entrenched government… What if we could use that for the power of good in oncology?” he said. Twitter has played an increasing role in the global cancer conversation occurring every day between physicians, researchers, advocates, health-care systems, pharmacists, patients, and survivors the world over. For example, the 2013 ASCO Annual Meeting’s #ASCO13 hashtag (hashtags are a tool used to organize tweets surrounding a single subject) trended on Twitter’s homepage for 3 days straight—meaning the meeting was among the mostdiscussed subjects on Twitter during that time.

Over the course of the meeting, more than 18,000 tweets engaged in a real-time discussion of breaking advances in cancer care and research, all at the fingertips of anyone who wanted to participate.

engage and educate ASCO members and the public is useful. They’re doing so many good things.”

Tweeting for the Greater Good

Dr. Thompson pointed out that the number one thing an individual can do to get started helping the Conquer Cancer Foundation (@iConquerCancer) on social media is simply to follow the organization. “See what they’re doing, understand their mission, and amplify that,” he said. “Number two is retweeting,” he continued, and “Number three is putting out your own tweets about it, especially when you give.” “When you say ‘I gave money to the Conquer Cancer Foundation’ and tweet that out it’s like having a little sticker saying ‘I donated blood’ or ‘I voted’,” he said. “People are like ‘Oh, tell me about that’ or ‘Oh, that’s good that you did that’… They become curious and [think] ‘Well, they donated. Maybe I should check that out.’” There are, of course, innumerable ways to raise awareness about the Conquer Cancer Foundation, but if you have a smartphone and a Twitter handle, this one might be one for you. Donate to the Conquer Cancer Foundation at www.conquercancerfoundation.org /donate or create a personalized fundraising page at support .conquercancerfoundation.org. n

While he’s no Lady Gaga (the Twitter user with the most followers at 41 million), Dr. Thompson’s more than 4,000 followers mean that when he retweets a message from the Foundation (putting it on his own feed for his followers to see) he increases the reach and audience of the original message by those followers and those followers’ followers. He likens it to a signal transduction cascade that amplifies the message. In December 2013, Dr. Thompson retweeted a message from the Conquer Cancer Foundation urging followers to consider a donation in honor of Giving Tuesday. Thanks to Dr. Thompson and four others who retweeted the message, its reach increased by nearly 2,000%. These small interactions may seem trivial, but they can have a big impact in raising awareness (and donations) for a nonprofit. According to a report in The Huffington Post, 69% of Twitter follows are at the suggestion of a friend, meaning that the act of retweeting or tweeting about an organization can help them increase their reach—and potential donor base— dramatically. As Dr. Thompson put it, “I think [this is] one component of how you engage people about your mission, and I think anything we can do for Conquer Cancer Foundation to help

First Steps to Supporting the Conquer Cancer Foundation on Twitter

When donors give by making online purchases on Amazon via AmazonSmile (http://smile.amazon.com/), they have the opportunity to automatically share a tweet about their gift.

Thanks to Dr. Thompson and four other Conquer Cancer Foundation Twitter advocates, this tweet reached more than 30,000 people.

ASCOPost.com | MARCH 1, 2014

PAGE 33

Direct From ASCO

Connecting to Conquer Cancer

o you share our passion to conquer cancer? Connect with the Conquer Cancer Foundation online to receive up-to-the-minute news and events, researcher spotlights, videos, and updates on progress against cancer worldwide. • Visit our website to learn more about our mission and the programs we support: www.conquercancerfoundation.org • Follow us on Twitter for the latest news and events: @iConquerCancer • Like us on Facebook to show your friends and family your commitment to conquer cancer: facebook. com/ConquerCancerFoundation

• Subscribe to our YouTube channel and learn more about our high-impact programs and hear from Foundation-funded researchers about their work: youtube.com/conquercancerfdtn You can also help fund breakthrough research, share knowledge with physicians and patients worldwide, and support initiatives to ensure that all people have access to high-quality cancer care by making a donation at www.conquercancerfoundation/donate. n © 2014. American Society of Clinical Oncology. All rights reserved.

Visit the

CONQUER CANCER FOUNDATION on the Web

Website

www.conquercancerfoundation.org

Twitter

@iConquerCancer

Facebook

facebook.com/ConquerCancerFoundation

YouTube

youtube.com/conquercancerfdtn

ASCO to Release Report on the State of Cancer Care in America

SCO is committed to ensuring that Americans have access to high-quality, high-value cancer prevention and treatment services—and that all patients benefit fully from our nation’s investments in cancer research. In mid-March, the Society will be releasing The State of Cancer Care in America: 2014, a report that examines

the many factors that affect our nation’s ability to reach these goals, from current and projected demand for services and oncologist workforce supply to the full range of economic, regulatory, and administrative pressures that oncology practices face. This report also examines how a growing emphasis on quality measure-

ment and demonstration of value, together with the rapid expansion of health information technology, stands to improve the care that patients receive. After presenting this overview of the current state of cancer care in the United States, the report includes recommendations intended for policymakers, cancer care professionals, researchers, and oth-

ers with a stake in improving our nation’s cancer care system. The report will publish in the Journal of Oncology Practice on March 12, and can be accessed at www.asco.org /stateofcancercare. n

and shares how sequestration and budget cuts have affected his work, even necessitating a reduction in staff

and a narrowing of research. In the second article in the series, Monica M. Bertagnolli, MD, Group Chair of the Alliance for Clinical Trials in Oncology, outlines the direct impact that declines in federal funding have had on new clinical trial activation, patient enrollment, and resulting scientific publications. To read the article, please go to www.asco.org/nihfunding. n

Cancer Progress in Jeopardy: Stories From the Front Lines

SCO is exploring what is happening on the front lines in the laboratory and the clinic due to the shrink-

Robert Clark, PhD, DSc

ing federal funding for cancer research and clinical trials with a series of stories about oncologists. The series is posted on ASCO.org (www.asco.org/ nihfunding). In the first article, Robert Clark, PhD, DSc, Dean for Research at Georgetown University Medical Center and Co-Director of the Breast Cancer Program at the Lombardi Comprehensive Cancer Center in Washington, DC, discusses his concerns about the future of research in the United States

Monica M. Bertagnolli, MD

The ASCO Post | MARCH 1, 2014

PAGE 34

Direct From ASCO

Cancer.Net Expands Its Social Media Presence With Launch of Blog

n an effort to continue to bring patients and those who care about and for them the most timely, comprehensive cancer information, ASCO’s patient education website, Cancer.Net, has added a new interac-

tive resource—the Cancer.Net Blog (www.cancer.net/blog). “We decided that a blog made sense for Cancer.Net, since it allows us to share information about cancer in a more timely and responsive

manner,” said Cancer.Net’s Editor-inChief, Robert S. Miller, MD, FACP. Using the blog, Cancer.Net will be able to respond more adeptly to current events, including breaking news about cancer advances and oth-

er topics important to people affected by cancer.

Robert S. Miller, MD, FACP

Conversational in Tone, Authoritative in Content Authored by ASCO experts and staff, Cancer.Net Blog posts will provide practical tips for living with cancer, suggestions to help patients and families cope with the disease, and research news and guidelines from ASCO. The blog will also include stories from patients and patient advocates, interviews, podcasts, and much more. Some of the most recent posts include a welcome and introduction to the blog by Dr. Miller, tips for staying healthy during flu season, and ways to prevent frostbite and hypothermia during cold weather. “We strive to be conversational in continued on page 35

Updated Information on Clinical Trials

our patients can learn about clinical trials in a variety of ways at www. cancer.net/clinicaltrials. The articles available explain what clinical trials are, how they are used to learn more about cancer care, and how they are conducted. In addition, your patients can read a new article explaining how coverage for clinical trials is mandated by the Affordable Care Act and access a list of questions to ask doctors and researchers. They can also watch videos with ASCO experts explaining the clinical trials process at www.cancer.net/videos and listen to podcasts that provide a general overview at www.cancer.net/podcasts. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | MARCH 1, 2014

PAGE 35

Direct From ASCO Cancer.Net Blog

CANCER RESEARCH PROGRESS THREATENED

continued from page 34

tone, and at the same time, we hope to remain authoritative in content, so you can always be assured that what you read on Cancer.Net is accurate and reflects the best science and medical practice,” said Dr. Miller. The blog will be guided by Cancer.Net’s newest Associate Editor, Anas Younes, MD, Chief of Memorial Sloan-Kettering’s Lymphoma Service in the Division of Hematologic Oncology, Department of Medicine.

Cancer touches us all. The need for continued progress is urgent and growing. This year, 1.6 MILLION AMERICANS will receive a new cancer diagnosis. By 2030, 1,2 this number will rise by almost

40%

1 in every 4 deaths in the U.S. is caused by cancer1

...Putting U.S. scientific leadership in jeopardy

Yet federal funding for cancer research is at the lowest point in decades... National Institutes of Health Budget FY2003-20143 32

Dr. Younes is committed to using social media for patient education and has brought tremendous expertise in this area to the Cancer.Net Editorial Board.

Connect With Cancer.Net via Social Media The blog joins Cancer.Net’s growing list of social media channels, which also includes Twitter (@ CancerDotNet), Facebook (www .facebook.com/CancerDotNet), and YouTube (http://www.youtube.com/ cancerdotnet). Both medical professionals and patients are encouraged to subscribe to the blog via RSS feed to receive the latest updates. n

$ billions

Anas Younes, MD

NIH funding down 23% since 2003, after adjusting for inflation

28 26

22 20

Appropriation Adjusted for inflation, in FY 2003 dollars 2003

2014

FEWER CLINICAL TRIAL OPTIONS FOR CANCER PATIENTS Patient Enrollment in NIH’s Clinical Trials Network5

Visit AM.ASCO.org

U.S. oncologists report:

75%

26%

Current funding situation is directly impacting their ability to conduct cancer research Reduced time spent on research Delayed launching a clinical trial

For every one NIH grant dollar cut, $2.21 will be lost in local economies through lost business activity, jobs and wages7

20,000 PATIENTS in 2013

IT’S TIME TO RE-IGNITE OUR NATION’S COMMITMENT TO CANCER RESEARCH.

HARM TO LOCAL ECONOMIES

NEW TREATMENTS DELAYED

38%

PATIENTS IN 2009

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

China announced a 26% boost in basic research funding in 2012

NIH research funding cuts harm us all

29,000

ASCO 50th Annual Meeting

Europe increasing research spending 40% over seven years

Save the Date

Russia increasing basic research funding 65%4

ASCO is calling on Congress to provide a strong investment for NIH in 2015 to sustain the search for cures.

Sources: 1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013. 2. American Institute for Cancer Research. Number of US Cancer Cases Expected to Rise 55 Percent Higher by 2030 [Press Release]. Published February 1, 2012. 3. One Voice Against Cancer. Impact of Sequestration Cancer Research [Fact Sheet]. Published June 2013. 4. NIH Director: Impending NIH Budget Cut Would Be ‘Devastating’ [ASCO in Action News Brief]. Published March 27, 2012. 5. Comis R: Implementing a National Cancer Clinical Trials System for the 21st Century: Workshop #2. Presented at the National Cancer Policy Forum Workshop, Washington, DC, February 11, 2013. 6. American Society of Clinical Oncology. Impact Survey: Federal Funding Cuts to Cancer Research [Press Release]. Published September 16, 2013. 7. Families USA’s Global Health Initiative. In Your Own Backyard: How NIH Funding Help’s Your State’s Economy. Published June 2008.

For more information, go to: www.CancerProgress.Net

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. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events. Hemorrhagic events, including fatal events, have been reported. 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.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment. Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment. Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

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

What truly matters to you in 2nd-line mRCC?

EVIDENCE In the phase 3, head-to-head study of exclusively 2nd-line patients with mRCC...

INLYTA was the 1st agent to demonstrate

SUPERIOR EFFICACY to sorafenib

Primary endpoint: PFS HR=0.67 (95% CI: 0.54, 0.81; P<.0001)

6.7

months

4.7

months

median PFS

INLYTA

sorafenib

(n=361)

(n=362)

Data are from a multicenter, open-label, phase 3 trial of 723 patients with mRCC after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokinecontaining regimen). Patients were randomized to either INLYTA (5 mg twice daily ) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety and tolerability.1,2

95% CI: 6.3, 8.6 and 4.6, 5.6, respectively

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.

T:9.5”

AXU606813

AXIS3X0197_C_BS_9.5x13_Oct2013_r5.indd 1

(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. 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) (N=355) All Grade All Grade Gradesb 3/4 Gradesb 3/4 % % % % Diarrhea 55 11 53 7 Hypertension 40 16 29 11 Fatigue 39 11 32 5 Decreased appetite 34 5 29 4 Nausea 32 3 22 1 Dysphonia 31 0 14 0 Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 Weight decreased 25 2 21 1 Vomiting 24 3 17 1 Asthenia 21 5 14 3 Constipation 20 1 20 1 Hypothyroidism 19 <1 8 0 Cough 15 1 17 1 Mucosal inflammation 15 1 12 1 Arthralgia 15 2 11 1 Stomatitis 15 1 12 <1 Dyspnea 15 3 12 3 Abdominal pain 14 2 11 1 Headache 14 1 11 0 Pain in extremity 13 1 14 1 Rash 13 <1 32 4 Proteinuria 11 3 7 2 Dysgeusia 11 0 8 0 Dry skin 10 0 11 0 Dyspepsia 10 0 2 0 Pruritus 7 0 12 0 Alopecia 4 0 32 0 Erythema 2 0 10 <1 a Percentages are treatment-emergent, all-causality events b National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 Adverse Reactiona

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%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (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

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

Hematology Hemoglobin decreased 320 35 <1 316 52 4 Lymphocytes (absolute) decreased 317 33 3 309 36 4 Platelets decreased 312 15 <1 310 14 0 White blood cells decreased 320 11 0 315 16 <1 Chemistry Creatinine increased 336 55 0 318 41 <1 Bicarbonate decreased 314 44 <1 291 43 0 Hypocalcemia 336 39 1 319 59 2 ALP increased 336 30 1 319 34 1 Hyperglycemia 336 28 2 319 23 2 Lipase increased 338 27 5 319 46 15 Amylase increased 338 25 2 319 33 2 ALT increased 331 22 <1 313 22 2 AST increased 331 20 <1 311 25 1 Hypernatremia 338 17 1 319 13 1 Hypoalbuminemia 337 15 <1 319 18 1 Hyperkalemia 333 15 3 314 10 3 Hypoglycemia 336 11 <1 319 8 <1 Hyponatremia 338 13 4 319 11 2 Hypophosphatemia 336 13 2 318 49 16 a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase © 2013 Pfizer Inc.

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) and hypercalcemia (6% for INLYTA versus 2% for sorafenib). 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 September 2013 References: 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. 2. Data on file. Pfizer Inc, New York, NY. mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.

