TAP Vol 6 Issue 2 by Harborside Press LLC

Triple-Negative Breast Cancer

5, 6

| CAR T Cells in ALL

15, 19

| ‘Chemobrain’

| Rare Cancers

VOLUME 5, ISSUE 2

FEBRUARY 10, 2015

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

Gastrointestinal Cancers Symposium

Observation Appropriate for Some Patients With Rectal Cancer Following Neoadjuvant Therapy By Caroline Helwick

Cancer Genetics: Looking Back, Looking Ahead A Conversation With Mary-Claire King, PhD

ome patients with rectal cancer who achieve a complete response to neoadjuvant chemoradiation therapy can be monitored for tumor recurrence and may never need surgery, according to a retrospective review from patients at Memorial Sloan Kettering Cancer Center, New York, presented at the 2015 Gastrointestinal Cancers Symposium.1 At a press briefing, senior author Philip Paty, MD, a surgical oncologist at Memorial Sloan Kettering, said the results should “encourage more doctors to consider a ‘watch and wait’ approach in select patients with clinical complete response as an alternative to immediate rectal surgery.” Avoidance of surgery would allow patients to preserve rectal function. “Most patients who qualify for this approach are very interested in it,” he said. Total mesorectal excision can lead to sexual dysfunction, urinary problems, and issues with the ileostomy or diverting colostomy, the authors noted.

Philip Paty, MD

J. Joshua Smith, MD, PhD

J. Joshua Smith, MD, PhD, Chief Fellow in the Department of Surgery at Memorial, who presented the results at the meeting, pointed out that prior studies have shown that 12% to 38% of patients will obtain a pathologic complete response to neoadjuvant chemotherapy, and 5-year disease-free survival for these patients exceeds 90%. 2,3 “Since we know that clinical complete response is

—Peter Paul Yu, MD, FACP, FASCO

continued on page 90

Issues in Oncology

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

MORE IN THIS ISSUE

The report was published in the Journal of Clinical Oncology1 and on CancerProgress.Net (see pages 42-43 for more on ASCO’s Advance of the Year). This year’s report also features “A Decade in Review,” and “The 10-Year Horizon”, which previews trends likely to shape the next decade of cancer care, and highlights progress in rare cancers. In addition, the report includes information on advances in combination, targeted, and immunotherapy treatment, patient care, and tumor biology.

We cannot underestimate the importance of federal investment for answering critical cancer care questions.

You have a long history of advocating for disenfranchised groups, such as the farm workers in

continued on page 3

By Jo Cavallo SCO recently released its report, Clinical Cancer Advances 2015: An Annual Report on Progress Against Cancer, and for the first time announced its cancer Advance of the Year: gains made in the treatment of chronic lymphocytic leukemia (CLL). The report credited improvements in CLL care with four newly approved therapies: two immunotherapy drugs for previously untreated CLL and two molecularly targeted drugs for treatment-resistant or relapsed CLL.

Empowering Women

Dr. King is American Cancer Society Professor in the Department of Medicine (Medical Genetics) and the Department of Genome Sciences, at the University of Washington School of Public Health, Seattle.

ASCO Releases Annual Report on Progress Against Cancer

t the 2014 San Antonio Breast Cancer Symposium, The ASCO Post sat down with geneticist Mary-Claire King, PhD, for some personal musings about her career and how she might guide young researchers who want to follow in her footsteps. Dr. King is known for a variety of accomplishments in genetics, including identification of the “breast cancer gene” BRCA1 (see page 10).

The 10-Year Horizon The Clinical Cancer Advances report previews the following trends that will likely shape the next decade of cancer care: the eradication of cancer

Oncology Meetings Coverage Gastrointestinal Cancers Symposium �� 1, 3–4 San Antonio Breast Cancer Symposium �� 5, 6, 10–13, 48–54 American Society of Hematology �� 14–19, 55–56 American College of Surgeons �� 21 Derek Raghavan, MD, PhD, FASCO, on Bladder Cancer ��27 Direct From ASCO �� 41–44 Thomas A. Gallo, MS, on Value in Cancer Care ��58 Serena Wong, MD, on ‘Chemobrain’ ��82 Brian P. Rubin, MD, PhD, on a Rare Cancer ��87

continued on page 8

Send your comments to editor@ASCOPost.com

A Harborside Press® Publication

The ASCO Post | FEBRUARY 10, 2015

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Jame Abraham, MD Cleveland Clinic

Louis B. Harrison, MD Moffitt Cancer Center

Manmeet Ahluwalia, MD, FACP Cleveland Clinic

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Joseph S. Bailes, MD Texas Oncology

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

Laurence H. Baker, DO University of Michigan Health System

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

Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center

Hagop M. Kantarjian, MD MD Anderson Cancer Center

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

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

Douglas W. Blayney, MD Stanford University Medical Center

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

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

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

Jamie Von Roenn, MD American Society of Clinical Oncology

Stanley H. Winokur, MD Singer Island, Florida

Sarah McGullam, Web Editor Sarah@harborsidepress.com

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

Michael Buckley, Art Director Michael@harborsidepress.com

International Editors

Terri Caivano, Layout Artist Terri@harborsidepress.com

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

Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com

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

Elizabeth Janetschek, Editorial Assistant Elizabeth@harborsidepress.com

Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

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

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Jay S. Cooper, MD Maimonides Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

John Cox, DO Texas Oncology

James L. Mulshine, MD Rush University Medical Center

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

E. David Crawford, MD University of Colorado

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

George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January 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 ©2015 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-

Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

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: $300;

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

Lynn D. Wilson, MD Yale University School of Medicine

Robert W. Carlson, MD National Comprehensive Cancer Network

Steven T. Rosen, MD City of Hope National Medical Center

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Randi Londer Gould and Susan Reckling, Senior Editors Randi@harborsidepress.com Susan@harborsidepress.com

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

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

Jacek Jassem, MD Medical University of Gdansk, Poland

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan John F. Smyth, MD University of Edinburgh Edinburgh, Scotland Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Canada: $436; Individual International: $575; Institutional Domestic: $370; Canada: $507; Institutional International: $645. Single Copy Domestic: $57; Canada: $65; International: $72. Contact subscriptions@harborsidepress.com.

Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Jeannine Coronna, Vice President, Director of Operations Jeannine@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, Margot Fromer, Alice Goodman, Caroline Helwick, Susan London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

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

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 | FEBRUARY 10, 2015

PAGE 3

Gastrointestinal Cancers Symposium Observation in Rectal Cancer continued from page 1

Oncologically Safe, With Rectal Preservation

associated with a pathologic complete response, the question is, in patients who obtain a pathologic complete response, is surgical resection always necessary?” commented Dr. Smith. The investigators compared outcomes

After a median follow-up of 3.5 years, 74% of the 73 patients who were observed achieved a durable and sustained clinical complete response, and no surgical intervention was required. For the 19 patients (26%) who had local regrowth

We set the bar very high and found that nonoperative management appears to compare favorably. —Philip Paty, MD

among 145 patients with stage I to III rectal cancer, 73 of whom achieved a clinical complete response (no detectable tumor by clinical exam, endoscopy, or imaging) after neoadjuvant chemoradiation therapy and were treated nonoperatively. This cohort was compared with 72 patients treated conventionally who achieved a pathologic complete response and underwent total mesorectal excision. The neoadjuvant treatment given to the nonoperative patients was not standardized in this retrospective series. All patients received pelvic radiation (45–55 Gy) plus a fluoropyrimidine. Since 2011, most received induction FOLFOX (fluorouracil [5-FU]/leucovorin/oxaliplatin) as initial treatment, then chemoradation, then assessment for surgery. If clinical complete response was obtained, patients were offered the nonoperative, watch-and-wait approach. Patients were monitored frequently, especially during the first year, when they underwent clinical and endoscopic exams every 3 months and imaging every 6 months. Examinations became less frequent over time, but patients were still closely followed for the first 5 years.

of tumor, salvage surgery was undertaken, and all were successful. One patient had tumor recurrence after resection of local tumor regrowth, yielding a local control rate of 98%, Dr. Smith reported. In addition, 77% of patients were able to complete treatment with rectal preservation, and this conservative ap-

a pathologic complete response, which was not significantly different. At the press briefing, Dr. Paty commented that by comparing patients with a clinical complete response with those with a pathologic complete response, “We set the bar very high and found that nonoperative management appears to compare favorably.” He acknowledged that “practicing ‘watch and wait’ can be difficult for surgeons,” but this approach is being increasingly accepted. “Centers are adopting it, and many leaders in clinical trials of rectal cancer recognize that this option is not only reasonable, but perhaps it is necessary to inform patients that it is an option,” Dr. Paty said. Dr. Smith stressed the importance of a careful discussion between the patient and the surgeon and obtaining consent with both parties acknowledging the risks, possible benefits, and al-