November 2013

10/24/13 3:32 PM

T:13”

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 coadministered, 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 [see Adverse Reactions]. 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. 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 μU/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

ASCOPost.com | MARCH 1, 2014

PAGE 39

San Antonio Breast Cancer Symposium Breast Cancer

In Stage IV Breast Cancer, the Primary May Not Need to Be Removed By Caroline Helwick

astectomy is unnecessary in many women with stage IV breast cancer, according to a study from Indian investigators, reported at the 2013 San Antonio Breast Cancer Symposium.1 The study randomly assigned 350 patients with metastatic breast cancer to mastectomy, complete axillary dissection, plus radiation therapy, vs no locoregional treatment, and found that the nonsurgical group had no worse survival than those who underwent mastectomy. “The clinical conclusion would

Role of Locoregional Therapy in Stage IV Breast Cancer ■■ A randomized trial of 350 metastatic breast cancer patients found no detriment to overall survival when the primary tumor was not removed; at approximately 5 years, overall survival was approximately 20% in each arm. ■■ Locoregional treatment led to an improvement in local progression-free survival, but distant progression-free survival was better in patients who did not undergo surgery. Rajendra A. Badwe, MD

be that locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit, and hence should not be offered as a routine practice, but should be restricted as an op-

tion for palliation,” according to Rajendra A. Badwe, MD, Director of the Tata Memorial Hospital, Mumbai. All patients received anthracyclines, with or without taxanes, and were strat-

EXPERT POINT OF VIEW

t the San Antonio Breast Cancer Symposium, press briefing moderator C. Kent Osborne, MD, Director of the Dan Duncan Cancer Center at Baylor College of Medicine, Houston, predicted the findings of the study by Badwe et al could be practice-changing. “This is not to say that we shouldn’t perform mastectomies in appropriate patients, but this trial would argue against doing it routinely in all C. Kent Osborne, MD patients with stage IV disease. Perhaps we should offer it only in patients for whom a large, infected mass will be a cosmetic problem on the chest wall,” he explained. Laura J. Esserman, MD, MBA, Professor of Surgery and Radiology at the University of California, San Francisco, told The ASCO Post, “I don’t think there is any evidence that we should be operating on people with primary tumors to improve Laura J. Esserman, MD, MBA their outcomes at this time. If you are doing it for local disease control, okay. But so far, [surgery on the primary for stage IV breast cancer] should only be done in the trial setting. And we need a more definitive trial.” n Disclosure: Drs. Osborne and Esserman reported no potential conflicts of interest.

Bernard Fisher, MD

ified by metastatic site, number of metastases, and hormone receptor status, then randomized to either locoregional therapy or no locoregional therapy. For any progression, women received appropriate systemic treatment. At 72 months, overall survival was 20.5% for the nonsurgical group and 19.2% for the surgical group. Local progression-free survival was better with surgery plus radiation (hazard ratio [HR] = 0.16), but distant progressionfree survival was worse in this group (HR = 1.42; P = .01), Dr. Badwe reported. No differences were observed according to subgroup.

Biologic Hypothesis The difference in local vs distant re-

currence suggests that by removing the primary tumor, surgeons might be enabling the disease to spread, he said at a press briefing. “The biologic fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases,” he commented. This was the conclusion, in fact, of a decades-old study from the laboratory of Bernard Fisher, MD, at the University of Pittsburgh. Dr. Fisher and his team reported that the removal of a primary tumor in mice appeared to release a growth factor that fostered the growth of distant tumors.2 They postulated that removal of the primary “can influence the outcome of a host to its tumor.” n Disclosure: Dr. Badwe reported no potential conflicts of interest.

References 1. Badwe R, Parmar V, Hawaldar R, et al: Surgical removal of primary tumor and axillary lymph nodes in women metastatic breast cancer at first presentation: A randomized controlled trial. 2013 San Antonio Breast Cancer Symposium. Abstract S2-02. Presented December 11, 2013. 2. Fisher B, Gunduz N, Coyle J, et al: Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49:1996-2001, 1989.

Download

The ASCO Post iPad App FREE from iTunes today!

The ASCO Post | MARCH 1, 2014

PAGE 40

ASH Annual Meeting Hematology

Haploidentical Stem Cell Transplantation Producing Good Outcomes, Expanding Transplant Pool By Caroline Helwick

LA-haploidentical hematopoietic stem cell transplantation can be performed safely, yield good outcomes, and greatly expand the number of patients with hematologic malignancies who can be treated with stem cell transplant, studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting suggested.

Strategic Rationale A major obstacle to success with allogeneic bone marrow transplant has been the frequent lack of suitable matched donors. Only one-quarter of siblings will be an HLA-match, and there is only a 50%

When a fully matched donor is not available, reduced-intensity bone marrow transplants using haploidentical, or halfmatched, related donors can be safe and effective even in elderly patients, ASH presentations suggested. “Almost every patient has at least one HLA-haploidentical relative,” according to Yvette L. Kasamon, MD, Associate Professor of Oncology and Medicine at Johns Hopkins University, Baltimore, where haploidentical transplants were pioneered. “But until recently, [haploidentical transplant] carried excessive risk.” These have included an increased risk of graft rejection and of graft-vs-host dis-

Haploidentical Hematopoietic Stem Cell Transplant ■■ Haploidentical hematopoietic stem cell transplantation can be made safer and more efficacious through a process that eliminates the alpha/beta–positive T cells and CD19-positive B cells from the graft, leaving behind the mature natural killer cells and gamma/delta–positive T cells, which are protective ■■ Advanced age does not confer worse outcomes or produce prohibitive toxicities with haploidentical transplantation using a reduced-intensity regimen and high-dose post-transplant cyclophosphamide. ■■ In an Italian study of 50 children with acute leukemia, the cumulative incidence of transplant-related mortality was 4%, the relapse rate was 19%, the leukemiafree survival rate was 77%, and acute graft-vs-host disease was observed in 26%.

chance overall—and much lower for African Americans and ethnic minorities—of finding a matched unrelated donor. Time is also a factor: It can take months to coordinate an unrelated transplant.

ease. Reduced-intensity regimens have made them safer, and further advances in safety and efficacy are being achieved through novel approaches, investigators reported at the ASH meeting.

Almost every patient has at least one haploidentical relative. But until recently, [haploidentical transplant] carried excessive risk. —Yvette L. Kasamon, MD

Post-Transplant Cyclophosphamide The Johns Hopkins investigators showed that advanced age was not associated with prohibitive toxicities from haploidentical transplant when patients are otherwise transplant-eligible.1 “We found no apparent decrement in overall outcomes in patients aged 60 and older or even 70 to 75, compared to those in their 50s,” Dr. Kasamon said. “Since many elderly patients may lack a suitable matched sibling donor, the haploidentical option becomes even more attractive.” Investigators retrospectively evaluated 273 patients aged 50 to 75 with various hematologic malignancies who received a nonmyeloablative related haploidentical bone marrow transplant with post-transplant high-dose cyclophosphamide (50 mg/kg either once on day 3 or twice on days 3 and 4) plus mycophenolate mofetil and tacrolimus for graft-vs-host disease prophylaxis. She called post-transplant cyclophos-

phamide a “major advance” that renders haploidentical bone marrow transplant “safe and effective” and allows for outpatient treatment.

Key Data Median time to neutrophil recovery was 16 days and to platelets ≥ 20,000 was 26 days. Risk of acute graft-vs-host disease was low (32% for all grades and 3% for grade 3/4), as was risk for chronic graftvs-host disease (12% at 1 year). The 1-year relapse rate was 37%, and at 6 months, the nonrelapse mortality rate was 11%. By age, outcomes were comparable at a median follow-up of 2.1 years. Two-year progression free survival was 39% for patients aged 50 to 59, 36% for those aged 60 to 69 and 39% for those aged 70 to 75. Estimated 2-year overall survival was 51%, 56%, and 44%, respectively. “Of 27 patients aged 70 to 75, there were four nonrelapse deaths (15%), nine relapses (33%) and 14 patients alive without relapse (52%) at a median of 11

EXPERT POINT OF VIEW

effrey Miller, MD, Professor of Medicine at the University of Minnesota and Deputy Director of the Masonic Cancer Clinic in Minneapolis, commented on the haploidentical hematopoietic stem cell transplantation studies presented at the American Society of Hematology meeting for The ASCO Post “The problem with haploidentical transplants is doing them safely, without the occurrence of lethal [graft-vshost disease],” he said, estimating the risk is about 70% under the conventional approach. “This is why most transplant centers have not adapted haploid transplants. Most look for adult unrelated

donors, and with this there is a problem with [unequal] access,” he said.

Society of Hematology meeting. He said the first patient engrafted quickly

Safer Procedure “T-cell alpha/beta depletion presumes that the [graft-vs-host disease]–causing cells are T-cell receptor alpha/beta–positive, so if we eliminate them we can do the transplant more safely, without the use of post-transplant immune-suppressive drugs,” Dr. Miller explained. “You leave the NK and gamma/delta–positive cells.” His center was the first in the United States to try this approach, mirroring the experience described by the Italian investigators at the American

Jeffrey Miller, MD

and is doing well. “Anecdotally, the results are very promising. We believe in this enough to get this program up and running,” he reported. “This approach has things in com-

mon with the Hopkins approach, which gives post-transplant cyclophosphamide to blunt or knock down the [graft-vs-host disease]–reactive T-cells in a way that seems relatively safe. But high-dose [cyclophosphamide] blunts NK cells, so we personally favor alpha/beta depletion, which will allow immune reactivity to occur, perhaps somewhat better,” Dr. Miller continued. “The limiting factor in doing haploid transplant is [graft-vs-host disease], and both of these approaches are intended to blunt this. Both can also be used in older patients,” he said. n Disclosure: Dr. Miller reported no potential conflicts of interest.

ASCOPost.com | MARCH 1, 2014

PAGE 41

ASH Annual Meeting months after [bone marrow transplant],” Dr. Kasamon said. Nonrelapse mortality was not significantly different among the three age groups.

Donor May Be ‘in the Same Room’ “These results underscore that a reduced-intensity, related haploidentical transplant should be considered a very reasonable treatment option for suitable patients—up to at least age 75—who require a transplant,” Dr. Kasamon suggested. In most cases, Johns Hopkins no longer searches for a matched unrelated donor for patients with a relative who is a potential haplolid donor. Laurence J.N. Cooper, MD, Professor of Pediatrics and Director of the Immunology Laboratory at The University of Texas MD Anderson Cancer Center, Houston, who moderated the press conference where the Johns Hopkins study was described, said the approach “moves the technology forward in terms of efficacy.”

Alice Bertaina, MD

graft,” she said. NK and gamma/delta– positive T cells help prevent relapse and protect against infection. “The selective graft manipulation results in effective prevention of both acute and chronic [graft-vs-host disease], rapid recovery of neutrophil and platelet counts and low transplant-related mortality,” she said. “Although the median observation time

is still limited, the cumulative incidence of disease recurrence is encouraging.”

Italian Study Outcomes Their study included 50 children (median age, 10) with acute lymphoblastic or acute myeloid leukemia with a parent serving as the haploidentical donor. The docontinued on page 42

Laurence J.N. Cooper, MD

“First, with this new stem cell modification technology, we can pull out just the cells we want,” he said. “The second advantage is that this shortens the time to finding the donor. We don’t have to identify potential donors from a massive registry. We will be able to find a donor in the same room as the patient.”

Graft Manipulation T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation can be made safer and more efficacious through the removal of alpha/beta–positive T cells and CD19-positive B cells from the graft, an approach pioneered and reported at the ASH meeting by Italian investigators.2 Alice Bertaina, MD, of the Department of Pediatric Hematology-Oncology, IRCCS Bambino Gesù Children’s Hospital in Rome, and colleagues selectively removed those cells that are most likely to trigger donor cells to attack recipient cells. “We recently developed a new method of graft manipulation based on the physical removal of alpha/beta–positive T cells and CD19-positive B cells, which permits us to leave mature natural killer (NK) cells and gamma/delta–positive T cells in the

Advertisement not displayed in digital edition at advertiser’s request

The ASCO Post | MARCH 1, 2014

PAGE 42

ASH Annual Meeting Haploidentical Stem Cell Transplants continued from page 41

nor’s blood was filtered through a column where magnetic microbeads captured and separated the T cells to be retained from those slated for elimination. Patients underwent a myeloablative regimen, with or without total-body irradiation, and re-

ceived anti–thymocyte globulin and rituximab (Rituxan). With a median follow-up of 18 months (range, 6–36 months), the cumulative incidence of transplant-related mortality was only 4%, the relapse rate was just 19%, and the leukemia-free survival rate was 77%, rising to 80% in the subset of patients with acute lymphoblastic leukemia.

The incidence of acute graft-vs-host disease was 26%, and no child developed gut or liver acute disease. Only two patients developed skin-limited chronic graft-vshost disease. The cumulative infection rate was 53%, Dr. Bertaina reported. Sustained primary engraftment occurred in all patients, and median time to reach an absolute neutrophil count > 0.5 ×

109/L and platelet count > 50 × 109/L was 13 days and 11 days, respectively. Chimerism at engraftment was 100%.

Time-Saving Approach “The recovery of both innate and adaptive immunity after this type of allograft is accelerated in comparison to the infusion of CD34-positive selected

Advertisement not displayed in digital edition at advertiser’s request

ASCOPost.com | MARCH 1, 2014

PAGE 43

ASH Annual Meeting cells,” she noted. “A low tumor burden and the use of total-body irradiation during the preparative regimen can further optimize the outcomes.” Dr. Bertaina predicted that using this approach, more patients will receive transplants and fewer will die during the procurement of an unrelated donor. “Until now, we have searched for un-

related volunteer donors, but it is difficult to propose to the parents that we must wait for this search, before we treat,” she said. “These results open another avenue, and show that it can actually be advantageous to choose a haploidentical relative.” n Disclosure: Drs. Kasamon, Bertaina, and Cooper reported no potential conflicts of interest.

References 1. Kasamon YL, Prince G, BolanosMeade J, et al: Encouraging outcomes in older patients following nonmyeloablative haploidentical BMT with high-dose posttransplantation cyclophosphamide. 2013 ASH Annual Meeting. Abstract 158. Presented December 7, 2013. 2. Bertaina A, Pagliara D, Pende D, et

Advertisement not displayed in digital edition at advertiser’s request

al: Removal of alpha/beta+ T cells and of CD19+ B cells from the graft translates into rapid engraftment, absence of visceral graft-versus-host disease and low transplant-related mortality in children with acute leukemia given HLA-haploidentical hematopoietic stem cell transplantation. 2013 ASH Annual Meeting. Abstract 157. Presented December 7, 2013.

The ASCO Post | MARCH 1, 2014

PAGE 44

FDA Update

FDA Approves Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia

he U.S. Food and Drug Administration (FDA) has expanded the approved use of ibrutinib (Imbruvica) for the treatment of patients

with chronic lymphocytic leukemia (CLL) who have received at least one previous therapy. Ibrutinib, an oral Bruton’s tyrosine kinase inhibitor,

was previously granted accelerated approval by the FDA for patients with mantle cell lymphoma who received at least one prior therapy.