Organ Preservation in Responders With Rectal Cancer ■■ A retrospective review of patients at Memorial Sloan Kettering Cancer Center showed that patients with stage I to III rectal cancer who achieved a clinical complete response to neoadjuvant therapy can often forego resection. ■■ Cohorts with clinical complete responses and those with pathologic complete responses who underwent surgery had similar disease-free survival and overall survival. ■■ Of the nonoperatively managed patients, 77% had rectal preservation. ■■ The local recurrence rate was 26%; all but one patient was successfully salvaged.

proach did not compromise outcomes, Dr. Smith emphasized. The disease-specific and overall survival rates were similar between the two groups. The rate of distant tumor recurrence was 13% with nonoperative management and 7% with surgery following

ternatives compared with uniform offering of total mesorectal excision. “Patients need to know this is nonstandard management, off protocol; that there is a 25% risk of local tumor regrowth; that nonoperative management requires frequent endoscopic

and radiographic surveillance; that there’s a risk for salvage abdominal perineal resection or extended resection; and that there’s a potential risk of compromising cure,” he said. Most local regrowth occurs within 12 to 13 months and can be salvaged successfully, he indicated. “However, prospective trials are needed to confirm these findings, and they are in progress,” he said. A phase II multicenter randomized trial studying the use of neoadjuvant treatment in locally advanced rectal cancer patients and the use of nonoperative management in those with clinical complete response is ongoing at Memorial Sloan Kettering led by the Colorectal Service, which includes Julio GarciaAguilar, MD, Philip Paty, MD, Karyn A. Goodman, MD, Mark Gollub, MD, and Leonard Saltz, MD (ClinicalTrials.gov identifier NCT02008656). n

Disclosure: Drs. Paty and Smith reported no potential conflicts of interest.

References 1. Smith JJ, Chow OS, Eaton A, et al: Organ preservation in patients with rectal cancer with clinical complete response after neoadjuvant therapy. 2015 Gastrointestinal Cancers Symposium. Abstract 509. Presented January 17, 2015. 2. Garcia-Aguilar J, Shi Q, Thomas CR Jr, et al: A phase II trial of neoadjuvant chemoradiation and local excision for T2N0 rectal cancer: Preliminary results of the ACOSOG Z6041 trial. Ann Surg Oncol 19:384-391, 2012. 3. Maas M, Nelemans PJ, Valentini V, et al: Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: A pooled analysis of individual patient data. Lancet Oncol 211:835-844, 2010.

EXPERT POINT OF VIEW

eorge J. Chang, MD, Chief of Colon and Rectal Surgery and Director of Clinical Operations, Minimally Invasive and New Technologies in Oncologic Surgery Program at The University of Texas MD Anderson Cancer Center, Houston, shared his insights on the study by Dr. Smith and colleagues with The ASCO Post. “Currently, 15% to 20% of patients with rectal cancer who are treated with chemoradiation therapy will be observed to have complete pathologic response with no evidence of residual tumor. Thus, it is an often unsettling discussion that surgeons and patients must have—of the good news of a

pathologic complete response and the reality that an abdominal perineal resection with a permanent colostomy was needed,” he said.

“We know that among patients undergoing radical surgery, those achieving pathologic complete response have an excellent prognosis. Thus, the

For now, radical surgery should remain the standard treatment. But rigorous protocol-based treatment should be pursued to help us consider options that reduce the impact of our treatments, such as organ preservation with ‘watch and wait.’ —George J. Chang, MD

bar we must achieve is very high not to compromise a patient’s outcomes when considering a nonoperative strategy,” Dr. Chang noted. “I think the group at Memorial Sloan Kettering Cancer Center has the right approach, in that all patients were treated on a prospective trial, that [Memorial] is an expert center in the multidisciplinary treatment of rectal cancer, that there was input from all disciplines, that the patients were closely monitored, and that clinicians had the necessary expertise to perform salvage surgery when the tumors grew,” he said. continued on page 4

The ASCO Post | FEBRUARY 10, 2015

PAGE 4

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Modified Nab-Paclitaxel/Gemcitabine in Pancreatic Cancer: Efficacious, Less Toxic, Less Costly By Caroline Helwick

less intensive regimen of nab-paclitaxel (Abraxane) plus gemcitabine appears to be as efficacious as the standard regimen in first-line treatment for metastatic pancreatic cancer, but less toxic and far less expensive, according to a study that earned a Merit Award at the 2015 Gastrointestinal Cancers Symposium in San Francisco.1 The modified regimen, adopted by oncologists at The Ohio State University, Columbus, combines gemcitabine at 1,000 mg/m2 and nabpaclitaxel at 125 mg/m2 every 2 weeks. “Chemotherapy is administered on days 1 and 15 of a 28-day cycle, eliminating day 8 dosing. Granted, this is a retrospective study and the numbers are small, but overall the modified regimen looks equivalent to outcomes from the MPACT trial, and the toxicity looks significantly better,” said Kavya Krishna, MBBS, a third-year oncology fellow at the University.

MPACT Trial The phase III MPACT trial established the benefit of the gemcitabine/nab-paclitaxel regimen after showing a modest improvement in overall survival, vs gemcitabine alone, as first-line treatment.2 The standard regimen gives gemcitabine at 1,000 mg/m2 and nab-paclitaxel at 125 mg/m2, both administered on days 1, 8, and 15 of a 28-day cycle. In MPACT, only 71% of the nab-paclitaxel doses and 63% of the gemcitabine doses remained at full dose due to protocol-driven reductions secondary to toxicities. One-quarter of patients required growth factors, and 17% had grade 3 or higher neuropathy. “Based on our interpretation of the data and on data suggesting that biweekly administration of gemcitabine-

George J. Chang, MD continued from page 3

Dr. Chang noted that the disease persistence rate in the Memorial study was 26% vs a local recurrence risk approaching 0% after radical surgery.1

Not So Fast With ‘Watch and Wait’ “I disagree with Dr. Paty’s comment that we should encourage more doctors to consider ‘watch and wait,’” he said. “We have to acknowledge that these

based chemotherapy combinations preserves efficacy, with improved toxicity profile, we adopted a modified regimen,” she said.

Retrospective Analysis Dr. Krishna presented a retrospective analysis of a prospectively established database of patients who received the modified regimen first-line between April 1, 2013, and August 31, 2014. Sixty-three patients were evaluable for toxicity, and 47 were evaluable for response. Patients on the modified regimen had a median progression-free survival of 4.8 months (95% confidence interval [CI] = 2.6–7.4) and median overall survival of 11.1 months (95% CI = 5.3–not

Cost Savings The Ohio State University investigators teamed up with Daniel A. Goldstein, MD, of Emory University School of Medicine, Atlanta, to determine the cost savings, which they figured at $3,000 per patient per month, compared to standard gemcitabine/nab-paclitaxel. When taking into account other costs such as growth factor utilization, the savings amounts to $5,500 per month. “Growth factor support is also a major driver of costs at $3,369 per dose,” noted Dr. Goldstein, “but there is no clear guidance as to who should receive it. The precise reporting of growth factor usage is variable between trials.” In a comparison of several regimens for metastatic pancreatic cancer, Dr. Gold-

Nab-Paclitaxel/Gemcitabine in Pancreatic Cancer ■■ A modified regimen of nab-paclitaxel plus gemcitabine, delivered every 2 weeks, resulted in median overall survival of 11.1 months (compared with 8.5 months for standard dosing in the MPACT trial). ■■ The regimen produced less peripheral neuropathy (2% grade 3/4). ■■ The regimen could save $5,500 per month over the standard regimen.

reached). In MPACT, the median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group, and median overall survival was 8.5 months and 6.7 months, respectively. With the modified regimen, 27% of patients experienced neurotoxicity of any grade, with the rate of grade 3 or 4 toxicity less than 2%. The rate of grade 3 or 4 neutropenia was 10%, and growth factor support was required in only 8% of the patients, compared with 26% from the MPACT trial.