Advertisement not displayed in digital edition at advertiser’s request

Accelerated Approval “Today’s approval provides an important new treatment option for CLL patients whose cancer has progressed despite having undergone previous therapy,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s

Center for Drug Evaluation and Research. “The FDA completed its review of [ibrutinib’s] new indication under the agency’s accelerated approval process, which played a vital role in rapidly making this new therapy available to those who need it most.” Under the agency’s accelerated approval process, the FDA may approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Drugs receiving accelerated approval are usually subject to an agreement to conduct confirmatory trials verifying and describing clinical benefit. Ibrutinib for CLL also received priority review and orphan-product designation because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease, respectively.

Clinical Study The FDA’s accelerated approval of ibrutinib for CLL is based on a clinical study of 48 previously treated participants. On average, participants were diagnosed with CLL 6.7 years prior to the study and had received four previous therapies. All study participants received a 420 mg orally administered dose of ibrutinib until the treatment reached unacceptable toxicity or the disease progressed. Results showed an overall response rate of nearly 58%, with the duration of response ranging from 5.6 to 24.2 months. An improvement in survival or disease-related symptoms has not been established. The most common side effects observed in the clinical study include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness. n

ASCOPost.com | MARCH 1, 2014

PAGE 45

ASH Annual Meeting Hematology

First-Line Obinutuzumab/Chlorambucil Improves Outcomes Over Rituximab/Chlorambucil in Older CLL Patients With Comorbidities By Alice Goodman

binutuzumab (Gazyva) plus chloramubucil outperformed rituximab (Rituxan) plus chlorambucil (Leukeran) as first-line therapy in older patients with chronic lymphocytic leukemia (CLL) and comorbidities in the large CLL 11 trial. Final results showed that obinutuzumab/ chloramubucil improved overall survival compared to chlorambucil alone and improved progression-free survival, complete response rate, and minimal residual disease status compared to chlorambucil/rituximab. “These results suggest that obinutuzumab can replace rituximab in combination with chlorambucil as first-line therapy in older patients with comor-

regimen, translating to less toxicity for patients,” said Valentin Goede, MD, a hematologist/oncologist and gerontologist at University Hospital Cologne, Germany, who presented the results during the Plenary Session at the 2013 Annual Meeting of the American Society of Hematology (ASH).1 “These findings are significant and potentially practice-changing for this large patient population of older CLL patients with comorbidities,” he stated at a press conference. Obinutuzumab, an anti-CD20 antibody, is more potent than the anti-CD20 antibody rituximab, a current standard of care. Experts have said that obinutuzumab may turn out to be superior to

These findings are significant and potentially practice-changing for this large patient population of older CLL patients with comorbidities. —Valentin Goede, MD

bidities. This could mean a potential decrease in the amount of chemotherapy required for an effective combination

rituximab in other patient populations as well as other hematologic malignancies, but those data are not yet available.

Role of Obinutuzumab in CLL ■■ Obinutuzumab plus chlorambucil is a new option for treatment of older patients with chronic lymphocytic leukemia (CLL) and comorbidities who cannot tolerate fludarabine-based aggressive chemotherapy. ■■ Obinutuzumab can replace rituximab in combination with chlorambucil as first-line therapy in this setting. ■■ Further studies are needed to determine the role of obinutuzumab vis-àvis rituximab in other CLL patient populations and in other hematologic malignancies.

CLL 11 Study The CLL 11 study randomly assigned 781 patients in a 2:1:2 ratio to three arms: obinutuzumab/chloramubucil for six cycles, chlorambucil for six cycles (control), or rituximab/ chlorambucil for six cycles. Median age of patients was 73 years, and almost 40% were older than age 75. Patients had typical age-related comorbidities, including cardiovascular disease, chronic obstructive pulmonary disease, hypertension, diabetes, and hyperlipidemia and were taking medications for these conditions. “Looking at this group of patients together, experts would agree they are less suitable for aggressive fludarabinebased chemotherapy,” Dr. Goede said. Obinutuzumab/chloramubucil was associated with more grade 3 or higher

adverse events than rituximab/chlorambucil—in particular, infusion-related reactions that occur during the first infusion (20% vs 4%, respectively). “We are vigilant about preventing these reactions to increase safety,” Dr. Goede said. No increased risk of infection was observed with obinutuzumab/chloramubucil. More grade 3 or higher thrombocytopenia (10% vs 3%) and neutropenia (33% vs 28%) were seen in the obinutuzumab/chloramubucil arm, compared with the rituximab/ chlorambucil arm.

Key Data Overall response rate was higher with obinutuzumab/chloramubucil vs rituximab/chlorambucil: 78% vs 65% (P < .0001). Obinutuzumab/ continued on page 46

Encouraging Early Results With Novel Agents in CLL

wo novel agents have shown promising activity in chronic lymphocytic leukemia (CLL), including poor-risk patients: the Bcl-2 inhibitor ABT-199 and the small-molecule PI3K inhibitor IPI-145. Both drugs achieved excellent response rates in heavily pretreated relapsed/refractory patients including those with poor-risk cytogenetics. If preliminary results are validated in phase III studies, ABT-199 and IPI-145 will be poised to join an explosion of new therapies—obinutuzumab (Gazyva), ibrutinib (Imbruvica), and idelalisib among them—that promise to improve outcomes for all CLL patients.

agent is to inhibit Bcl-2 and induce apoptosis in tumors. The phase I trial of ABT-199 included 57 evaluable patients with relapsed or treatment-resistant CLL or

Our ongoing studies [of ABT-199] will seek to improve the efficacy while carefully monitoring toxicities to deliver the maximum benefit to high-risk patients where conventional chemotherapy has proven inadequate. —John Seymour, MBBS, PhD

ABT-199 ABT-199 is targeted to the B-cell lymphoma (Bcl)-2 protein associated with tumor cell proliferation and survival. The goal of therapy with the

the first cohort began at 200 mg, with all three showing laboratory features of tumor lysis syndrome, prompting a modification to begin at 50 mg in subsequent cohorts with a stepwise dose

small lymphocytic leukemia.1 Patients were allocated to dose cohorts ranging from 150 to 1,200 mg. Patients in

escalation. With this graduated dosing scheme, tumor lysis syndrome occurred in three of 43 patients, leading

to a reduction in initial dose to 20 mg for the first week and a slower increase in dose escalation up to 400 mg over the first few weeks of treatment in the safety expansion cohort. In addition, prophylaxis and monitoring have been instituted. This strategy appears to prevent or reduce the likelihood of tumor lysis syndrome, said lead author John Seymour, MBBS, PhD, Peter McCallum Cancer Center, Melbourne, Australia, at the 2013 Annual Meeting of the American Society of Hematology (ASH). Patients had received a median of four prior therapies (range, 1–11). Nineteen (37%) had 17p deletion, and 75% had unmutated immunoglobulin heavy chain variable region (IgHV). Of 57 patients, 50 (88%) had at continued on page 46

The ASCO Post | MARCH 1, 2014

PAGE 46

ASH Annual Meeting Obinutuzumab/Chlorambucil continued from page 45

chloramubucil was also superior in eradicating detectable disease in the bone marrow and in blood; the rate of minimal residual disease–negative status in bone marrow was 19.5% for obinutuzumab/chloramubucil vs 2.6% for rituximab/chlorambucil (P < .0001). Minimal residual disease–negative status in blood was observed in 37.3% vs 3.3% of the two groups, respectively (P < .0001). For the primary endpoint, obinutuzumab/chloramubucil led to a 61% improvement in the likelihood of being progression-free during the study follow-up so far, compared with rituximab/chlorambucil. Median progression-free survival was 26.7 vs 15.2 months in these two groups, respectively (P < .0001), and 11.1 months for the chlorambucil-alone control

Novel Agents in CLL continued from page 45

least a partial nodal response, and median time to 50% reduction in nodal masses was 6 weeks. The investigators observed at least a 50% reduction in the bone marrow infiltrate at 24 weeks

arm (P < .0001, compared with obinutuzumab/chlorambucil). Overall survival data are not yet mature, but at present obinutuzumab/ chloramubucil “is significantly better” than chlorambucil alone, Dr. Goede noted (P = .0022). n Disclosure: Dr. Goede has received honoraria from Mundipharma and F. Hoffmann-La Roche, research funding from F. Hoffmann-La Roche, and is an advisor for F. Hoffmann-La Roche.

Reference 1. Goede V, Fischer K, Busch R, et al: Head-to-head comparison of obinutuzumab (GA101) plus chlorambucil versus rituximab plus chlorambucil in patients with chronic lymphocytic leukemia and co-existing medical conditions (comorbidities). ASH Annual Meeting. Abstract 6. Presented December 8, 2013.

maximum benefit to high-risk patients where conventional chemotherapy has proven inadequate,” Dr. Seymour stated. ABT-199 monotherapy and combination trials in CLL have begun enrolling patients. These include a phase II monotherapy study in patients with

While [IPI-145] has a tolerability profile similar to other drugs in its class, it may actually be more potent, which could contribute to its value for patients with relapsed or refractory disease in particular. —Ian W. Flinn, MD, PhD

in 89% of patients, and median time to 50% reduction in peripheral blood lymphocyte count was 15 days. Overall response rate was 84% (47 of 56 patients), with complete response in 13 (23%) and partial response in 34 (61%). Among patients with 17p deletion, the overall response rate was 82% (14 of 17 patients), with complete response in 12% (2 patients) and partial response in 71% (12 patients).

Ongoing Studies “We are very encouraged by these early results and, in particular, by the high rate of complete response among patients with treatment-resistant or relapsed CLL. Our ongoing studies will seek to improve the efficacy while carefully monitoring toxicities to deliver the

del(17p) and relapsed CLL, as well as combination studies of ABT-199 plus rituximab (Rituxan) or obinutuzumab in the relapsed setting.

IPI-145 IPI-145, a potent, oral small-molecule inhibitor of PI3K-gamma and -delta, is being studied in a range of hematologic malignancies. A phase I dose-escalation study of 193 patients included a total of 67 CLL patients, 52 with treatment-resistant or relapsed CLL and 15 with untreated CLL.2 Median age was 67. Twice-daily treatment with IPI-145 at doses of 8 to 75 mg in 28-day cycles showed clinical activity in relapsed or treatment-resistant CLL at all doses studied. Importantly, the drug was active in patients

EXPERT POINT OF VIEW

ommenting on the CLL 11 trial in chronic lymphocytic leukemia (CLL), Jennifer R. Brown, MD, PhD, Director of the CLL Center at DanaFarber Cancer Institute, Boston, said she agreed with first author Valentin Goede, MD, that in this study, replacing rituximab (Rituxan) with obinutuzumab (Gazyva) in combination with the same chemotherapy backbone demonstrated the superiority of obinutuzumab. “This is a fair assessment of the study results. Prior Jennifer R. Brown, MD, PhD to this, we thought it would be hard for any other anti-CD20 drug to beat rituximab. In this population, obinutuzmab clearly did. Going forward in other contexts, it will be important to see how obinutuzumab behaves,” she said. “With all the new therapies for CLL, it is an exciting time,” Dr. Brown continued. “We don’t know how best to sequence them yet. This will depend on the patterns of resistance. Combinations of these agents are of great interest in CLL, and studies including obinutuzumab are being planned. Stay tuned,” she said. n Disclosure: Dr. Brown has served as a consultant for Gilead Sciences.

with poor-risk cytogenetics (17p deletion or TP53 mutation). Nodal response was defined as a 50% or greater reduction in lymphadenopathy. Among 43 evaluable relapsed/refractory patients, 42 (98%) had a nodal response on computed tomography assessment, and 24 of 27 patients (89%) dosed at ≤ 25 mg twice daily had a nodal response. Nodal responses were seen in three of six evaluable treatment-naive patients, including two with a TP53 mutation. Overall response rate in 47 evaluable patients with relapsed refractory CLL was 47%, with one complete response defined by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Overall response rate was 50% in 12 patients with relapsed/refractory disease and poor-risk cytogenetics treated at < 25 mg twice daily and 29% in 7 patients with poor-risk cytogenetics treated at 75 mg twice daily. The drug was generally well tolerated without the degree of myelosuppression seen with traditional chemotherapy. The investigators selected the 25-mg twicedaily dose for phase III study.

Development Supported “These data support phase III development as monotherapy in CLL. Our study suggests that IPI-145 may lend itself well to long-term therapy of patients with CLL. While it has a tolerability profile similar to other drugs in its class, it may actually be more potent, which could contribute to its value for patients with relapsed or refractory dis-

ease in particular,” said lead author Ian W. Flinn, MD, PhD, Director of the Hematologic Malignancies Research Program at the Sarah Cannon Research Institute, Nashville. “Emerging data also support development of this compound in other hematologic malignancies, including indolent non-Hodgkin lymphoma and T-cell malignancies,” Dr. Flinn added. Another PI3K-delta inhibitor, idelalisib, showed promise in a phase III study of previously treated CLL patients reported at the ASH meeting.3 n

Disclosure: Dr. Seymour is a consultant and advisor for Genentech, Roche, and AbbVie. Dr. Flinn is a consultant for and has received research funding from Infinity Pharmaceuticals.

References 1. Seymour JF, Davids MS, Pagel JM, et al: Bcl-2 inhibitor ABT-199 monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory chronic lymphocyctic leukemia and small lymphocytic leukemia. ASH Annual Meeting Abstract 872. Presented December 10, 2013. 2. Flinn I, Patel M, Kahl BS, et al: Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinasedelta, gamma, in patients with chronic lymphocytic leukemia. ASH Annual Meeting. Abstract 677. Presented December 9, 2013. 3. Furman RR, Sharman JP, Coutre SE, et al: A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib and rituximab for previously treated patients with chronic lymphocytic leukemia. ASH Annual Meeting. Abstract LBA-6. Presented December 10, 2013.

FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2

EXTEND SURVIVAL

WITH ZELBORAF

Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)†‡ 100

HR=0.44 (95% CI, 0.33-0.59), P<0.0001

Percentage surviving

80 60 Not reached

7.9

40 20 0

ZELBORAF (n=337)

6 8 OS (months)

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.

Significant improvement in PFS ~4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE

The ASCO Post | MARCH 1, 2014

PAGE 50

Issues in Oncology

Leaders of ASCO, ASH, ASTRO, and NCCN Embrace Collaboration With Advanced Practitioners By Susan Reckling

early 250 advanced practitioners assembled at the first annual JADPRO Live educational symposium in St. Petersburg, Florida, hosted by

the Journal of the Advanced Practitioner in Oncology ( JADPRO). Leaders from four prominent oncology organizations championed Safety:7" collaborative practice as

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily. Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure. ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine. Reactions Reported in ≥ 10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade Grade All Grade All All a Other Malignancies Grades 3a Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies. Rash 37 8 2 0 52 7 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)]. 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)]. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)]. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

33 45 23 24 9 8 19 5 14

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.

7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF.