stein reported at the meeting that the standard gemcitabine/nab-paclitaxel regimen was the most expensive regimen.3 “Our objective was to analyze the costs of first-line regimens to further aid in decision-making and develop a platform upon which to assess value,” said Dr. Goldstein. “We calculated the monthly cost for multiple standard regimens: gemcitabine, FOLFIRINOX [leucovorin, fluorouracil, irinotecan, oxaliplatin], and gemcitabine/ nab-paclitaxel. We also calculated the cost for two novel regimens that have demonstrated good efficacy—modified-schedule

patients were monitored very closely on a protocol, and currently that is the only way this approach should be undertaken, unless there is some other contraindication to surgery.” Dr. Chang said he would not encourage nonoperative management outside of a protocol in which patients are carefully selected, closely monitored, and have given true informed consent. “As rectal cancer management becomes increasingly complex, it

is becoming clear,” he said, “that some patients do not routinely need chemoradiation therapy. Perhaps, similarly, routine surgery will not be necessary for select patients,” he said. “For now, however, radical surgery should remain the standard treatment,”2 according to Dr. Chang. “But rigorous protocol-based treatment should be pursued to help us consider options that reduce the impact of our treatments, such as organ preservation with ‘watch and wait,’” he concluded. n

gemcitabine/nab-paclitaxel and carboplatin/paclitaxel—in pancreatic cancer.” With these chemotherapy regimens, median overall survival ranged from 6 to 11 months. FOLFIRINOX and modified gemcitabine/nab-paclitaxel had the highest median overall survival at 11.1 months, while gemcitabine alone had the lowest at 6.7 months. The monthly cost of the regimens (combining drug costs, administration costs, and costs for grade 3/4 adverse events) and their associated median overall survival were as follows: gemcitabine/nab-paclitaxel, $12,221 (8.5 months, phase III data); FOLFIRINOX, $7,234 (11.1 months, phase III data); modified gemcitabine/nab-paclitaxel, $6,716 (11.1 months, retrospective study); carboplatin/paclitaxel, $2,154 (8.9 months, phase III data); singleagent gemcitabine, $1,363 (6.7 months, several phase III trials). “Health-care systems have finite resources, so there is increasing emphasis on metrics to define value in health care,” Dr. Goldstein commented. “These data provide useful financial information to incorporate into the decision-making process for both clinicians and policymakers.” n

Disclosure: Drs. Krishna and Goldstein reported no potential conflicts of interest. For full disclosures of all study authors, view the abstracts at meetinglibrary.asco.org.

References 1. Krishna K, et al: 2015 Gastrointestinal Cancers Symposium. Abstract 366. Presented January 16, 2015. 2. Von Hoff DD, et al: N Engl J Med 369:1691-1703, 2013. 3. Goldstein D, et al: 2015 Gastrointestinal Cancers Symposium. Abstract 368. Presented January 16, 2015.

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

References 1. Park IJ, You YN, Agarwal A, et al: Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 30:1770-1776, 2012. 2. Chang GJ: ‘Watch-and-wait’ for rectal cancer: What’s the way forward? Oncology (Williston Park) 28:617-618, 2014.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 5

San Antonio Breast Cancer Symposium Breast Cancer

Enzalutamide Shows Encouraging Activity in Triple-Negative Breast Cancer By Caroline Helwick

he androgen receptor inhibitor enzalutamide (Xtandi) showed encouraging activity as a single agent in advanced triple-negative breast cancer patients expressing the androgen receptor, according to an international study presented at the 2014 San Antonio Breast Cancer Symposium.1

more potent agent” than bicalutamide— having eight times higher affinity for the receptor. Bicalutamide is approved in prostate cancer and has shown some activity in breast cancer as well.2 “We have now asked whether enzalutamide is active in breast cancer, and in the era of precision medicine, this study

We have now asked whether enzalutamide is active in breast cancer, and in the era of precision medicine, this study really resonates. —Clifford A. Hudis, MD, FACP

Enzalutamide directly binds to the androgen receptor and is a potent inhibitor of signaling. It is approved in metastatic castration-resistant prostate cancer. Clifford A. Hudis, MD, FACP, of Memorial Sloan Kettering Cancer Center, New York, one of the study’s investigators, commented on the findings from this study and the drug’s potential in this subset of patients. “We have been pursuing the role of androgen receptor inhibitors for years, after discovering that a small percentage of [patients with triple-negative disease], who historically have not been responsive to hormone therapy, express the androgen receptor,” he said. Enzalutamide is “a more modern,

really resonates,” Dr. Hudis said. “While this is a small subset—20% to 40% of the triple-negative subtype, which is a modest percentage of all breast cancers—we saw that enzalutamide as a single agent can be given to these patients, whose standard treatment is chemotherapy, and yield meaningful palliation and even RECIST responses, with modest and limited toxicities.”

Two-Stage Study Design The study screened 404 patients with advanced triple-negative breast cancer and enrolled 118 shown to express the androgen receptor (androgen receptor–positive > 0% staining; androgen receptor– negative = 0% staining). Patients were

EXPERT POINT OF VIEW

he poster presented by Traina et al attracted great interest at the 2014 San Antonio Breast Cancer Symposium. One viewer who was impressed was Ramesh Narayanan, PhD, of the University of Tennessee Health Science Center in Memphis. He noted that the clinical benefit rate of 24% at 24 weeks in the intent-to-treat population is not substantially better than the 19% rate seen with bicalutamide in a phase II study; however, patients receiving bicaluRamesh Narayanan, PhD tamide were required to have at least 10% of cells stain positive, compared to > 0% staining in this study, to qualify for treatment. In other words, there were “androgen receptor–low” patients who still responded. “I am encouraged to see the androgen receptor evolving as a new therapeutic target in triple-negative and estrogen receptor–positive breast cancer,” Dr. Narayanan said, noting that these agents will probably be associated with less bone loss, muscle complaints, and other side effects than traditional hormonal therapies. “These results are quite good, and enzalutamide is definitely a better drug than bicalutamide,” he commented. n Disclosure: Dr. Narayanan reported no potential conflicts of interest.

Enzalutamide in Triple-Negative Breast Cancer ■■ Enzalutamide binds more potently to androgen receptor than bicalutamide. ■■ In patients with any degree of staining for the androgen receptor and assessable for response, the clinical benefit rate at 16 weeks was 42%. ■■ In patients with a genomic profile deemed relevant to androgen signaling, the clinical benefit rate was 60%.

treated with single-agent enzalutamide at 160 mg daily until disease progression. The primary endpoint was clinical benefit rate at 16 weeks in evaluable patients—ie, those with androgen receptor staining in ≥ 10% of tumor and at least one postbaseline tumor assessment.

Tiffany A. Traina, MD

Stage 1 of the study included 42 patients; the study required that at least 3 of 26 evaluable patients obtain clinical benefit, (ie, complete response, partial response, or stable disease) in order to be expanded to stage 2. In stage 2 (n = 76), at least 9 of 62 evaluable patients must meet the endpoint, for the null hypothesis to be rejected. In the current analysis of the stage 1 patients, single-agent enzalutamide demonstrated strong antitumor activity, with a clinical benefit rate at 16 weeks of 42% in 26 evaluable patients (24% in the intentto-treat population). Of these, 82% also maintained clinical benefit at 24 weeks. In addition, “the first objective responses from anti–androgen receptor therapy were observed with enzalutamide,” reported Tiffany A. Traina, MD, of Memorial Sloan Kettering Cancer Center, who was the study’s first author. Two patients in stage 1 had a complete or partial response. In stage 2, one additional patient to date has achieved a complete response, and three have achieved a partial response. Pointing to CT scan images on the poster from a patient treated at Memorial Sloan Kettering, Dr. Traina said, “She had a clear, confirmed response after visceral metastases and multiple sites of disease. It was a real-deal response, and she is still on therapy.”

Novel Diagnostic Assay “It may be possible to identify patients who benefit from enzalutamide,” Dr. Traina indicated. A novel genomicbased biomarker was tested [not further described], and investigators concluded “it may be superior to immunohistochemistry.” In diagnostic-positive patients, median progression-free survival was 2.5 times greater than for diagnostic-negative patients (20 vs 8 weeks) and the clinical benefit rate at 24 weeks in diagnostic-positive patients (42%–60%) parallels that of hormonal agents in hormone receptor–positive disease, the investigators reported. Approximately 50% of the intentto-treat population was diagnosticpositive by this methodology. Work is ongoing to confirm these findings in the stage 2 population. Dr. Traina added that for the population with a positive diagnostic profile and treated in the first or second line, the clinical benefit rate at 24 weeks was 60%. “This is phenomenal for a hormonal agent in triple-negative breast cancer,” she indicated. Enzalutamide was well tolerated. Toxicities were primarily mild-to-moderate fatigue and gastrointestinal symptoms, and appeared similar to other hormonal therapies for breast cancer. Seven percent of patients discontinued treatment due to an adverse event. This is the largest prospective clinical study conducted in patients with androgen receptor–positive triple-negative breast cancer. Mature data from all 118 patients are expected in 2015. n

Disclosure: Dr. Traina reported that she is a consultant for Genentech, Eisai, Halozyme, Celgene, and Prostrakan and has received research support from Medivation, AstraZeneca, Eisai, Janssen, Genentech, and Novartis. Dr. Hudis reported no potential conflicts of interest.

References 1. Traina TA, et al: San Antonio Breast Cancer Symposium. Abstract P5-19-09. Presented December 12, 2014. 2. Gucalp A, et al: Clin Cancer Res 19:5505-5512, 2012.

The ASCO Post | FEBRUARY 10, 2015

PAGE 6

San Antonio Breast Cancer Symposium Breast Cancer

E1199 Update: It’s Weekly Paclitaxel for Triple-Negative Breast Cancer By Caroline Helwick

n update of clinical trial E1199 showed that weekly paclitaxel and every-3-week docetaxel were both more effective than every-3-week paclitaxel in preventing deaths and tumor recurrences, according to Joseph Sparano, MD, Professor of Medicine and Women’s Health at the Albert Einstein College of Medicine, New York, who presented a 10-year update of E1199 at the 2014 San Antonio Breast Cancer Symposium.1

Triple-Negative, Hormone Receptor–Positive Disease For the 1,025 patients with triplenegative disease, however, the most effective taxane regimen was weekly paclitaxel. With this regimen, 10-year disease-free survival improved to 69%, from 59% with every-3-week paclitaxel, 57% with weekly docetaxel, and 62% with every-3-week docetaxel (P = .032). The overall survival improved to

In the entire population, adjuvant weekly paclitaxel and every-3-week docetaxel were associated with significantly improved disease-free survival and marginally improved overall survival compared with every3-week paclitaxel. —Joseph Sparano, MD

E1199 compared the efficacy of the two taxanes, in two different schedules, in the adjuvant treatment of 4,950 women with axillary node-positive or high-risk node-negative tumors. Patients were randomized to receive 4 cycles of doxorubicin and cyclophosphamide (AC) every 3 weeks, followed by either paclitaxel or docetaxel, either weekly or every 3 weeks. The weekly doses were 80 mg/m2 of paclitaxel and 35 mg/m2 of docetaxel, whereas the every-3-week doses were 175 mg/m2 and 100 mg/m2, respectively. The current analysis was performed after 12.1 years of follow-up; the prior analysis was at 5.3 years.2

Every-3-Week Paclitaxel Not as Effective “In the entire population, adjuvant weekly paclitaxel and every-3-week docetaxel were associated with significantly improved disease-free survival and marginally improved overall survival compared with every-3-week paclitaxel, when given sequentially after adjuvant AC,” Dr. Sparano reported. There was no difference between the combined paclitaxel arms and the combined docetaxel arms in terms of diseasefree or overall survival. There was also no difference in the combined weekly vs combined every-3-week arms.

75% from 66%, 69%, and 69%, respectively (P = .094), Dr. Sparano reported. For hormone receptor–positive, HER2-negative/unknown disease, there was a trend toward improved outcomes for the experimental taxane arms seen at 5 years and consistently observed at 10 years. “But attention to extended adjuvant endocrine therapy may be more relevant in this population, who have a risk for late relapse,” he suggested. Strong associations with inferior outcomes were observed for patients who were obese or black (independent of obesity), confirming previous reports. Nonobese black patients had more than a doubling in the risk for disease progression and death.

Room for Improvement Although AC followed by weekly paclitaxel appears to be the choice for triple-negative patients, Dr. Sparano suggested, “There is still room for improvement.” The NRG-BR003 trial may help to determine the optimal regimen for this subset of patients. It will randomize node-positive or highrisk node-negative triple-negative patients to receive 4 cycles of AC, followed by paclitaxel weekly for 12 cycles, with or without carboplatin AUC 5 every 3 weeks for 4 cycles, be-

E1199 Update on Adjuvant Taxane Treatment ■■ The 10-year follow-up of E1199, which evaluated taxane schedules after adjuvant AC, concluded that weekly paclitaxel and every-3-week docetaxel yielded similar disease-free and overall survival and were better than every3-week paclitaxel. ■■ In triple-negative patients, however, weekly paclitaxel significantly improved disease-free and overall survival over all other regimens. ■■ For hormone receptor–positive disease, outcomes were poorest for obese patients and black patients, independent of obesity status.

ginning with weekly paclitaxel. For hormone receptor–positive patients, late relapse remains “a vexing problem,” he added, and for these patients, the results of TAILORx and E5103, with analyses of biospecimens, are awaited. n

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

References 1. Sparano JA, Zhao F, Martino S, et

al: Ten year update of E1199: Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk nodenegative breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract S303. Presented December 11, 2014. 2. Sparano JA, Wang M, Martino S, et al: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663-1671, 2008.

EXPERT POINT OF VIEW

nn H. Partridge, MD, MPH, Associate Professor of Medicine at Harvard Medical School, commented on this study to The ASCO Post: With taxanes after doxorubicin/cyclophosphamide (AC), it’s “dealer’s choice.” However, she noted that most oncologists do not give every-3-week paclitaxel now. “Many have shifted to every-2-week AC followed by paclitaxel (ie, the dose-dense schedule) given the benefits of dose density, particularly in patients with hormone receptor–negative disease, unless they are giving it with trastuzumab [Herceptin], in which many give it weekly the way it was done in the large adjuvant trials.” With weekly dosing, one can forego routine growth factors, she pointed out but acknowledged that growth factors are often dropped after the first

Many have shifted to every-2week AC followed by paclitaxel. But we still don’t know if giving paclitaxel every 2 weeks is better than weekly administration. —Ann H. Partridge, MD, MPH

cycle of treatment. “I personally think that docetaxel given every 3 weeks is a much bigger hit in terms of side effects,” she added. She said although E1199 and its ilk may feel like “Coke vs Pepsi” chemotherapy comparisons, they remain necessary and important. “We are always learning how to get at the cell cycle better,” she said. n Disclosure: Dr. Partridge reported no potential conflicts of interest.

LOOK TO ZELBORAF EXPERIENCE The first treatment approved for BRAF V600E(+) unresectable or metastatic melanoma More than 7000 patients with metastatic melanoma treated since 20111*

*Estimated number of metastatic melanoma patients treated with ZELBORAF from August 2011 to July 2014.

Learn more at Zelboraf.com/EXPERIENCE 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 The following can occur in patients treated with ZELBORAF: New primary malignancies including cutaneous squamous cell carcinoma, non-cutaneous squamous cell carcinoma, new primary melanoma, and other malignancies Tumor promotion in BRAF wild-type melanomas Serious hypersensitivity reactions including anaphylaxis Severe dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis QT prolongation

Hepatotoxicity including liver injury leading to functional hepatic impairment (including coagulopathy or other organ dysfunction); increases in transaminases and bilirubin when concurrently administered with ipilimumab Photosensitivity Ophthalmologic reactions ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. 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. Reference: 1. Data on file, Genentech, Inc.

The ASCO Post | FEBRUARY 10, 2015

PAGE 8

Issues in Oncology ASCO Releases Report continued from page 1

Importance of Federal Funding

stem cells, faster, less expensive, and more sophisticated genomics technology, liquid biopsies, nanomedicine, and the untapped possibilities of health information technology, such as the CancerLinQ initiative, in cancer care.

The Clinical Cancer Advances report also recognizes the unique and vital role of federally funded research in advancing progress against cancer. “This has truly been a banner year Safety:7" for CLL and for clinical cancer research as a whole,” said ASCO President The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2. Table 1 Adverse Reactions Reported in ≥ 10% of Patients Treated with ZELBORAF* Trial 1: Treatment Naïve Patients

ADRs

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

ZELBORAF n= 336 Grade All Grades 3a (%) (%)

Trial 2: Patients with Failure of at Least One Prior Systemic Therapy Dacarbazine ZELBORAF n= 287 n= 132 Grade Grade All All Grades 3a Grades 3 (%) (%) (%) (%)

37 33 45 23 24 9 8 19 5 14

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

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

0 0 0 0 0 0 0 0 0 0

52 49 36 30 28 21 17 16 13 8

7 3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

*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, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0 * For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELBORAF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation [see Warnings and Precautions (5.1)].