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®

7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

38 17 19 11

21 24 10

of Hematology (ASH), the American Society for Radiation Oncologists (ASTRO), and the National Comprehensive Cancer Network (NCCN) offered their perspectives on the role of advanced practitioners in oncology (APs) in the interdisciplinary care of patients

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

Robert W. Carlson, MD

with cancer during a roundtable panel discussion, moderated by the Editorin-Chief of the Journal of the Advanced Practitioner in Oncology (JADPRO), Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®, Associate Clinical Professor, Department of Physiological Nursing (volunteer series), the University of California, San Francisco. “To continue the approach of the past will not work in the future,” predicted Robert W. Carlson, MD, who is Chief Executive Officer of NCCN. The demands are changing, and the oncology treatments available are too complicated for the current work force to deliver, he added. With the well-known ASCO Workforce Study of 2007 projecting a significant shortfall of oncologists and medical providers in oncology by the year 2020,1 the panel clearly acknowledged the expanding role of the advanced practitioner in filling that gap. “Training programs are not going to make up for the shortfall projected in hematology,” remarked Steven L. Allen, MD, FACP, of the Monter Cancer Center, Hofstra North Shore‒LIJ School of Medicine, Lake Success, New York, who is also Chair of the Committee on Practice of ASH. In fact, 25% of practicing hematologists will retire in the next 5 years, based on

Safety:10"

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

not only good for patients but for practitioners as well. Representatives of the American Society of Clinical Oncology (ASCO), the American Society

ASCOPost.com | MARCH 1, 2014

the responses to a September 2013 survey of ASH’s practice-based members.

Educational Initiatives “All of us on the panel are on the same page regarding the value of collaborative practice, but our professional

Steven L. Allen, MD, FACP

organizations may be at different levels of maturation in this area,” admitted Louis B. Harrison, MD, FASTRO, of Mount Sinai-Beth Israel, Mount SinaiRoosevelt, and Mount Sinai-St. Luke’s Hospitals, New York, who is Past President and Past Chairman of ASTRO. As cancer has evolved into a chronic disease model, the interdisciplinary medical team approach, involving oncologists, advanced practitioners, pharmacists, physician assistants, physical therapists, social workers, and nutritionists (among others), has been supported by ASCO, remarked Peter P. Yu, MD, of Palo Alto Medical Foundation, who is President-Elect of ASCO. “As a society, there is no question in our minds that

Louis B. Harrison, MD, FASTRO

to deliver high-quality care for patients with cancer, we need to embrace the view of collaborative practice,” he added. With an emphasis on education, ASCO has collaborated with many organizations, including the European Society for Medical Oncology and the National Board of Medical Examiners, to implement educational programs for advanced practitioners in oncology. For instance, mirroring their tools for fellows, ASCO launched a digital comprehensive program for newly graduated APs, which focuses on team care for oncology patients, symptom management, genetics, and skills for communicating with patients. “Many advanced practitioners do not have an oncology background,

PAGE 51

so this is a very useful tool,” added Ms. Viale. In addition, ASCO offers tumorspecific educational modules. To foster awareness and interest among APs in hematology, ASH provides hematology-specific educational resources for advanced practitioners. ASH offers joint educational tools for advanced practitioners, works with oncology nursing societies, and adapts courses for both advanced nurse practitioners and physician assistants. Furthermore, APs are encouraged to join ASH’s grassroots network to become involved in online advocacy campaigns. For the upcoming 2014 ASH Annual Meeting, a lunch program is being considered concerning how to incorporate advanced nurse practitioners and physician assistants into a hematology/oncology practice, added Dr. Allen. As for NCCN, its best practices committee has conducted surveys focusing on APs among its 23 member institutions,

APSHO: New Society for Advanced Practitioners

he Advanced Practitioner Society for Hematology and Oncology (APSHO) was launched during JADPRO Live. The Society is focused on meeting the unique educational and professional needs of this group of health-care professionals (nurse practioners, physician assistants, clinical nurse specialists, advanced degree nurses, and pharmacists). See page 60 in this issue of The ASCO Post for more information about this new Society, including a welcoming message from ASCO’s CEO Allen S. Lichter, MD, FASCO. n

diation oncologists, practice managers of radiation oncology, and APs. However, there is a growing awareness at ASTRO that the only way to embrace the future is in collaborative practice, and ASTRO and ASCO are working together on the workforce issue. “Cancer patients identify with advanced practitioners more than anyone,” noted Dr. Harrison, “and we need

As a society, there is no question in our minds that to deliver high-quality care, we need to embrace the view of collaborative practice. —Peter P. Yu, MD

partnering with me,” he revealed. In fact, in Dr. Harrison’s program, the advanced practitioners are known as “the gurus” of toxicity management. “We turn to them for help as the protectors of patient safety.” Finally, Dr. Carlson revealed that he worked closely with one nurse practitioner for 18 years, another nurse practitioner for 17 years, and a physician assistant for 7 years in his outpatient clinic. “You need to set the standards incredibly high and insist on excellence,” he explained. “Every one of my advanced practitioners is empowered to question anything I do at any time, and they have on many occasions.” Being able to trust an AP to triage patients quickly and appropriately is essential, added Dr. Carlson.

Research on the Value of APs and there is no question that advanced practitioners are of value, reported Dr. Carlson. The traditional roles of care are changing, he added, and we need to be the messengers of change rather than resist it. At the heart of a shared team approach and agreement of standards are the NCCN guidelines, according to Dr. Carlson. “They are the generally accepted best clinical practice guidelines across the continuum of care in the world in medicine—period,” he pronounced. Not only do these guidelines define an evidence-based accepted system of delivery of care, they can facilitate the expansion of care to new professional groups. Dr. Carlson noted that many challenges facing the oncology care team are more systems-oriented than educative in nature. “We need to reconfigure how we care for patients and make that care more efficient, so the workforce available will be adequate to service the needs,” he noted. As for ASTRO, Dr. Harrison admitted that his society has been a little “slower to the punch” with respect to navigating a course with advanced practitioners. He acknowledged a disconnection in the perception of the workforce among ra-

to use that unique relationship to build patient satisfaction.”

Collaborative Practice in Action Some of the oncologists on the panel shared their own positive professional experiences working with advanced practitioners in oncology. First, Dr. Allen noted that members of ASH are collaborating with APs both in daily practice and in clinical research. In fact, in his own practice (which includes 32 physicians and 16 nurse practitioners/physician assistants), the responsibilities of APs center on direct patient care under a collaborative agreement with a physician, supervision, and clinical management of treatment infusion suites, and assistance in managing data for clinical trial programs. “Our program could not function and maintain its high standards without the assistance of our advanced practice colleagues,” he stated. As for Dr. Harrison, he has worked collaboratively with an advanced practitioner for his entire career. “I have not spent a day in my life as a radiation oncologist without an advanced practitioner

Research is clearly needed to assess the expanding role of APs on the oncology care team. Dr. Carlson mentioned the necessity of benchmarks for assessing their productivity and how many patients they should be seeing. Thus, health-care delivery research should be considered legitimate oncologic research, added Dr. Harrison. Both Drs. Harrison and Carlson noted that the team role may not be the same for every institution. “Guidelines may be similar among institutions, but the care pathways of delivering that care may be different among institutions,” explained Dr. Harrison. It may be a matter of finding “the sweet spot” for how best to use the skill set of an AP within the team model, concluded Dr. Carlson. n Disclosure: Ms. Viale and Drs. Carlson, Yu, and Harrison reported no potential conflicts of interest. Dr. Allen owns stock with Bristol-Myers Squibb and has received honoraria from Celgene.

Reference Forecasting the Supply of and Demand for Oncologists: A Report to the American Society of Clinical Oncology (ASCO) from the AAMC Center for Workforce Studies. March 2007. Available at www.asco.org. Accessed February 11, 2014.

EARN MOC POINTS DURING ASCO’S ANNUAL MEETING Sign up for ASCO’s Annual Meeting Core Session MOC Activity, a helpful resource for those looking to fulfill Maintenance of Certification (MOC) requirements, refresh their knowledge, or prepare for board certification or MOC examination. After successfully completing the post-examination, participants will be eligible for 10 MOC points in Self-Assessment of Medical Knowledge. Registration Includes: • Access to an online pre-examination intended to highlight areas of educational need • Personalized list of Core Sessions to attend while at the meeting to help fill knowledge gaps • An online post-examination

REGISTRATION FOR THIS ACTIVITY CLOSES FRIDAY, MAY 16, 2014.

am.asco.org/maintenance-certification

Visit university.asco.org/MOC to learn more about all of ASCO’s collection of MOC resources.

ASCOPost.com | MARCH 1, 2014

PAGE 53

2014

2014 Oncology Meetings March 31st Annual Miami Breast Cancer Conference® March 6-9 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/31st-Annual-MiamiBreast-Cancer-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/emoncreviewcourse

38th Annual Meeting of the American Society of Preventive Oncology March 8-11 • Arlington, Virginia For more information: www.aspo.org

9th European Breast Cancer Conference March 19-21 • Glasglow, Scotland For more information: www.ecco-org.eu 20th Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 20-22 • Sunriver, Oregon For more information: www.ohsu.edu/bbb Illinois Medical Oncology Society 2014 Membership Conference March 21 • Chicago, Illinois For more information: www.imos-illinois.com/

ELCC 2014 European Lung Cancer Conference March 26-29 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2014-Lung-Cancer ACCC 40th Annual National Meeting March 31-April 2 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ AM2014.asp

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

April ESTRO 33 April 4-8 • Vienna, Austria For more information: www.estro.org/congressesmeetings/items/estro-33

May Oncology Nursing Society 39th Annual Congress May 1-4 • Anaheim, California For more information: www.ons.org Association for Value-Based Cancer Care – 4th Annual Conference May 6-9 • Los Angeles, California For more information: http:// avbcconline.org/ Accelerating Anticancer Agent Development and Validation Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/ ASPHO’s 27th Annual Meeting May 14-17 • Chicago, Illinois For more information: www.aspho.org Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics Symposium May 15-17 • Houston, Texas For more information: www.mdanderson.org/conferences 2014 State of the Art Radiation Therapy: Practical Treatment, Biology and Imaging May 16-18 • San Antonio, Texas For more information: www.astro.org

16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

July 2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

August

Society of Surgical Oncology Annual Cancer Symposium March 13 - 16 • Phoenix, Arizona For more information: www.surgonc.org 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 24th Annual Interdisciplinary Breast Cancer Conference March 15-19 • Las Vegas, Nevada For more information: www.breastcare.org/

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

ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June 6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org/ Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org/ Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org/ continued on page 54

The ASCO Post | MARCH 1, 2014

PAGE 54

2014

2014 Oncology Meetings continued from page 53

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: http://aonnonline.org Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/ home/scientists/meetings--workshops/ special-conferences/advances-inmelanoma-from-biology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29 - October 2 • Cambridge, Massachusetts For more information: http://steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org 2014 Second Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ breastcancer/pages/index.aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: http://www.cutaneousmalignancies .com 20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ ce/home/programs/physicians 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: http://www .mayo.edu/cme/surgical-specialties2014s306 EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014 Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

December

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org

July 21-25, 2014

American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org

The Kohala Coast, Hawaii

Abstract Submission Deadline: Early Registartion Deadline:

April 11, 2014 May 20, 2014

u nm c . e d u/p a n p a c i fi c l y m p h o m a

Amgen is exploring the expanded potential of biomarker analysis in metastatic colorectal cancer (mCRC)

When is your RAS analysis complete?

Expanding the potential of biomarker analysis means helping physicians not only determine what options are appropriate for patients but, equally as important, understanding what options are not appropriate for patients. Amgen is investigating extended RAS testing to further biomarker analysis in mCRC.

Learn more at www.amgenoncology.com

77929-R1-V1

11-13

The ASCO Post | MARCH 1, 2014

PAGE 56

JCO Spotlight Supportive Care

Short-Term Follow-Up Reveals Suboptimal Pain Relief and Marked Pain Worsening in Ambulatory Patients With Cancer By Matthew Stenger

n an analysis reported in the Journal of Clinical Oncology, Fengmin Zhao, MS, PhD, Dana-Farber Cancer Institute, Boston, and colleagues assessed factors associated with pain severity changes in ambulatory patients with invasive solid tumors (breast, prostate, colon/rectum, or lung) in the Eastern Cooperative Oncology Group E2Z02 (Symptom Outcomes and Practice Patterns [SOAPP]) trial.1 They found that approximately one-third of patients with pain at baseline had pain improvement and one-fifth had worsened pain during 4 or 5 weeks of follow-up and that pain developed in 28% of patients without pain at baseline.

significant change. Pain ratings of 1 to 3 were considered as mild, 4 to 5 as moderate, and 6 to 10 as severe pain. A total of 2,761 patients (88%) who reported pain scores at both initial assessment and follow-up were

One third of patients have pain improvement and one fifth experience pain deterioration within 1 month after initial assessment. Inadequate pain management, baseline pain severity, and certain patient demographic and disease characteristics are associated with pain deterioration.

Study Details The study involved 3,106 patients with invasive cancer of the breast, prostate, colon/rectum, or lung. At baseline and at 28 or 35 days, patients rated their pain level on a 0 to 10 numeric scale (MD Anderson Symptom Inventory, 10 = worst pain). A 2-point change in pain score was defined as a clinically

at initial assessment regardless of analgesic use (group 1), those without pain and taking no analgesics at initial assessment (group 2), and those without pain and taking analgesics at initial assessment (group 3).

—Fengmin Zhao, MS, PhD

included in the analysis. Among these patients, 50% had breast cancer, 24% had colorectal cancer, 10% had prostate cancer, and 16% had lung cancer. Patients were categorized into subgroups consisting of patients with pain

The Pain Management Index, calculated by subtracting pain score from analgesic score, was used to measure the adequacy of pain treatment. The index ranges from –3 (patient with severe pain receiving no analgesic drugs)

to +3 (patient receiving strong opioids and reporting no pain. Patients were dichotomized into two groups based on index values of < 0, indicating undertreatment, and ≥ 0, indicating adequate treatment.