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and Precautions (5.3)]. Blood and lymphatic systems disorder: Neutropenia 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment. 8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Health care providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with ZELBORAF is indicated [see Dosage and Administration (2.1)]. • ZELBORAF increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin [see Warnings and Precautions (5.1)]. • Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Advise patients to stop taking ZELBORAF and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and Precautions (5.3)]. • Severe dermatologic reactions can occur in patients receiving ZELBORAF. Advise patients to stop taking ZELBORAF and to contact their health care provider for severe dermatologic reactions [see Warnings and Precautions (5.4)]. • ZELBORAF can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during ZELBORAF treatment [see Warnings and Precautions (5.5)]. • Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF. Advise patients of the importance of laboratory monitoring of their liver during ZELBORAF treatment and to contact their health care provider for relevant symptoms [see Warnings and Precautions (5.6)]. • ZELBORAF can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn [see Warnings and Precautions (5.7)]. • Ophthalmologic reactions can occur in patients treated with ZELBORAF. Advise patients to contact their health care provider immediately for ophthalmologic symptoms [see Warnings and Precautions (5.8)]. • ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. Advise patients to contact their health care provider immediately if they become pregnant [see Warnings and Precautions (5.9) and Use in Special Populations (8.1)].

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

tance of federal investment for answering critical cancer care questions, particularly in rare, understudied cancers.” “The U.S. federal cancer research enterprise faces critical funding challenges that threaten the pace of research progress,” added Richard L. Schilsky, MD, FACP, FASCO, A SCO’s Chief Medical Officer. “Now is the time to increase our nation’s investment in cancer research to ensure that we can build on these advances well into the future.”

Richard L. Schilsky, MD, FACP, FASCO

Progress in Rare Cancers The report details information on the first viable alternative to surgery for pigmented villonodular synovitis, a rare joint disease that affects about 600, mostly young, Americans each year. According to the report, early results from two small studies of oral therapies targeting a protein known as CSF-R1—PLX3397 and RG7155— are showing promise in tumor shrinkage. If confirmed in larger studies, these therapies may offer patients relief from the debilitating adverse

Safety:10"

ZELBORAF ® (vemurafenib) tablet for oral use Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1)]. 5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)]. 5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of ZELBORAF for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias). 5.6 Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive ZELBORAF 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Table 1 presents adverse reactions reported in at least 10% of patients treated with ZELBORAF. The most common adverse reactions of any grade (≥ 30% in either study) in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.

Peter Paul Yu, MD, FACP, FASCO, in a statement. “Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients. It is also remarkable that almost one-third of the year’s top studies were made possible by federal research dollars. We cannot underestimate the impor-

ASCO Releases Cancer Progress Report ■■ Two newly approved treatments for previously untreated chronic lymphocytic leukemia (CLL), were named ASCO’s Cancer Advance of the Year (see pages 42-43 for more information). ■■ ASCO named genomic technology, nanomedicine, and health information technologies as the next advances likely to shape the next decade of cancer care. ■■ Progress made in rare cancers include two oral agents, PLX3397 and RG7155, which showed promise in clinical studies for pigmented villonodular synovitis, and bevacizumab in the treatment of a rare form of ovarian cancer.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 9

Issues in Oncology

effects of pigmented villonodular synovitis and the possibility of avoiding joint replacement or amputation. The second promising achievement in the progress against rare cancers is reflected by early results from a clinical trial showing that bevacizu mab (Avastin) may be active against recurrent sex cord–stromal tumors

Contact

The ASCO Post

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

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

Advertising

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

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

of the ovaries, a rare form of ovarian cancer. n Study Authors The following individuals contributed to ASCO’s Clinical Cancer Advances Progress Report: Gregory A. Masters, Lada Krilov, Howard H. Bailey, Marcia S. Brose, Harold Burstein, Lisa R. Diller, Don S. Dizon, Howard

A. Fine, Gregory P. Kalemkerian, Mark Moasser, Michael N. Neuss, Steven J. O’Day, Olatoyosi Odenike, Charles J. Ryan, Richard L. Schilsky, Gary K. Schwartz, Alan P. Venook, Sandra L. Wong, and Jyoti D. Patel. Lada Krilov, PhD, of the American Society of Clinical Oncology, is the corresponding author. For disclosure of potential conflicts of interest of all authors, visit jco.ascopubs.org/content/

early/2015/01/16/JCO.2014.59.9746.

Reference 1. Masters GA, Krilov L, Bailey HH, et al: Clinical Cancer Advances 2015: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol. January 20, 2015 (early release online).

The ASCO Post | FEBRUARY 10, 2015

PAGE 10

San Antonio Breast Cancer Symposium Breast Cancer

Dr. Mary-Claire King Proposes Population Screening in All Young Women for BRCA Mutations By Caroline Helwick

t is not enough for Mary-Claire King, PhD, to have identified the germline BRCA1 mutation associated with hereditary breast and ovarian cancers. Her clinically applicable discovery is one of the world’s greatest in genetics and one for which she has been highly lauded. But not one to rest on her laurels, Dr. King will not be satisfied, she says, until genetic screening for BRCA1 and BRCA2 is offered to all young women, regardless of family history of cancer. “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention,” she says. Dr. King discussed her proposal at the 2014 San Antonio Breast Cancer Symposium, where she was honored with the American Association of Cancer Research Distinguished Lectureship in Breast Cancer Research. Dr. King is Professor of Medical Genetics and Genome Sciences at the University of Washington, Seattle. “Here’s what an evolutionary biologist thinks we should do next about BRCA1 and BRCA2,” Dr. King began. “My proposal is that we offer population screening for unambiguously damaging mutations in these genes to all women at about age 30. In other words, we move beyond testing only women in severely affected families to testing women regardless of family history of breast or ovarian cancer—who can then undertake preventive action if they learn they carry a mutation.”

She offered a “profound” reason behind this proposal: “Every breast cancer patient we identify after she develops cancer clearly represents a missed opportunity for prevention.” According to Dr. King, these missed opportunities are more common than one might think. “When we evaluated BRCA1 and BRCA2 in unselected breast cancer patients, at the time of their diagnoses, we found that roughly 50% of patients who carry a damaging mutation in BRCA1 or BRCA2 had no close family history of breast or ovarian cancer,” she indicated. This happened because 50% of women with mutations inherited them from their fathers, who were not affected, and familes were generally small.

More on Population-Based Screening Dr. King indicated that population-based screening meets the World Health Organization criteria: The disease is an important health problem in the target population, the risk of disease due to the mutation is high, mutations responsible for the disease can be accurately identified, and effective interventions exist. Although the current official recommendation by the U.S. Preventive Services Task Force is that screening for unaffected women be limited to those with a family history of breast or ovarian cancer,1 new data make this conservative position questionable, she said,

adding, “I agreed with that statement at the time it was made.” The recent study coauthored by Dr. King, conducted in Israel and published in Proceedings of National Academy of Sciences, confirmed her experience with previous family-based studies: BRCA1-

three loss-of-function mutations, which collectively account for most inherited risk due to BRCA1 and BRCA2 in this population. “Men were tested as a gateway to families because men were unaffected by breast cancer themselves, thus en-

Every breast cancer patient we identify after she develops cancer clearly represents a missed opportunity for prevention. Roughly 50% of patients who carry an unambiguously damaging mutation have no close family history. —Mary-Claire King, PhD

and BRCA2-associated risks are independent of family history, and population-based screening is the best way to find women whose mutations would otherwise remain undetected.

50% of Carriers Have No Family History To determine cancer risks in BRCA1- and BRCA2-mutation carriers identified from the general population, the researchers conducted a study of population-based screening in the Ashkenazi Jewish population of Israel.2 Families were identified through the recruitment of more than 8,000 healthy men, who were screened for

abling female mutation carriers to be identified only by relationship to a healthy male relative, not based on their personal or family history of cancer,” the authors explained.2 Genetic testing was offered to all female relatives of the 175 men with these mutations, and the female relatives with mutations were found to have very high cancer risks: 60% by age 60 for BRCA1 carriers and 33% for BRCA2 carriers. These risks were significantly higher at every age among women born more recently than among older women, a “birth cohort effect” seen in prior studies, and one that likely represents the increasing prevalence of nongenetic risk

SABCS 2014—Mary-Claire King, PhD, is presented with the AACR Distinguished Lectureship in Breast Cancer Research. Dr. King (right) is shown here with Carlos L. Arteaga, MD, AACR President.

SABCS 2014—Over 7,500 physicians, researchers, patient advocates and health-care professionals from over 90 countries were in attendance at the meeting, which featured the latest research on breast cancer treatment and prevention.

Photo Courtesy SABCS/©MedMeetingImages/Todd Buchanan 2014

B:7.875 in T:7.625 in S:6.625 in

In mCRPC therapy…

Is there more to the story?

T:10.5 in

Please see additional Important Safety Information on the next page. Please see brief summary of full Prescribing Information on subsequent pages.

B:10.75 in

mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

S:10 in

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

B:7.875 in T:7.625 in S:6.625 in

For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days. And every day tells a story. 35.3 5.2 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached. Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival. ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

Please see brief summary of full Prescribing Information on subsequent pages.

B:7.875 in T:7.625 in S:6.625 in

003307-130924

Learn more today at

www.zytigahcp.com.

Every day tells a story.

T:10.5 in

†At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

B:10.75 in

S:10 in

T:10.5 in

B:10.75 in

S:10 in

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. 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. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

ZYTIGA® (abiraterone acetate) Tablets

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

ASCOPost.com | FEBRUARY 10, 2015

PAGE 11

San Antonio Breast Cancer Symposium factors, such as early age at menarche and late age at first pregnancy. Notably, 50% of the index males harboring mutations had no close family history of breast or ovarian cancer that would have triggered attention, Dr. King emphasized. “In our view, this provided information to fill the gap that rightly concerned the Preventive Services Task Force. Women who carry a mutation in BRCA1 or BRCA2 are at high risk for breast or ovarian cancer, even if they are ascertained from the general population, regardless of their own personal or family history,” she emphasized.

More Details of the Proposal Dr. King emphasized that screening should begin with BRCA1 and BRCA2, the two most well-characterized genes, and then perhaps evolve into broader screening once testing is in place. Variants of unknown significance would not be part of the reports. “Our goal is to make the lives of oncologists more straightforward, not muddier. That means getting rid of the problem of “variants of unknown significance,”…which were invented in the course of commercial activity and have run amok since,… wreaking havoc for patients and despair for providers who need to give patients clear information,” she maintained. She would form an expert panel to define a reference list of the thousands

of different unambiguously damaging mutations in BRCA1 and BRCA2. These mutations can now be provided in a clear manner, with mutations identified in the future added later. “No test in genetics picks up absolutely every damaging allele. Almost no regulatory mutations are yet detected, for example. We learn as we go along and add to the list of damaging mutations,” she said.

plan along the lines of prevention, both through surveillance and consideration of prophylactic procedures.” Population screening, she estimated, would identify a damaging BRCA1 or BRCA2 mutation in approximately 1 in 300 women. A conservative estimate is that 250,000 to 420,000 women would be affected, and their cancers preventable. Although the prospect may sound

Key Components of Dr. King’s Breast Cancer Screening Proposal ■■ Offer every woman complete sequencing of BRCA1 and BRCA2 at age 30 or so as part of routine medical care. ■■ Refer every woman with an unambiguously damaging mutation in BRCA1 or BRCA2 to a high-risk clinic for appropriate follow-up. ■■ Report only mutations of demonstrated damaging consequence (avoid variants of unknown significance). A reference list of these mutations should be made public. ■■ Begin with the two best-known genes, and, in the future, add other variants proven to be deleterious.

After screening for BRCA1 and BRCA2, she would refer two groups for genetic counseling and follow-up: patients with a damaging mutation in either gene and those lacking mutations but with a severe family history, as presently defined by federal guidelines, who would be candidates for genetic panel testing. She believes age 30 (or thereabouts) is the appropriate age for such screening—at a routine visit to the gynecologist—because “this is the right age for women to begin to think of a 10-year

daunting to health economists, its costeffectiveness has been shown in a recent study from the United Kingdom.3 Compared with family history–based screening, population screening saved 0.090 more life-years and 0.101 more quality-adjusted life-years and was cost saving. It lowered the incidence of ovarian and breast cancers by 34% and 62%, respectively, and reduced treatment costs by £3.7 million (between $5 and $6 million). “Based on UK parameters, the costeffectiveness would be absolutely accept-

able,” she indicated, adding the actual cost of testing is about one-tenth of the current commercial charge, and market forces will likely further bring down prices. She concluded her talk with a somber prediction. “Everything I’ve said may soon be moot,” she suggested. “The provision of genetic testing directly to consumers, with U.S. Food and Drug Administration approval, without involving any of us, is imminent. I would like very much for us as geneticists and physicians who are working with patients to be involved in formulating testing and follow-up in a way that makes sense to us.” n Disclosure: Dr. King reported no potential conflicts of interest.

References 1. Moyer V; U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160:271-281, 2014. 2. Gabai-Kapara E, Lahad A, Kaufman B, et al: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A 111:14205-14210, 2014. 3. Manchanda R, Legood R, Burnell M, et al: Cost-effectiveness of population screening for BRCA mutations in Ashkenazi Jewish women compared with family history-based testing. J Natl Cancer Inst 107:380, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post David A. Kooby, MD, on Minimally Invasive Techniques and GIST Lesions see page 21

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, on Bladder Cancer see page 27

Anirban P. Mitra, MD, PhD, on Genomic Signature in High-Risk Bladder Cancer see page 31

Cora N. Sternberg, MD, FASCO, on Molecular Classification in High-Risk Bladder Cancer see page 32

Michael Dixon, MD, on Letrozole Response see page 52

Thomas A. Gallo, MS, on Cancer Care see page 58

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | FEBRUARY 10, 2015

PAGE 12

San Antonio Breast Cancer Symposium Breast Cancer

News Roundup From the 2014 San Antonio Breast Cancer Symposium By Caroline Helwick

ighlighted here are summaries of four abstracts presented at the 2014 San Antonio Breast Cancer Symposium: They focus on the EPOANE-3010 clinical trial of epoetin alfa (Epogen, Procrit) in anemic patients with metastatic breast cancer, a New York Cancer Consortium trial of fulvestrant (Faslodex) and bortezomib (Velcade) in hormone receptor–positive metastatic breast cancer, the use of a 25gene hereditary cancer panel, and the BEACON trial of etirinotecan pegol in patients with metastatic breast cancer.

mined progressive disease, did not meet the protocol-defined noninferiority criteria of 1.15,” Dr. Leyland-Jones announced. A 9% increased risk in disease progression or death and a 6% increased

risk in death were observed, although overall survival data are not yet mature. The median progression-free survival was 7.4 months with epoetin alfa (95% confidence interval [CI] = 6.9–

7.6) and 7.5 months in the control arm (95% CI = 7.1–7.6, hazard ratio [HR] = 1.089). For the epoetin alpha and control arms, respectively, the median time to tumor progression was 7.5 months

ADVERTORIAL

Risks Associated With Epoetin Alfa Confirmed The use of epoetin alfa led to increased mortality and tumor progression in metastatic breast cancer patients who were evaluated in the U. S. Food and Drug Administration (FDA)-mandated EPO-ANE-3010 trial, based on safety concerns that arose with erythropoiesis-stimulating agents in 2002.1 “The results were consistent with the black box warning. We had hoped for better,” said Brian Leyland-Jones, MD, of the Avera Medical Group Oncology and Hematology in Sioux Falls, South Dakota.

Cancer Stem Cells

Signal Pathways

Understanding M

Brian Leyland-Jones, MD

The recommendation remains, he said, that epoetin alfa should only be used for chemotherapyrelated anemia in patients where cure is not the anticipated outcome. For the management of anemia in the first or second line of chemotherapy in metastatic breast cancer, “transfusion would be the preferred approach,” he emphasized. EPO-ANE-3010, which began in 2004, enrolled 2,100 patients with metastatic breast cancer and a hemoglobin level ≤ 11 g/dL. Patients underwent chemotherapy and were randomized to receive standard supportive care or supportive care plus epoetin alfa 40,000 IU weekly. “The primary endpoint of progression-free survival, per investigator-deter-

alignancies, like normal adult tissue, have been shown to contain a subset of cells that have the capacity to both selfrenew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

EDU-NPS-0009

12/2014

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6 Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence. Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

ASCOPost.com | FEBRUARY 10, 2015

PAGE 13

San Antonio Breast Cancer Symposium (95% CI = 7.4–7.9) and 7.5 months (95% CI = 7.4–8.0, HR = 1.094), respectively. At cutoff, the median overall survival was 17.2 months (95% CI = 16.1–18.5) and 17.4 months (95% CI = 16.0–18.9, HR = 1.057), respectively. “The separation of the time to disease progression Kaplan-Meier curves was completely unanticipated,” Dr.