Changes in Pain Severity Of the 2,761 patients, 47% had pain at the initial assessment (group 1, n = 1,298) and 53% had no pain (group 2 = 909, group 3 = 554). Among all patients, 23.5% had mild pain, 10% moderate pain, and 13% severe pain at initial assessment compared with 26%, 11.5%, and 14% at follow-up. Among group 1 patients (pain at baseline), 32% had reduced pain, 20% had worse pain, and 48% had stable pain at follow-up. The proportions of group 1 patients with pain improvement and worsening varied by baseline pain level; improvement vs worsening occurred in 16% vs 26% of those with mild pain,

Cancer Pain: The Humbling Reality By Michael J. Fisch, MD, MPH

s a medical oncologist and palliative care physician, I’ve had the privilege of caring for cancer patients and delivering primary palliative care and symptom control, as well as the chance to care for patients especially referred for complex pain and symptom problems (in secondary and even tertiary care).1 This work is tremendously gratifying, but I can assure you that it is humbling. Pain management often sounds fairly straightforward when explained to patients with cancer. If you visit the National Cancer Institute’s website (www. cancer.gov), for example, you find that “People who have cancer don’t always have pain. Everyone is different. But if you do have cancer pain, you should know that you don’t have to accept it. Cancer pain can almost always be reDr. Fisch is Chairman of the Department of General Oncology and Medical Director of the Community Clinical Oncology Program Research Base, The University of Texas MD Anderson Cancer Center, Houston.

lieved.” Pain management sounds easier here than it really is. What makes cancer pain management challenging? One reason is that there are no validated biomarkers to help physicians tailor therapy to individual patients. As such, pain care is based on rigorous assessment and reassessment and the use of time-limited therapeutic trials of analgesics (and sometimes pain procedures). Getting the best results in pain management requires excellent communication and negotiation skills to establish a therapeutic alliance and get buy-in from patients and family members. It also entails painstaking education and teachback methods to assess understanding. And the best results come from multidisciplinary teams of skilled clinicians (including nurses, pharmacists, social workers, and others).

Revealing Studies In 1994, Dr. Charles Cleeland and colleagues published a landmark paper

in The New England Journal of Medicine showing that two-thirds of patients with metastatic cancer have pain, and 42% of those patients are undertreated if you use the pain management index as the indicator of appropriate analgesic prescribing.2 This brought attention to the problem of pain, but the attention was focused on finding cancer patients who were having pain. The idea was that pain should be the fifth vital sign, and it was thought that once unmasked, pain was readily manageable. After all, this landmark study was cross-sectional, and one might figure that if there had been follow-up data, nearly all of these patients would have been treated and would improve over a short time frame. Based on our humbling clinical experiences, most oncologists knew better. The SOAPP study (Symptom Outcomes And Practice Patterns) conducted by the Eastern Cooperative Oncology Group and two pain-related papers published in the Journal of Clini-

cal Oncology certainly show this.3,4 Even when the cohort of ambulatory cancer patients is not limited to patients with metastatic cancer, we still find that twothirds of patients have pain or require analgesics, and only one-third get adequate analgesic prescribing. In the recent Zhao et al SOAPP publication in the Journal of Clinical Oncology—reviewed in this issue of The ASCO Post—we find what happens when we follow patients over a 4- to 5-week period after initial assessment.4 They do not all get better. About one-third significantly improve, but one-fifth get worse and 28% of those who didn’t have pain subsequently develop pain (9% of them in the moderate-to-severe range). These are patients being followed on a study where their pain and symptoms are being actively recorded and carefully watched by teams that are actively involved in cancer research. One might expect this to be the best-case scenario. So now we know just how inadequate pain management can be, and these data

ASCOPost.com | MARCH 1, 2014

PAGE 57

JCO Spotlight

40% vs 22.5% of those with moderate pain, and 56% vs 6% of those with severe pain at baseline. Among group 2 and 3 patients combined (no pain at baseline), 28% had pain at follow-up, including 19.5% with mild pain, 5% with moderate pain, and 4% with severe pain.

Changes in Pain Management Among all patients, 55% had adequate pain management at both visits, 11% had adequate pain management at baseline but were undertreated at followup, 10% were undertreated at baseline but had adequate pain management at follow-up, and 12% were undertreated at both visits. Patients in group 2 had the highest proportion of change from adequate pain management to undertreatment (20% vs 8% for group 3 and vs 7% for group 1; P < .001 for both). In group 1, patients with severe pain at initial assessment had the highest proportion of undertreatment at both visits (35% vs 20.5% for mild pain and vs 22% for moderate pain at baseline; P < .01 for both). Among group 1 patients, the proportion of patients with worsening pain was highest for patients with pain management that changed from adequate to undertreated (67%), whereas patients with management that changed from undertreated to can be used to adjust our language about the success of pain treatment and to motivate us to find ways to improve care.

Challenges and Solutions Among the findings reported by Zhao et al, we note that the biggest barrier to improving pain is the obvious factor, the undertreatment of pain. Other factors make clinical sense, too. Constipation, coprescribing of multiple drugs, and unemployment all represent barriers to adherence to opioids prescribed for pain control. Neuropathic pain is an adverse predictor, and this type of pain is famously less responsive to commonly prescribed (and less expensive) analgesics like acetaminophen, nonsteroidal anti-inflammatory agents, and opioids. And community institutions were less successful than academic institutions in pain control, perhaps an issue related to having less access (on average) to pain and palliative care specialists. How could cancer pain care improve such that the next prospective cohort study yields a much brighter set of data? First and foremost, better drugs and procedures for cancer pain

adequate were more likely to have pain relief (64%; P < .001 for both) regardless of pain level at initial assessment. Among group 2 patients, 23.5% had developed pain at follow-up, with 85.5% of these patients receiving inadequate pain management. Among group 3 patients, 36% had pain at follow-up, with 21% of these patients receiving inadequate pain management for the recurrent pain.

Factors Predictive of Worsening Pain Multivariate logistic analyses adjusted for factors associated with worsening pain in group 1 patients and for factors associated with development of moderate-to-severe pain in group 2 and group 3 patients. Factors significantly associated with worsening pain (all P < .05) in group 1 patients included change in pain management from adequate at baseline (odds ratio [OR] = 0.68) to undertreated at follow-up (OR = 11.8). Increased odds of worsening pain were also associated with patients who had the following characteristics at baseline: neuropathic pain (OR = 1.97) or pain due to moderate-to-severe constipation (OR = 1.69), comorbidityrelated discomfort (OR = 1.57), greater number of medications currently taken (OR = 0.57), lung cancer (OR = 0.44 for are needed. Progress in this regard requires many more investigators to be involved in studying basic mechanisms of cancer pain. Change in this regard will require more funding to build this workforce. Another element of change would be in the realm of incentives. Better

Pain in Ambulatory Cancer Patients ■■ Among patients with pain at baseline, 32% had reduced pain and 20% had worse pain at follow-up. ■■ Among patients with no pain at baseline, 28% had pain at follow-up, including 9% with moderate or severe pain.

prostate vs lung, OR = 0.45 for colorectal vs lung), unemployment (OR = 2.05 vs full employment), and treatment in community institutions (OR = 2.22 vs academic institutions). Factors significantly associated with occurrence of moderate-to-severe pain in group 2 patients on multivariate analysis (all P < .05) consisted of Hispanic ethnicity (OR = 3.38), constipation severity (OR = 1.18), and age < 55 years (OR = 2.28). Factors significantly associated with moderateto-severe pain in group 3 patients (all P < .05) consisted of nonopioid (OR = 2.09) or weak opioid (OR = 3.96) vs strong opioid use, years since cancer diagnosis (OR = 0.89), and accompaniment to study visit (OR = 2.09). The investigators concluded, “One third of patients have pain improvement and one fifth experience pain deterioration within 1 month after initial assessment. Inadequate pain management, baseline pain severity, and certain patient generally build toward overcoming barriers to pain management.

Routine Quality Measures Finally, incorporation of routine quality measures related to pain management and transparent reporting of such data would enhance the focus

The goal we seek with these efforts is to make an impact on patients’ lives. Improving the care of cancer pain would be a good place to start. —Michael J. Fisch, MD, MPH

reimbursement for clinicians to counsel patients about the goals of care and options and barriers related to pain management would allow for better staffing and staff training in this realm. Educational reform and health-care delivery reform that enhance the early integration of palliative care would make a big difference in outcomes, too.5 The elements of palliative care

of individuals and organizations on pain management. Such quality measures need to go beyond just documenting pain. For example, in our Regional Cancer Centers, oncologists are participating in the Quality Oncology Practice Initiative (QOPI), and their citizenship metrics (and pay) are affected by their performance in terms of docu-

demographic and disease characteristics are associated with pain deterioration.” They noted, “[P]ain remains a significant concern in ambulatory oncology. Pain is not only prevalent but also persistent and dynamic. Knowing that pain management practices and baseline pain severity are key factors for change in pain severity should enable better designs of clinical trials intended to measure the impact of cancer therapeutics or supportive care measures on the short-term patient experience of pain.” n

Disclosure: The study was supported by National Cancer Institute and MD Anderson Cancer Center grants. The study authors reported no potential conflicts of interest.

Reference 1. Zhao F, Chang VT, Cleeland C, et al: Determinants of pain severity changes in ambulatory patients with cancer: An analysis from Eastern Cooperative Oncology Group trial E2Z02. J Clin Oncol. December 23, 2013 (early release online).

menting a plan of care for moderate/ severe pain by the second office visit. This is a part of a new model and a trend in oncology toward identifying and rewarding performance that goes beyond standard measures of productivity and includes a focus on aspects of performance that have high impact on patients.6 Ultimately, the goal we all seek with these individual, organizational, and health policy efforts is to make an impact on patients’ lives. Improving the care of cancer pain would certainly be a good place to start. n Disclosure: Dr. Fisch reported no potential conflicts of interest.

References 1. von Gunten CF: JAMA 287:875881, 2002. 2. Cleeland C, et al: N Engl J Med 330:592-596, 1994. 3. Fisch MJ, et al: J Clin Oncol 30:1980-1988, 2012. 4. Zhao F, et al: J Clin Oncol 32:312319, 2014. 5. Parikh RB, et al: N Engl J Med 369:2347-2351, 2013. 6. Fisch MJ, et al: J Oncol Pract 10:7981, 2014.

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

ASCOPost.com | MARCH 1, 2014

PAGE 59

Health-Care Policy Repeal of SGR continued from page 1

Community Oncology Alliance, told The ASCO Post.

A Flawed Mechanism In short, the SGR is a component of the formula the Centers for Medicare & Medicaid Services (CMS) uses to calculate physician payments for providing services to Medicare patients. Generally, it is a method to ensure that the yearly increase in the expense per Medicare beneficiary does not exceed the growth in gross domestic product. On March 1 of each year, the physician fee schedule is updated accordingly, and if actual expenditures surpass the gross domestic product, physicians’ payments are cut.

Senator Max Baucus

from one ‘doc fix’ to the next, creating a new, unnecessary threat to seniors’ care each time. Enough is enough. This proposal would bring that cycle to and end and fix the broken system. Our bill makes Medicare’s physician payments more modern and efficient, and it will protect seniors’ access to their doctors.” Senator Baucus’s reference to a “more modern and efficient” payment

After years of short-term patches and fixes, it seems that everyone, from the provider community to CMS to lawmakers, is finally ready to enact a long-term solution to the SGR formula. —Matthew Farber, MA

Since 2002, when physician payments were cut by 5%, the SGR formula has annually called for reductions in Medicare reimbursements, some as steep as 29%. Congress has enacted 16 “patches” to stop Medicare physician payment cuts. Experts contend that the cumulative cost of these patches has been $153.7 billion, which exceeds the cost of simply repealing the SGR. By repealing the flawed SGR mechanism, Congress has averted a 23.7% cut in physician fees scheduled for this year.

Changes Worth Noting In a press release, Senator Max Baucus (D-MT), former Chairman of the Senate Committee on Finance said, “Congress has spent a decade lurching

system referred largely to sections of the legislation that create a meritbased incentive payment system that will recognize physician performance related to quality measure reporting, resource use, electronic health record– meaningful use, and clinical improvement activities. Matthew Farber, MA, Director of Economics and Public Policy for the Association of Community Cancer Centers (ACCC), commented to The ASCO Post, “ACCC is happy to see the continued interest by Congress to try and solve the issue of the SGR in the long term. After years of short-term patches and fixes, it seems that everyone, from the provider community to CMS to lawmakers, is finally ready to

enact a long-term solution to the SGR formula. Even with the reduced cost, the roughly $120 billion price tag is still the final hurdle that may prove difficult to overcome. We still think this effort is the best chance to pass long-term SGR reform that we have ever had.” The bill removes the threat of draconian cuts to Medicare providers by ensuring a 5-year period of annual updates of 0.5% during the transition to the new system, which is centered on quality, value, and accountability. In 2018, a new Merit-Based Incentive Payment System, as it will be called, will consolidate the Physician Quality Reporting System, Value-Based Modifier, and “meaningful use” program for electronic health records (EHRs) starting in 2018. Some policy experts question whether abstract terms such as value and accountability will be actionable enough to cover the costs of SGR repeal estimated between $120 and $150 billion. “As for the bill itself, ACCC is happy to see that Congress has included a positive update for physicians in the first transition phase. Even though a 0.5% update is small, and we would like to see a larger adjustment, the fact that it is an increase, and that it provides certainty after years of unknowns [is appreciated],” stressed Mr. Farber. Mr. Farber pointed out that the consolidation of various quality reporting mechanisms would hopefully make it easier for providers to achieve benchmarks and thus attain a bonus payment. “As many members of ACCC are currently researching, or transitioning into new payment models, including medical homes and [accountable care organizations], the bonus payment for participation in alternative payment models may prove to be beneficial. Hopefully the final law will include numerous types of payment modalities, as we have seen many of our members incorporating innovative models into their practices and hospitals. ACCC

will be discussing this and other issues during our Capitol Hill day on March 31st,” noted Mr. Farber.

Prepare for Post-SGR Changes According to a summary offered by the committees that fashioned the SGR repeal bill, the “payment implications” of the current incentivepayment programs would end at the end of 2017. That simply means that Medicare would eliminate scheduled reductions in reimbursement in the form of 3% penalties for failing to comply with the meaningful use criteria, as well as escalating penalties up to 5% in 2019. The 2% penalty for failure to report quality measures per the Physician Quality Reporting System in 2017 would also be dropped. It is important to realize that during this period of change, the many moving parts of the new SGR repeal bill will be conflated with changes already enacted in the Affordable Care Act, and the oncology community needs to keep fully engaged. For example, the term “meaningful use,” which is part of the Medicare & Medicaid EHR Incentive Programs, is staged in three steps with increasing requirements for participation. Understanding how to comply with the new incentive payment programs is essential for the fiscal stability of community practices as the new legislation unfolds. Repealing the SGR is certainly a step in the right direction, but altering the current payment system is easier said than done, and the oncology community must remain cautiously optimistic. “While ACCC would like to see larger annual increases, we are pleased that positive updates were included in the final repeal bill. The biggest hurdle to passage remains the price tag—which is now estimated to be roughly $120 billion to $140 billion over 10 years. And legislators have yet to spell out how Congress will pay for this fix,” said Mr. Farber. n

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | MARCH 1, 2014

PAGE 60

Announcements Interdisciplinary Care

Advanced Practitioner Society for Hematology and Oncology (APSHO) Welcoming Members

he Advanced Practitioner Society for Hematology and Oncology (APSHO) is issuing a call for members to oncology nurse practitioners, physician assistants, clinical nurse specialists, advanced degree nurses, and pharmacists. The Society was launched recently during JADPRO Live, a meeting of the Journal of the Advanced Practitioner in Oncology (JADPRO) (see pages 50-51 for coverage from JADPRO Live). JADPRO is the official journal of the new Society. Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®, JADPRO’s Editorin-Chief and a Founding Member of APSHO, said the new Society is focused on meeting the unique educational and professional needs of the advanced practitioner in hematology and oncology.