Leyland-Jones commented. “The progression-free survival and time to progression curves separated after about 12 months and overall survival after about 18 months. The difference is driven by 30% of patients who were progression-free at 12 months. There do not appear to be any factors that explain the divergence.”

Regrowth

Transfusion rates were low in both groups—11.4% with standard care vs 5.8% with epoetin alfa —although epoetin alfa did reduce the need by 51% (P < .001). Thrombotic vascular events were infrequent, 1.4% vs 2.8%, respectively, “although they were serious when they occurred,” he said. Grade ≥ 3 adverse events were similar in both groups.

Metastasis

Cancer Stem Cells proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10 Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

www.bostonbiomedical.com

Fulvestrant Plus Bortezomib In the randomized phase II New York Cancer Consortium NCI Trial 8457, the addition of bortezomib to fulvestrant significantly reduced the rate of disease progression (HR = 0.73, P = .06) and significantly improved the 12-month progression-free survival, from 14% to 28% (P = .03) in treatment-refractory patients [note: P < .1 for significance), reported Kerin B. Adelson, MD, of Yale University School of Medicine, New Haven, Connecticut.2 Bortezomib did not, however, improve progression-free survival at 6 months or median progression-free survival. “We estimated the median

The study provides proof of principle that targeting the proteasome may prevent and/or delay the emergence of acquired resistance to endocrine therapy with fulvestrant. —Kerin B. Adelson, MD

progression-free survival in the fulvestrant-alone arm would be 5.4 months. The observed median of 2.7 months suggests a more hormone-resistant population than expected, and this may have impacted our median progressionfree survival calculations.” The study enrolled 118 women with estrogen receptor–positive metastatic breast cancer resistant to aromatase inhibitors. Patients were randomly assigned to receive fulvestrant (500 mg) alone or with bortezomib (1.6 mg/m2). Almost half the fulvestrant arm crossed over to the combination. In this group, the clinical benefit (progressionfree for ≥ 24 weeks) was observed in 18%. Five patients had a longer progression-free survival after crossover than they did on fulvestrant alone. The doublet increased nausea, diarrhea, and neuropathy, but there was litcontinued on page 48

The ASCO Post | FEBRUARY 10, 2015

PAGE 14

ASH Annual Meeting Hematology

Strong Showing for Anti-CD38 Antibodies in Multiple Myeloma By Caroline Helwick

n investigational class of agents in multiple myeloma, the anti-CD38 monoclonal antibodies, could be the next blockbusters in this malignancy, myeloma experts predicted at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition. Anti-CD38 antibodies target multiple myeloma cells by binding to the CD38 antigen expressed on the cell surface and then signaling the patient’s immune system to attack the tumor. Although the data reported at the ASH meeting came from only phase Ib studies, the findings

quite promising and justify bringing these drugs into the front-line setting.”

SAR650948 in Heavily Pretreated Patients Dr. Martin presented the results from a dose-escalation study of SAR650948,1 which was given in combination with a standard regimen of lenalidomide (Revlimid)/dexamethasone in 31 patients with relapsed/refractory disease. There was no upper limit on the number of prior lines of therapy. “These were very heavily pretreated

These anti-CD38 monoclonal antibodies will be blockbuster drugs and an important component of multiple myeloma treatment. In the next 5 years, I think we will see them moved from the refractory setting, even to front line eventually. —Thomas Martin, MD

The data from part 1 are mature and show an impressive rate of complete response (31%). Our median follow-up is still less than 6 months, and only 2.7 months for the last patient dosed in the analysis. —Torben Plesner, MD

were considered impressive. Despite the success of the proteasome inhibitors and immunomodulating drugs, there are still unmet needs that might be filled by new classes of agents, said Thomas Martin, MD, of the University of California, San Francisco. “These anti-CD38 monoclonal antibodies, I believe, will be blockbuster drugs and an important component of multiple myeloma treatment,” he predicted. “Clinicians should definitely be referring patients to these trials. We finished ours in record time. Doctors were on the telephone line, trying to get a spot on our trial.” Press briefing moderator Brad Kahl, MD, Associate Professor of Medicine at the University of Wisconsin in Madison, commented, “Obviously, it’s very, very early with these drugs, and it’s too early to plant the victory flag in the ground, but having said that, the early data are

patients,” he noted. “More than 90% had prior lenalidomide, 90% had prior bortezomib (Velcade), about 30% had prior pomalidomide (Pomalyst), and 50% had prior carfilzomib (Kyprolis) exposure. Many patients were double-refractory.” The combination produced responses in 58% of patients overall, rising to 63% in patients receiving the highest dose, 10 mg/kg every 2 weeks. The

Brad Kahl, MD

clinical benefit rate was 65% overall and 67% with the maximum dose. Responses were achieved in 50% of patients who had relapsed on or were refractory to previous treatment with immunomodulating drugs, in 44% who had relapsed on or were refractory to bortezomib, 40% who had relapsed on or were refractory to carfilzomib, and 33% who had relapsed on or were refractory to pomalidomide. Referring to the robust reduction in the M protein, a marker of disease, Dr. Martin observed the waterfall plot to be “dramatic.” Only 4 of the 31 patients did not demonstrate at least a 25% reduction in paraprotein, and the majority of patients achieved at least a 50% reduction. The median progression-free survival was 6.2 months, but it had not been reached in patients who had received only one or two prior lines of therapy. The median duration of response was 9 months. “In my mind, SAR650984 in combination with lenalidomide and dexamethasone produced fairly dramatic responses,” he said. “In the relapsed/refractory setting, you must look at prior treatments, and this was a very refractory group.” The addition of SAR650984 did not increase toxicity. The pharmacokinetics of SAR650984 and lenalidomide appear to be independent, he noted. The most common adverse events were mild fatigue, nausea, diarrhea, neutropenia, and upper respiratory infection. Two patients discontinued treatment due to infusion-related reac-

Anti-CD38 Monoclonal Antibodies in Multiple Myeloma ■■ In patients with relapsed or refractory multiple myeloma, phase Ib data were highly encouraging for two anti-CD38 monoclonal antibodies: SAR650948 and daratumumab. ■■ Responses to daratumumab in combination with standard regimens were observed in 100% of newly diagnosed patients and in approximately 50% of relapsed patients. ■■ Responses to SAR650948 plus lenalidomide/dexamethasone were observed in 63% of patients who received the highest dose; the median progressionfree survival was 6.3 months in heavily pretreated patients.

tions, but most such reactions resolved after one cycle. “These are the next blockbusters, drugs that will show benefit in myeloma, and in the next 5 years, I think we will see them moved from the refractory setting, even to front line eventually, and that will be great,” Dr. Martin commented at a press briefing.

Daratumumab Tested in Four Combinations Philippe Moreau, MD, of the University Hospital in Nantes, France, reported preliminary data for a second anti-CD38 antibody, daratumumab. Daratumumab, which had shown single-agent activity, was combined with one of four standard regimens in the treatment of 18 newly diagnosed patients and 6 relapsed/refractory patients in the MMY1001 study.2 Regimens in-

Philippe Moreau, MD

cluded bortezomib/dexamethasone, bortezomib/thalidomide (Thalomid)/ dexamethasone, bortezomib/melphalan/prednisone, and, for previously treated patients, pomalidomide/dexamethasone. Fully 100% of newly diagnosed patients responded to daratumumab (16 mg/kg) plus a standard regimen. The response rate was 50% in the relapsed group, Dr. Moreau noted. After a median treatment duration of 44 days, no additional toxicity was observed with the addition of daratumumab to these regimens. The most serious adverse events were related to the backbone therapy. Four patients had infusion reactions, but they did not interrupt treatment. All other adverse events were consistent with those previously reported with the standard regimens. Torben Plesner, MD, of Vejle Hospital in Denmark, also reported findings on daratumumab from an international study of 45 relapsed/refractory patients who received daratumumab with lenalidomide plus dexamethasone.3 “Daratumumab plus lenalidomide continued on page 15

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

In appropriate patients with advanced melanoma

KEYTRUDA:

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

24% overall response rate in the 2 mg/kg arm (95% confidence interval [CI], 15–34; n=89); 1 complete response (1%) and 20 partial responses (23%). 86% of patients with an objective response (n=18/21) had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with ongoing responses of 6 months or longer. Releases programmed death receptor-1 (PD-1) pathway–mediated inhibition of the immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or diseaserelated symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

SELECTED SAFETY INFORMATION • Immune-mediated adverse reactions occurred with KEYTRUDA, including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information on the next page. Please see additional Selected Safety Information on the next page and the Brief Summary of Prescribing Information on the adjacent pages.