ASCO Welcomes APSHO Following the JADPRO Live First Annual Meeting and the announcement of APSHO’s launch, Allen S. Lichter, MD, FASCO, CEO of ASCO, said in a letter to the Society: “ASCO also wishes to congratulate you on your new venture with the creation of the Advanced Practitioner Society for Hematology and Oncology (APSHO). We recognize the shared missions of our organizations [ASCO and APSHO] to improve the quality of care

ter in Tucson, Wendy H. Vogel, MSN, FNP, AOCNP®, of the Wellmont Cancer institute in Kingsport, Tennessee, and Christopher J. Campen, PharmD, BCPS, of The University of Arizona Can-

cer Center. Charter members of APSHO include the more than 250 advanced practitioners in hematology and oncology who attended the first annual JADPRO Live meeting in St. Petersburg, Florida.

For More Information To register for membership or recieve more information, visit APSHO.org or e-mail the Society at info@APSHO.org. n

Redefine treatment goals with YERVOY (ipilimumab) is the ONLY metastatic melanoma therapy proven in a phase 3 study to deliver a durable long-term survival benefit1

46% 1-YEAR survival rate*

24% 2-YEAR survival rate*

Some patients were still alive up to 4.5 years2 The overall survival curve shows 2, 1, and 0 patients were still in follow-up in the YERVOY arm at 48, 52, and 56 months at the time of study closure. *Estimate based on Kaplan-Meier analysis.1

Median overall survival was 10 months in the YERVOY arm3

YERVOY + gp100 vs gp100: HR=0.68 (95% CI: 0.55, 0.85, P=0.0004) YERVOY vs gp100: HR=0.66 (95% CI: 0.51, 0.87, P=0.0026)a YERVOY + gp100 vs YERVOY: HR=1.04 (95% CI: 0.83, 1.30, P=0.76) Not adjusted for multiple comparisons.

for patients with cancer. Our members collaborate every day in practice and research to strive for this important goal. We believe it is important that our two organizations similarly work together in education, research, professional development, and policy activities in an interdisciplinary, interprofessional team approach. “We look forward to working with you,” Dr. Lichter concluded.

Founding Members of APSHO In addition to Ms. Viale, of the University of California, San Francisco, APSHO Founding Members are Sandra E. Kurtin, RN, MS, AOCN®, ANP-C, of The University of Arizona Cancer Cen-

A phase 3, double-blind, double-dummy study that randomized 676 patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin (IL-2), dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive YERVOY 3 mg/kg in combination with an investigational gp100 peptide vaccine (gp100) (n=403), YERVOY 3 mg/kg (n=137), or gp100 (n=136). The primary endpoint was overall survival in the YERVOY + gp100 arm vs the gp100 arm.1

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

ASCOPost.com | MARCH 1, 2014

PAGE 61

Announcements

President’s Cancer Panel Issues Urgent Call to Action for HPV Vaccination

chieving widespread human papillomavirus (HPV) vaccination is one of the most profound opportunities for cancer prevention, according to a report recently released by the President’s Cancer Panel. The Panel’s report, Accelerating HPV Vaccine Uptake: Urgency for Action to

Prevent Cancer, issues an urgent call for energizing efforts to reach the HPV vaccines’ potential to save lives and prevent millions of avoidable cancers and HPV-related conditions in men and women. “Today, there are two safe, effective, approved vaccines that prevent infection

by the two most prevalent cancer-causing types, yet vaccination rates are far too low,” said Barbara K. Rimer, DrPH, Chair of the President’s Cancer Panel. “We are confident that if HPV vaccination for girls and boys is made a public health priority, Barbara K. Rimer, DrPH

durable long-term survival in metastatic melanoma

YERVOY is not indicated for patients under 18 years of age.

Indication

YERVOY® (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

See experts discuss redefining treatment goals for metastatic melanoma Find out at www.RedefineTreatmentGoals1.com

To learn more, visit www.YERVOY.com or call Support Services at 1-855-YERVOY1.

Please see detailed Important Safety Information, including Boxed WARNING regarding immune-mediated side effects, and brief summary of Full Prescribing Information on adjacent pages. ©2014 Bristol-Myers Squibb Company. All rights reserved. 731US13BR03586-03-01 01/14

continued on page 62

The ASCO Post | MARCH 1, 2014

PAGE 62

Announcements President’s Cancer Panel continued from page 61

hundreds of thousands will be protected from these HPV-associated diseases and cancers over their lifetimes.” According to the report, based on data from the Centers for Disease Control and Prevention, in 2012 only about one-third of 13- to 17-year-old girls

in the United States received all three recommended doses of HPV vaccine. Immunization rates for boys were even lower; less than 7% of boys ages 13 to 17 completed the vaccine series in 2012. The Panel’s report outlines three critical goals that must be achieved to increase HPV vaccine uptake: reducing missed clinical opportunities to recommend/

administer HPV vaccines; increasing parents’/adolescents’ acceptance of HPV vaccines; and maximizing access to HPV vaccination services, with the ultimate goal being completion of the full threedose series by all age-eligible adolescents. The Panel’s report also calls for continued investment in and implementation of HPV vaccination programs in

low-and middle-income countries, where the majority of HPVassociated cancer cases occur. The complete report can be accessed at http://deainfo.nci. nih.gov/advisory/pcp/annualReports/ HPV/index.htm. n

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY® (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: • Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day • Failure to complete full treatment course within 16 weeks from administration of first dose • Severe or life-threatening adverse reactions, including any of the following: – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation – AST or ALT >5× the upper limit of normal (ULN) or total bilirubin >3× the ULN – Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations – Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis – Severe immune-mediated reactions involving any organ system – Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy Immune-mediated Enterocolitis: • In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients • Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis • Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids • Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms • Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients • Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent) Important Safety Information continued on following page.

ASCOPost.com | MARCH 1, 2014

PAGE 63

Announcements

Dana-Farber Receives $900,000 Grant to Research Ovarian Cancer

he Ovarian Cancer Research Foundation has awarded researchers at Dana-Farber Cancer Institute a $900,000 grant to test new combinations of targeted drugs against the disease. Ursula Matulonis, MD, Director of the Gynecological Cancer Treatment Center in

Ursula Matulonis, MD

the Susan F. Smith Center for Women’s Cancers at Dana-Farber is the Principal Investigator of the Program Project Development Grant from Ovarian Cancer Research Foundation. This grant helped mark the Foundation’s 20th Anniversary for which an unprecedented $6.9 million

Important Safety Information (cont’d) Immune-mediated Hepatitis: • In the pivotal Phase 3 study in YERVOY (ipilimumab)-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% • 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2) • Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution • Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids • Withhold YERVOY in patients with Grade 2 hepatotoxicity • In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) Immune-mediated Dermatitis: • In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients – 1 (0.2%) patient died as a result of toxic epidermal necrolysis – 1 additional patient required hospitalization for severe dermatitis • There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis • Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated • Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms • Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week Immune-mediated Neuropathies: • In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported • Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported • Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes • Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies: • In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immunemediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients Important Safety Information continued on following page.

was awarded in research and program grants to support patients with gynecologic cancers. “The ultimate goal of this project is to quickly bring laboratory-tested and verified novel drug combinations into ovarian continued on page 64

The ASCO Post | MARCH 1, 2014

PAGE 64

Announcements Dana-Farber continued from page 63

cancer clinical trials,” said Dr. Matulonis. She noted that treatment advances in ovarian cancer have reached a plateau. “Newer agents that target ovarian cancer genetic abnormalities have shown some efficacy as single agents, but cancer cells eventually figure out ways to

grow despite the drug,” she said. Dr. Matulonis and her team will explore a number of strategies that combine drugs that simultaneously target several abnormal biologic pathways in ovarian cancer cells. In one project, researchers will test the effectiveness of a PARP inhibitor and another targeted therapy in blocking the abnormal PI3-kinase sig-

naling pathway in ovarian tumors. A second project will combine a heat shock protein (HSP) inhibitor and a PARP inhibitor aimed at preventing damaged ovarian cancer cells from repairing themselves. The third project will use BH3 profiling, which measures how close cancer cells are to destroying themselves, to

evaluate targeted drug combinations. Other researchers at Dana-Farber funded by the grant are Panagiotis Konstantinopoulos, MD, PhD, Anthony Letai, MD, PhD, Joyce Liu, MD, MPH, and William Barry, PhD, and investigator Gerburg Wulf, MD, PhD, of Beth Israel-Deaconess Medical Center. n

Important Important Safety Safety Information Information (cont’d) (cont’d) Immune-mediated Immune-mediated Endocrinopathies Endocrinopathies (cont’d): (cont’d): – All –9 All patients 9 patients had hypopituitarism, had hypopituitarism, and some and some had additional had additional concomitant concomitant endocrinopathies endocrinopathies suchsuch as adrenal as adrenal insufficiency, insufficiency, hypogonadism, hypogonadism, and hypothyroidism and hypothyroidism – 6 of– the 6 of9the patients 9 patients werewere hospitalized hospitalized for severe for severe endocrinopathies endocrinopathies • Moderate • Moderate endocrinopathy endocrinopathy (requiring (requiring hormone hormone replacement replacement or medical or medical intervention; intervention; Grade Grade 2) 2) occurred occurred in 12in(2.3%) 12 (2.3%) YERVOY YERVOY (ipilimumab)-treated (ipilimumab)-treated patients patients and consisted and consisted of hypothyroidism, of hypothyroidism, adrenal adrenal insufficiency, insufficiency, hypopituitarism, hypopituitarism, and 1 and case 1 case eacheach of hyperthyroidism of hyperthyroidism and Cushing’s and Cushing’s syndrome syndrome • Median • Median time time to onset to onset of moderate of moderate to severe to severe immune-mediated immune-mediated endocrinopathy endocrinopathy was 11 wasweeks 11 weeks and and ranged ranged up toup 19.3 to 19.3 weeks weeks after after the initiation the initiation of YERVOY of YERVOY • Monitor • Monitor patients patients for clinical for clinical signssigns and symptoms and symptoms of hypophysitis, of hypophysitis, adrenal adrenal insufficiency insufficiency (including (including adrenal adrenal crisis), crisis), and hyperand hyperor hypothyroidism or hypothyroidism – Patients – Patients may may present present with with fatigue, fatigue, headache, headache, mental mental status status changes, changes, abdominal abdominal pain,pain, unusual unusual bowel bowel habits, habits, and hypotension, and hypotension, or nonspecific or nonspecific symptoms symptoms which which may may resemble resemble otherother causes causes suchsuch as brain as brain metastasis metastasis or underlying or underlying disease. disease. Unless Unless an alternate an alternate etiology etiology has been has been identified, identified, signssigns or symptoms or symptoms should should be considered be considered immune-mediated immune-mediated – Monitor – Monitor thyroid thyroid function function teststests and clinical and clinical chemistries chemistries at theatstart the start of treatment, of treatment, before before eacheach dose,dose, and as andclinically as clinically indicated indicated based based on symptoms. on symptoms. In a limited In a limited number number of patients, of patients, hypophysitis hypophysitis was was diagnosed diagnosed by imaging by imaging studies studies through through enlargement enlargement of theofpituitary the pituitary glandgland • Withhold • Withhold YERVOY YERVOY in symptomatic in symptomatic patients. patients. Initiate Initiate systemic systemic corticosteroids corticosteroids (1-2 (1-2 mg/kg/day mg/kg/day of of prednisone prednisone or equivalent) or equivalent) and initiate and initiate appropriate appropriate hormone hormone replacement replacement therapy. therapy. Long-term Long-term hormone hormone replacement replacement therapy therapy may may be necessary be necessary OtherOther Immune-mediated Immune-mediated Adverse Adverse Reactions, Reactions, Including Including Ocular Ocular Manifestations: Manifestations: • In the • Inpivotal the pivotal Phase Phase 3 study 3 study in YERVOY-treated in YERVOY-treated patients, patients, clinically clinically significant significant immune-mediated immune-mediated adverse adverse reactions reactions seenseen in <1% in <1% were:were: nephritis, nephritis, pneumonitis, pneumonitis, meningitis, meningitis, pericarditis, pericarditis, uveitis, uveitis, iritis,iritis, and hemolytic and hemolytic anemia anemia • Across • Across the clinical the clinical development development program program for YERVOY, for YERVOY, likelylikely immune-mediated immune-mediated adverse adverse reactions reactions also also reported reported with with <1%<1% incidence incidence were:were: myocarditis, myocarditis, angiopathy, angiopathy, temporal temporal arteritis, arteritis, vasculitis, vasculitis, polymyalgia polymyalgia rheumatica, rheumatica, conjunctivitis, conjunctivitis, blepharitis, blepharitis, episcleritis, episcleritis, scleritis, scleritis, leukocytoclastic leukocytoclastic vasculitis, vasculitis, erythema erythema multiforme, multiforme, psoriasis, psoriasis, pancreatitis, pancreatitis, arthritis, arthritis, autoimmune autoimmune thyroiditis, thyroiditis, sarcoidosis, sarcoidosis, neurosensory neurosensory hypoacusis, hypoacusis, autoimmune autoimmune central central neuropathy neuropathy (encephalitis), (encephalitis), myositis, myositis, polymyositis, polymyositis, and ocular and ocular myositis myositis • Permanently • Permanently discontinue discontinue YERVOY YERVOY for clinically for clinically significant significant or severe or severe immune-mediated immune-mediated adverse adverse reactions. reactions. Initiate Initiate systemic systemic corticosteroids corticosteroids (1-2 (1-2 mg/kg/day mg/kg/day of prednisone of prednisone or equivalent) or equivalent) for severe for severe immune-mediated immune-mediated adverse adverse reactions reactions • Administer • Administer corticosteroid corticosteroid eye drops eye drops for uveitis, for uveitis, iritis,iritis, or episcleritis. or episcleritis. Permanently Permanently discontinue discontinue YERVOY YERVOY for immune-mediated for immune-mediated ocular ocular disease disease unresponsive unresponsive to local to local immunosuppressive immunosuppressive therapy therapy Pregnancy Pregnancy & Nursing: & Nursing: • YERVOY • YERVOY is classified is classified as pregnancy as pregnancy category category C. There C. There are no areadequate no adequate and well-controlled and well-controlled studies studies of YERVOY of YERVOY in pregnant in pregnant women. women. Use Use YERVOY YERVOY during during pregnancy pregnancy only only if theifpotential the potential benefit benefit justifies justifies the potential the potential risk to risk thetofetus the fetus • Human • Human IgG1IgG1 is known is known to cross to cross the placental the placental barrier barrier and YERVOY and YERVOY is anisIgG1; an IgG1; therefore, therefore, YERVOY YERVOY has the haspotential the potential to betotransmitted be transmitted fromfrom the mother the mother to thetodeveloping the developing fetusfetus • It is• not It isknown not known whether whether YERVOY YERVOY is secreted is secreted in human in human milk.milk. Because Because manymany drugsdrugs are secreted are secreted in in human human milk milk and because and because of theofpotential the potential for serious for serious adverse adverse reactions reactions in nursing in nursing infants infants fromfrom YERVOY, YERVOY, a decision a decision should should be made be made whether whether to discontinue to discontinue nursing nursing or to or discontinue to discontinue YERVOY YERVOY Common Common Adverse Adverse Reactions: Reactions: • The• most The most common common adverse adverse reactions reactions (≥5%) (≥5%) in patients in patients who who received received YERVOY YERVOY at 3 mg/kg at 3 mg/kg werewere fatigue fatigue (41%), (41%), diarrhea diarrhea (32%), (32%), pruritus pruritus (31%), (31%), rash rash (29%), (29%), and colitis and colitis (8%)(8%) PleasePlease see brief seesummary brief summary of Full of Prescribing Full Prescribing Information, Information, including including Boxed Boxed WARNING WARNING regarding regarding immune-mediated immune-mediated side effects, side effects, on following on following pages.pages. References: References: 1. Hodi 1. FS,Hodi O’Day FS,SJ, O’Day McDermott SJ, McDermott DF, et al.DF,Improved et al. Improved survivalsurvival with ipilimumab with ipilimumab in patients in patients with metastatic with metastatic melanoma. melanoma. N Engl JNMed. Engl2010;363(8):711-723. J Med. 2010;363(8):711-723. 2. YERVOY 2. YERVOY packagepackage insert. Princeton, insert. Princeton, NJ: Bristol-Myers NJ: Bristol-Myers Squibb Company. Squibb Company. 3. Data 3. onData file. YERV on file.008. YERV Bristol-Myers 008. Bristol-Myers Squibb Company. Squibb Company. Princeton, Princeton, NJ. AprilNJ. 2011. April 2011.

ASCOPost.com | MARCH 1, 2014

PAGE 65

Announcements

Cancer Treatment Centers Names Sr. Vice President, Patient Care Services

ancer Treatment Centers of America in Philadelphia has announced they have recently hired Nancy G. Hesse, MSN, RN, as the hospital’s Senior Vice President of Patient Care Services. In her new role, Ms. Hesse will work on several

key initiatives for her team related to engagement, communication, and research. Ms. Hesse earned her Master’s degree in Nursing Leadership from the University of Pennsylvania and a Bachelor of Science in Nursing

YERVOY® (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information.] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions.] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning.] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range: 1.6–13.4) and 6.3 weeks (range: 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information.] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event. Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution. Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information.] Concurrent Administration with Vemurafenib In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous,

Yrv1213pbs731US13BR02790_0101wip3.indd 1

Nancy G. Hesse, MSN, RN

or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY (ipilimumab)-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis. The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY. Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information.] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information.] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information.] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information.] ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-mediated enterocolitis [see Warnings and Precautions]. • Immune-mediated hepatitis [see Warnings and Precautions]. • Immune-mediated dermatitis [see Warnings and Precautions]. • Immune-mediated neuropathies [see Warnings and Precautions]. • Immune-mediated endocrinopathies [see Warnings and Precautions]. • Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions].

12/13/13 1:32 PM

from Widener University in Chester, Pennsylvania. She is also certified in Emergency Nursing and credentialed in Trauma Nursing. Ms. Hesse previously served as the Chief Nursing Officer at Abington Health Lansdale Hospital in Pennsylvania. n

The ASCO Post | MARCH 1, 2014

PAGE 66

Announcements

David A. Fullerton, MD, Named President of The Society of Thoracic Surgeons

avid A. Fullerton, MD, of the University of Colorado School of Medicine, was elected President of The Society of Thoracic Surgeons (STS) at the Society’s 50th Annual Meeting in Orlando, Florida. “STS has been a preeminent medical

society for many years,” said Dr. Fullerton. “It is truly a great honor to lead such a tremendous organization. Its influences span far beyond our own specialty, and I plan to continue that tradition during my tenure.” Dr. Fullerton heads the Division of Cardiothoracic Surgery at the University

of Colorado School of Medicine, where he is also a Professor of Surgery, holds the John T. M. Wright Endowed Chair in Heart Valve Surgery, and is the Director of Cardiothoracic Surgical Research and the Director of the University’s Thoracic Surgery Residency Program. In addition,

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information.] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1–4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

David A. Fullerton, MD

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY (ipilimumab) with the incidences of antibodies to other products may be misleading.

from the University of Missouri School of Medicine. After completing a residency in general surgery at the University of Washington, he moved to the University of Colorado for a residency in thoracic surgery. Dr. Fullerton remained on the faculty at the University of Colorado for the next 6 years before being recruited to Northwestern University in Chicago as Chief of Cardiothoracic Surgery and Director of the Thoracic Surgery Residency Program. He was recruited to the University of Colorado in 2003.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

DRUG INTERACTIONS

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

USE IN SPECIFIC POPULATIONS

Table 1:

Percentage (%) of YERVOY 3 mg/kg n=131 System Organ Class/ Preferred Term Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a

Pregnancy There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patientsa

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3–5

Any Grade

Grade 3–5

Any Grade

Grade 3–5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition, at exposure levels either 2.6 or 7.2 times higher by AUC than the exposures at the clinical dose of 3 mg/kg of ipilimumab. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab treated groups experienced higher incidences of severe toxicities including abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls. [See Nonclinical Toxicology (13.2) in Full Prescribing Information.] Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Nursing Mothers

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2:

No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

Pregnancy Category C

Selected Adverse Reactions in Study 1

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of 0.1 and 0.4 mcg/mL, representing a ratio of up to 0.3% of the serum concentration of the drug. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother. Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No dose adjustment is needed for patients with renal impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 × to 1.5 × the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 × to 3.0 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment. [See Clinical Pharmacology (12.3) in Full Prescribing Information.] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. •

Inform patients of the potential risk of immune-mediated adverse reactions.

• • •

Advise patients to read the YERVOY Medication Guide before each YERVOY infusion. Advise women that YERVOY may cause fetal harm. Advise nursing mothers not to breastfeed while taking YERVOY.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321675A0

Rev December 2013 731US13BR02790-01-01

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Yrv1213pbs731US13BR02790_0101wip3.indd 2

he is the Cardiac Surgeon-in-Chief and Co-Director of the Cardiothoracic Surgical Intensive Care Unit for the University of Colorado Hospital. Dr. Fullerton received his undergraduate degree from Southern Methodist University and graduated Magna Cum Laude

12/13/13

Leadership Roles A longtime STS member and volunteer, Dr. Fullerton served most recently as First Vice President on the STS Board of Directors. In 2013 to 2014, he also chaired the Workforce on Critical Care and served on the Executive Committee, the Workforce on Thoracic Surgery Resident Issues, and the Workforce on Research Development. In addition, Dr. Fullerton has held prominent leadership positions in several other organizations, including The American Board of Thoracic Surgery, the American College of Surgeons, the Thoracic Surgery Foundation for Research and Education, and the Residency Review Committee-Thoracic Surgery. He is a Past President of the Western Thoracic Surgical Association. He currently serves on the Board of Directors of CTSNet, Inc, as well as the Joint Council on Thoracic Surgery Education, and is President of the Thoracic Surgery Directors Association. “STS has always done a terrific job of bringing value to its membership, and I look forward to continuing that during my presidency,” said Dr. Fullerton. “I plan to build upon the Society’s strengths—the STS National Database and advocacy efforts—and add value 1:32 PM for our members and our specialty.” n

ASCOPost.com | MARCH 1, 2014

PAGE 67

Expert’s Corner

City of Hope’s New Chief Scientific Officer and Cancer Center Director Reflects on His Career Path and the Future of Cancer Care A Conversation With Steven T. Rosen, MD By Ronald Piana

ity of Hope in Duarte, California, has named Steven T. Rosen, MD, as its first Provost and Chief Scientific Officer. Dr. Rosen will guide the scientific direction of the center’s medical research, treatment, and education. He will also assume directorship of the comprehensive cancer institute, with his new duties officially beginning March 1. Dr. Rosen previously served as Director of the National Cancer Institute (NCI)-designated Robert H.

I became the Director in 1989. The cancer center was established in 1974 with brief NCI funding, but that core grant was not refunded. In 1993, the center received an endowment from Ann and Robert H. Lurie, and in 1998, the center’s name was modified to the Lurie Cancer Center, when we received NCI-designation as one of the nation’s 41 comprehensive cancer centers. Over the past 25 years, Lurie emerged as one of America’s outstand-

We’ve already seen major adjustments in models of care that have not resulted in a diminishment of quality. In fact, the future is bright; it’s a very exciting time in oncology. —Steven T. Rosen, MD

Lurie Comprehensive Cancer Center of Northwestern University and Director of Cancer Programs at Northwestern Memorial Hospital, Chicago, a position he held for 25 years. The ASCO Post recently spoke with Dr. Rosen about his time at Lurie and his vision for City Of Hope.

Northwestern Years Please give the readers a snapshot of your road to Northwestern. Actually, it was very direct. I grew up in Queens, New York, and I came to Northwestern University when I was 17 years old. I entered the 6-year honors program—after graduating college you go directly to the medical school. After completing medical school I did my residency at Northwestern and went from there to the NCI for my fellowship. Then I returned to Northwestern, where I spent the first part of my career at the Veterans Administration Hospital doing clinical research and laboratory investigation. In 1981, I moved into a full-time position at the University. When did you become the Director of the cancer center there?

ing cancer centers. Most recently, during a site visit from the NCI, we were asked to be the representative institution from Illinois for the National Comprehensive Cancer Network (NCCN). There were several additional core grants, and over the years, Lurie has emerged as the largest provider of cancer care, in terms of volume, in the state of Illinois. I’m very proud of having been part of Lurie’s incredible legacy, and I’m confident that my wonderful colleagues will continue to build on that legacy.

New Role at City of Hope What prompted your decision to accept a leadership role at City of Hope, after such a rich career at Lurie? It was a once-in-a-lifetime opportunity to be involved in a leadership role in one of the most distinguished freestanding cancer centers in America. City of Hope has enormous financial resources and talent, which gives the institution the ability to advance cancer diagnostics and therapeutics in a way that is almost unprecedented in today’s environment. Remarkably, City of Hope continues to grow, expanding its reach into bio-

medicine, translational research, and genetics. So although it was difficult to leave Lurie after so many incredible years there, the timing was perfect for this particular stage in my career.

Three Main Goals What is your vision for City of Hope? My job is to recruit the most talented scientists and clinicians who will be able to accelerate the institution’s missions in research and therapeutics. I want to help shape the future of City of Hope’s place in advancing cancer prevention, care, and survivorship. Those are the three main goals that I have as I step into a leadership role, which of course will encompass a variety of activities and initiatives. Of those three buckets, prevention is perhaps the most underserved, so that is something that I want to give a lot of attention to. And along with the better outcomes in survival that we’ve seen over the past few decades, learning how to better deal with the very specific needs of survivorship and quality of life after cancer is also an emerging challenge. We collabo-

rate with numerous other institutions through the NCCN and other groups, giving City of Hope even greater reach into the cancer community.

Challenges and Adjustments From your role as a leader in oncology, how do you see cancer care evolving in our rapidly changing health-care system? There will always be challenges in medicine, and clearly a major concern we have as a society is to be able to continue to finance all of the remarkable scientific work that has helped give doctors the tools to ease the burden of disease on humanity. We are certainly facing difficult challenges, but I am confident that we will figure out a way to not only maintain, but to accelerate the pace of medical advances. Speaking specifically about the oncology community, we’ve already seen major adjustments in models of care that have not resulted in a diminishment of quality. In fact, the future is bright; it’s a very exciting time in oncology. n

About City of Hope

ity of Hope was founded in 1913, but its focus on cancer research and care began in the late 1940s. The center has performed 11,000 hematopoietic stem cell transplants as of 2012 with patient outcomes that consistently exceed national averages. City of Hope received its NCI designation as a comprehensive cancer center in 1998. A founding member of the NCCN, the Center currently has more than 200 scientists and physicians dedicated to cancer research and treatment and handling about 147,175 outpatient visits and 3,260 inpatient admissions per year. n

registernow! March 13 – 15, 2014 The Westin Diplomat | Hollywood, FL

FEATURING:

Annual Conference topics include*:

ROUNDTABLE DISCUSSIONS The Child’s Experience When a Parent Has Cancer Thursday, March 13, 2014

• Biomarkes and Targeted Therapies • Bone Health • Breast Cancer • Chronic Lymphocytic Leukemia

Lillie Shockney, RN, BS, MAS (Moderator) The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• Chronic Myelogenous Leukemia • Colorectal Cancer

The Affordable Care Act: Where Are We Now? Friday, March 14, 2014

• Gallbladder Cancer • Melanoma

Clifford Goodman, PhD (Moderator) The Lewin Group

• Multiple Myeloma • Myeloid and Erythropoietic Growth Factors

BREAKOUT SESSIONS • Communicating with Patients about Optimal Post-Treatment Surveillance • Cultural Diversity in Delivering and Receiving Oncology Care • International Adaptation and Use of NCCN Guidelines • Targeted Agents: Management of Dermatologic Toxicities

• Non-Hodgkin’s Lymphomas • Non–Melanoma Skin Cancers • Non-Small Cell Lung Cancer • Prostate Cancer • Survivorship

This program (with the exception of the Roundtable Sessions and Meet the Experts) is approved for AMA PRA Category 1 Credit(s)TM for physicians and is also accredited for nurses, pharmacists, case managers, and tumor registrars.

* Topics subject to change

Attend for an opportunity to

Earn up to 15 CE credits! NCCN.org/AC2014 JNCCN-N-0190-0214

ASCOPost.com | MARCH 1, 2014

PAGE 69

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Nintedanib Combined With Docetaxel Is Effective SecondLine Option for Advanced NSCLC The combination of nintedanib and docetaxel “is an effective second-line option” for patients with advanced non–small cell lung cancer (NSCLC) who have received previous treatment with one line of platinum-based therapy, according to results from the phase III LUME-Lung 1 study published in The Lancet Oncology. The combination improved progressionfree survival for patients with refractory NSCLC irrespective of histology when compared to docetaxel (Taxotere) plus placebo, and “significantly prolonged overall survival of patients with adenocarcinoma, including patients with poor prognosis (ie, those who had progressed within 9 months of start of first-line therapy),” Martin Reck, MD, Lung Clinic Grosshansdorf, Germany, and colleagues reported for the LUME-Lung 1 Study Group.

Study Details Nintedanib (formerly BIBF 1120) is an oral angiokinase inhibitor previously shown to have antitumor activity in patients with solid tumors (including NSCLC), a manageable safety profile, and limited drug-drug interactions. The phase III trial involved patients from 211 centers in 27 countries. The median age was 60 years, and all patients had stage IIIB/IV recurrent NSCLC that had progressed after first-line chemotherapy. Patients were randomly assigned to receive docetaxel with nintedanib (655 patients) or with placebo (659 patients). “Patients were assigned to docetaxel 75 mg/m² by intravenous infusion on day 1 plus nintedanib 200 mg twice daily orally or matching placebo on days 2 to 21, every 3 weeks. Treatment was continued until unacceptable adverse events or disease progression,” the investigators explained. “The study was jointly designed by academic investigators and representatives of the sponsor, Boehringer Ingelheim,” the authors noted. As determined by central independent review, progression-free survival was significantly longer in the docetaxel-plusnintedanib group than in the docetaxelplus-placebo group (median, 3.4 months [95% confidence interval (CI) = 2.9–3.9] vs 2.7 months [2.6–2.8], hazard ratio [HR] = 0.79 [95% CI = 0.68–0.92], P = .0019), the investigators reported. “Similar results were noted both in patients

with adenocarcinoma and patients with squamous-cell carcinoma.” For all patients combined, there was no difference in overall survival between the two treatment groups, but for patients with adenocarcinoma, overall survival was significantly longer in the docetaxel/nintedanib group than in the docetaxel/placebo group (median, 12.6 months [95% CI = 10.6–15.1] vs 10.3 months [95% CI = 8.6–12.2], HR = 0.83 [95% CI = 0.70–0.99], P =.0359).

Poor-Prognosis Patients “The combination of nintedanib and docetaxel seems to be especially beneficial in adenocarcinoma patients with poor prognosis, for whom there is a high unmet need, such as patients with progressive disease in the first-line setting,” or those who have progression within 9 months after the initiation of first-line therapy, the authors commented. Among those patients, overall survival was significantly longer in the docetaxel/nintedanib group than in the docetaxel/placebo group (median, 10.9 months [95% CI = 8.5–12.6] vs 7.9 months [6.7–9.1], HR = 0.75 [95% CI = 0.60–0.92], P = .007. Several adverse events were more common in the docetaxel/nintedanib group than in the docetaxel/placebo group. These include diarrhea, which occurred in 42.3% of the combination group vs 21.8% of the placebo group; nausea, 24.2% vs 18.0%; decreased appetite, 22.2% vs 15.6%; and vomiting, 16.9% vs 9.3%. “Most of these adverse events were manageable with supportive treatment or dose reduction,” the authors wrote. Adverse events leading to death related to disease progression occurred in 72 (11.0%) of 652 patients in the docetaxel plus nintedanib group and in 52 (7.9%) of 655 patients in the docetaxel plus placebo group. Adverse events leading to death possibly unrelated to disease progression were reported in 35 patients (5.4%) in the docetaxel/ nintedanib group and in 25 patients (3.8%) in the docetaxel/placebo group. The authors noted that to the best of their knowledge, none of the antiangiogenic compounds tested in the first- or second-line setting have shown any effect on overall survival in advanced NSCLC. “Up to now, bevacizumab [Avastin] was the only antiangiogenic drug shown to prolong overall survival in advanced NSCLC when combined with chemotherapy (paclitaxel or carboplatin) in the

first-line setting,” they wrote. Reck M, et al: Lancet Oncol 15:143155, 2014.

LYMPHOMA R-GCVP Regimen for Patients With Diffuse Large B-Cell Lymphoma and Cardiac Comorbidity For patients with diffuse large B-cell lymphoma (DLBCL) who are unable to receive anthracycline-containing chemoimmunotherapy because of cardiac comorbidity, a regimen of rituximab (Rituxan), gemcitabine, cyclophosphamide, vincristine, and prednisolone (RGCVP) “is an active, reasonably well-tolerated treatment,” Paul A. Fields, MD, of Guys and St. Thomas and King’s College Hospital, London, and colleagues reported in the Journal of Clinical Oncology. The median age of the 62 patients recruited for the phase II study was 76.5 years and 69.4% had stage III or IV disease. “All patients had advanced disease; 27 (43.5%) had left-ventricular ejection fraction of ≤ 50%, and 35 (56.5%) had borderline ejection fraction of > 50% but ≤ 55% and comorbid cardiac risk factors such as ischemic heart disease, diabetes mellitus, or hypertension,” the investigators stated. All but one patient, who died before starting treatment as a result of lung abscess, received at least one cycle of R-GCVP, administered on day 1 with gemcitabine repeated on day 8 of a 21-day cycle. The median num-

ber of cycles received was six. The overall response rate was 61.3%. Complete response occurred in 18 patients (29.0%), undocumented/unconfirmed in 6 patients (9.7%), partial response in 14 patients (22.6%)]), “exceeding the minimum response rate required to indicate that the treatment was effective,” the researchers declared. Of the 10 patients (16.1%) who did not achieve disease response, 4 had stable disease and 6 had progressive disease. “Two-year progression-free survival for all patients was 49.8% [95% CI = 37.3–62.3], and 2-year overall survival was 55.8% [95% CI = 43.3–68.4],” the investigators reported. Grade ≥ 3 hematologic toxicity occurred among 34 patients. “There were 15 cardiac events, of which seven were grade 1 to 2, five were grade 3 to 4, and three were fatal, reflecting the poor cardiac status of the study population,” the authors noted. Overall, 14 patients died. “Given the group of patients presented in this study were at high risk, as defined by poor ejection fraction or borderline ejection fraction plus presence of multiple cardiac risk factors, the results emphasize that it is still possible to offer such groups of patients treatment with curative intent,” the researchers concluded. They predicted that the issue of treatment-limiting comorbidities “will become more critical in future studies as the number of elderly patients with DLBCL increases” and said that further testing of the R-GCVP regimen is warranted. n Fields PA, et al: J Clin Oncol 32:282287, 2014.

The ASCO Post | MARCH 1, 2014

PAGE 70

Perspective Francis S. Collins, MD, PhD

Impact of Sequestration

continued from page 1

impact that budget stagnation is having on biomedical research and on the careers of young investigators, his optimism for the future, and the outlook for improvements in global health care.

Please talk about the short-term impact sequestration has had on biomedical research. The impact in fiscal year 2013 was extremely damaging. ASCO conducted a survey1—as did others, including the American Society for Biochemistry and Molecular Biology (ASBMB)2—show-

ing that scientists trying to do research found this to be an extremely difficult period. Some had to cut back on projects, some had to let people go, and some found that even though their research was very exciting, it was unfundable. Last year has been the worst year on record, I think, in terms of the ability of scientists to get their work supported

Markers in Cancer

Diagnostic Development Tutorial A WORKSHOP FOR EARLY-CAREER ONCOLOGY PROFESSIONALS

May 5-6, 2014 Bethesda North Marriott Hotel and Conference Center Bethesda, Maryland, USA

Steps in Developing a Biomarker after Discovery

Define

clinically relevant goals

Validate analytical and clinical utility

Assess feasibility

Implement into clinical practice

Discover innovative approaches to biomarker development at each step in the process.

Open to academic and industry applicants. Apply today at markersincancer.org Application deadline: Tuesday, March 11, at 11:59 PM (EDT) New: This activity has been approved for AMA PRA Category 1 Credit ™

through NIH, with the success rate of grant applications plummeting down to about 16%.

Turning a Corner What steps are being taken to adapt to the budget limitations in biomedical research? First, let me say that while I would love to have seen an even better uptick in support in FY2014 compared to FY2013, it is a relief to see that after many years of a downward spiral in real support for NIH, we seem to have finally turned a corner. All those watching this situation should be grateful to House Appropriations Chair Congressman Hal Rogers (R-KY) and Senate Appropriations Chair Senator Barbara Mikulski (D-MD) for working out a genuine appropriations process, as opposed to the gridlock that has led us successively downward in terms of financial support. One hopes that this turning of the corner will portend an upward trajectory going forward in FY2015 and beyond. The latest action only recovered slightly more than half of what NIH had lost in the sequester, so we are still going to have fewer resources in FY2014 than we did in FY2012. That will stress the system in very serious ways as we try to prioritize and support the very best science. Clearly, success rates for grant applicants will get a little better than they were in FY2013 but not dramatically so. We at NIH are doing everything we can with these resource constraints to try to keep this amazing engine of discovery moving forward. We are particularly concerned that early-stage investigators may not be in a situation to get their research programs going. To address this, we will continue the process of having first-time investigators compete against each other in peer review instead of going up against the entire pool of research applicants. This seems like a fairer way to give them a chance to get started. We are also looking at the current organizational structure of our peer-review system to see if there are ways to assess how well it meshes with today’s areas of greatest scientific opportunity, or whether we need to do some rethinking about how peer-review study sections are organized. But that’s a complicated question. In circumstances where we really want to encourage people to be innovative and take risks, we are looking at whether we should consider investing a somewhat larger proportion of our research dollars into programs like the NIH Director’s Pioneer Award Program, which we have now been funding for about 10 years. Those awards allow indi-

ASCOPost.com | MARCH 1, 2014

PAGE 71

Perspective

viduals who have a groundbreaking idea, but haven’t yet developed a whole raft of preliminary data, to come forward and seek support to pursue the idea. Those awards, which are for up to a half-a-million dollars per year for 5 years, have produced pretty impressive results. Perhaps we ought to think about expanding that model beyond a rather small program in the NIH Common Fund, which is coordinated by my office, to some of the other NIH institutes.

Making the Most of Funding Is the NIH experiencing a loss in younger researchers, especially cancer researchers? Yes, and it is true across the board. The way in which the sequester was applied provided no flexibility to move money around within the NIH. We had to apply the same 5% cut to all of the institutes, including the National Cancer Institute. There was no chance to prioritize anything at that point. Cancer research right now is at an incredibly important juncture. It’s exciting to see the revelations coming forward in basic, translational, and clinical cancer research. I would love to see this effort move forward at the pace that it could with better funding, instead of being hobbled by the current resource constraints. We are going to be forced to be very creative in trying to make the most of the dollars that are available because—at least for this year and next year—it’s unlikely that we are going to see significant relief from the stress on the system that has been increasing over the past 10 years.

Greatest Concerns What worries you most about the effect the reduced budget will have on advances in biomedical medicine? I worry most about our most critical resource, which are our people. I worry that the scientists who have great ideas— who are energized and inspired about coming up with answers to how life works and how disease occurs—will increasingly be discouraged and demoralized. I worry that these scientists will become reluctant to take risks in their research because of concerns that their efforts won’t be supported. I worry that these scientists will begin to seriously consider doing something other than research as their primary career choice. The ASBMB report documented that about 18% of the people surveyed were seriously considering going to another country to do their research. And it might be better for them. At the moment, the United States is unique in the way medical research has been suffering cutbacks. The rest of the

world looks at the United States as a role model and is trying to replicate our success, but we seem to have forgotten that success and what it took to achieve it.

Looking Ahead Are you optimistic about the future of biomedical research in the United States? I think that there is room for guarded optimism. After essentially 3 years of complete congressional gridlock in terms of support for scientific research in the United States, we have now seen the first evidence that it is possible for the parties to get together and formulate a plan. It’s not a perfect plan, but it certainly portends some chance of moving forward to do something better. I’m convinced that our case, which is a strong one, will be listened to, and the value of biomedical research, including cancer research, will be seen for what it is: an incredibly important means to learn

world economic downturn. This time, it seemed as if the participants were generally supportive of the idea that an economic corner had been turned. So, we could talk more optimistically about proactive things the world could do to make people, particularly those from countries with limited resources, have a better chance at a full and happy life. There was a lot of conversation about global health advances and what could be done to further accelerate progress. It’s gratifying to see that progress. I think that not everybody is aware of what’s happened over the course of the past decade or more in terms of improvements in longevity around the world. I think also that many people don’t know that a major factor contributing to these improvements is the improved control of communicable diseases, such as HIV/AIDS, malaria, and tuberculosis. Al-

After 3 years of congressional gridlock in terms of support for scientific research, we have seen the first evidence that the parties can get together and formulate a plan. It’s not a perfect plan, but it certainly portends some chance of moving forward to do something better. —Francis S. Collins, MD, PhD

new ways to prevent and treat disease, which will reduce our health-care costs and offers a great way of stimulating the economy. I think that message is increasingly being heard in important places like the U.S. Congress. I am hopeful—although I must admit to being a diehard optimist— that this will result in getting NIH back on a stable funding trajectory in the next couple of years, a trajectory by which researchers will have some sense of what they can count on for support, instead of the crazy roller-coaster budget ride that we’ve been on.

though we still have a long way to go with these diseases, we are making progress. Now, it’s the noncommunicable diseases including cancer that are emerging as the fastest growing causes of mortality and morbidity around the world. So in Davos, there were a lot of conversations about whether we have a plan in place to address these health problems. One suggestion put forward by some of us was to

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

References 1. 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. 2. 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.

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.

Progress in Global Health You attended the World Economic Forum in Davos, Switzerland, where the focus was on global health. What was the consensus on the state of global health? I’ve been going to the World Economic Forum almost every year for the past 18 years. It was interesting this year because the mood was more optimistic than it’s been in the previous 3 or 4 years, since the beginning of the

build upon the health delivery systems that were established to deliver antiretroviral therapy. Perhaps we can turn those systems into more comprehensive healthcare delivery options to provide good preventive care and treatment for diseases like hypertension, diabetes, and cancer. There was also a sense in Davos that we should stop thinking so much about health as a cost. We should think about health as an investment. Even in low-income countries, there is very strong evidence that if you invest in improving the health of the population, the economy will respond positively because you will have more of your citizens who are physically able to work. Furthermore, if you reduce childhood mortality, experience shows that almost inevitably there is a drop in the fertility rate, because couples decide that they don’t need to keep having more children in order for some of them to make it to adulthood. That translates into what’s called the “demographic dividend,” where a higher proportion of a nation’s population is working instead of being dependent (as young children would be). All of those points on health, which I don’t think had been emphasized as much in previous meetings, were front and center at this year’s World Economic Forum. n

Write to The ASCO Post at editor@ASCOPost.com

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

In Ph+ CML

A BCR-ABL assay that reads between the lanes GenoTRACE® reveals what you don’t want to miss Standardized to the International Scale (IS) Ability to truly assess major molecular response (MMR) High sensitivity to 4.5 logs (below baseline) to assess whether undetectable disease has been achieved1 Only routine, highly sensitive molecular monitoring standardized to the International Scale (IS) gives you the confidence to make clinical decisions.2

National Comprehensive Cancer Network® (NCCN®) recommends INTERNATIONAL SCALE RQ-PCR with 4.5-log sensitivity every 3 months1

Ph+ CML, Philadelphia chromosome–positive chronic myeloid leukemia; RQ-PCR, real-time quantitative polymerase chain reaction. References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia Version 4.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed July 19, 2013. To view the most recent and complete version of the guidelines, 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. 2. Jabbour EJ, Quintás-Cardama A. Molecular monitoring 101: helping your patients with chronic myeloid leukemia to understand the meaning of molecular response. Leuk Lymphoma. 2012;53(8):1452-1460.

LOOK DEEPER at www.GenoTRACE.com A N OVA R T I S C O M PA N Y

7/13

GNP-1070093