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

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

11%% 23 23%%

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

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

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

• •Similar Similaroverall overallresponse responserate rateresults resultswere wereobserved observed in in the the10-mg/kg 10-mg/kgarm. arm. • •Patients Patientscontinued continuedtreatment treatmentwith with KEYTRUDA KEYTRUDA until until unacceptable unacceptable toxicity toxicity or or disease disease progression progression that that was wassymptomatic, symptomatic,was wasrapidly rapidlyprogressive, progressive, required required urgent urgent inter intervention, vention, occurred occurred with with aa decline decline in in performance performancestatus, status,ororwas wasconfirmed confirmedat at44to to66 weeks weeks with withrepeat repeatimaging. imaging.

Study design: AA multicenter, open-label, Study design: multicenter, open-label,randomized, randomized,dose-comparative dose-comparativestudy studycohort cohortofofthe theongoing ongoingKEYNOTE-001 KEYNOTE-001Phase Phase1b1btrial trialininpatients patientswith with unresectable or or metastatic melanoma and progression unresectable metastatic melanoma and progressionofofdisease. disease.Key Keyeligibility eligibilitycriteria criteriaincluded includedprior priortreatment treatmentwith withipilimumab ipilimumab(2(2orormore moredoses doses at at 3 mg/kg or or higher) and a BRAF oror MEK inhibitor, if BRAF 3 mg/kg higher) and a BRAF MEK inhibitor, if BRAFV600 V600mutation–positive; mutation–positive;and anddisease diseaseprogression progressionwithin within2424weeks weeksfollowing followingthe thelast lastdose dose of of ipilimumab. Patients were randomized to toreceive ipilimumab. Patients were randomized receive2 mg/kg 2 mg/kg(n=89) (n=89)oror1010mg/kg mg/kg(n=84) (n=84)ofofKEYTRUDA KEYTRUDAevery every3 3weeks weeksuntil untilunacceptable unacceptabletoxicity toxicityoror disease progression. The major efficacy disease progression. The major efficacyoutcome outcomemeasures measureswere wereconfirmed confirmedoverall overallresponse responserate, rate,asasassessed assessedbybyblinded blindedindependent independentcentral central review using Response Evaluation Criteria in in Solid review using Response Evaluation Criteria SolidTumors Tumors(RECIST (RECIST1.1), 1.1),and andduration durationofofresponse. response.Tumor Tumorresponse responsewas wasassessed assessedevery every1212weeks. weeks.

SELECTED SELECTEDSAFETY SAFETYINFORMATION INFORMATION • Pneumonitis • Pneumonitisoccurred occurredin in1212(2.9%) (2.9%)ofof411 411patients, patients,including including Grade 2 or 3 cases in in 8 (1.9%) and 1 (0.2%) Grade 2 or 3 cases 8 (1.9%) and 1 (0.2%)patients, patients,respectively, respectively, receiving KEYTRUDA. Monitor patients forfor signs and receiving KEYTRUDA. Monitor patients signs andsymptoms symptomsofof pneumonitis. Evaluate pneumonitis. Evaluatesuspected suspectedpneumonitis pneumonitiswith withradiographic radiographic imaging. imaging.Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater pneumonitis. TRUDA pneumonitis.Withhold WithholdKEY KEY TRUDAforforGrade Grade2;2;permanently permanently discontinue KEYTRUDA forfor Grade 3 or 4 pneumonitis. discontinue KEYTRUDA Grade 3 or 4 pneumonitis. • Colitis • Colitis(including (includingmicroscopic microscopiccolitis) colitis)occurred occurredinin4 4(1%) (1%)ofof411 411 patients, including patients, includingGrade Grade2 2oror3 3cases casesinin1 1(0.2%) (0.2%)and and2 2(0.5%) (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients, respectively, receiving KEYTRUDA. Monitorpatients patientsforfor signs and symptoms signs and symptomsofofcolitis. colitis.Administer Administercorticosteroids corticosteroidsfor for Grade 2 or greater colitis. Withhold Grade 2 or greater colitis. WithholdKEYTRUDA KEYTRUDAforforGrade Grade2 2oror3;3; permanently discontinue KEYTRUDA forfor Grade 4 colitis. permanently discontinue KEYTRUDA Grade 4 colitis. • Hepatitis (including autoimmune hepatitis) occurred • Hepatitis (including autoimmune hepatitis) occurredinin2 (0.5%) 2 (0.5%)ofof 411411 patients, including a Grade 4 case in in 1 (0.2%) patient, receiving patients, including a Grade 4 case 1 (0.2%) patient, receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforchanges changesininliver liverfunction. function. Administer Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greaterhepatitis hepatitis and, based onon severity ofof liver enzyme elevations, and, based severity liver enzyme elevations,withhold withholdoror discontinue KEYTRUDA. discontinue KEYTRUDA. • Hypophysitis occurred in in 2 (0.5%) ofof 411411 patients, including • Hypophysitis occurred 2 (0.5%) patients, includinga aGrade Grade2 2 case in in 1 and a Grade 4 case case 1 and a Grade 4 casein in1 (0.2% 1 (0.2%each) each)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Monitor Monitorpatients patientsforforsigns signsand andsymptoms symptomsofof hypophysitis. Administer hypophysitis. Administercorticosteroids corticosteroidsforforGrade Grade2 2ororgreater greater hypophysitis. hypophysitis.Withhold WithholdKEYTRUDA KEYTRUDAforforGrade Grade2;2;withhold withholdoror discontinue forfor Grade 3; 3; and permanently discontinue discontinue Grade and permanently discontinueKEYTRUDA KEYTRUDA forfor Grade 4 hypophysitis. Grade 4 hypophysitis.

• Nephritis • Nephritisoccurred occurredinin3 3(0.7%) (0.7%)patients, patients,consisting consistingofofone onecase caseofof Grade Grade2 2autoimmune autoimmunenephritis nephritis(0.2%) (0.2%)and andtwo twocases casesofofinterstitial interstitial nephritis nephritiswith withrenal renalfailure failure(0.5%), (0.5%),one oneGrade Grade33and andone oneGrade Grade4.4. Monitor Monitorpatients patientsfor forchanges changesininrenal renalfunction. function. Administer Administer corticosteroids corticosteroidsfor forGrade Grade2 2ororgreater greater nephritis. nephritis. Withhold Withhold KEYTRUDA KEYTRUDAfor forGrade Grade2;2;permanently permanentlydiscontinue discontinueKEYTRUDA KEYTRUDAfor for Grade Grade3 3oror4 4nephritis. nephritis. • Hyperthyroidism • Hyperthyroidismoccurred occurredinin5 5(1.2%) (1.2%)ofof411 411patients, patients,including including Grade Grade2 2oror3 3cases casesinin2 2(0.5%) (0.5%)and and1 1(0.2%) (0.2%)patients, patients,respectively, respectively, receiving receivingKEYTRUDA. KEYTRUDA.Hypothyroidism Hypothyroidismoccurred occurredinin34 34(8.3%) (8.3%)ofof411 411 patients, patients,including includinga aGrade Grade3 3case caseinin11(0.2%) (0.2%)patient, patient,receiving receiving KEY TRUDA. KEY TRUDA.Thyroid Thyroiddisorders disorderscan canoccur occuratatany anytime timeduring during treatment. treatment.Monitor Monitorpatients patientsfor forchanges changesininthyroid thyroidfunction function(at (atthe the start startofoftreatment, treatment,periodically periodicallyduring duringtreatment, treatment,and andas asindicated indicated based basedononclinical clinicalevaluation) evaluation)and andfor forclinical clinicalsigns signsand andsymptoms symptomsofof thyroid thyroiddisorders. disorders.Administer Administercorticosteroids corticosteroidsfor forGrade Grade33ororgreater greater hyperthyroidism. hyperthyroidism.Withhold WithholdKEYTRUDA KEYTRUDAfor forGrade Grade3;3;permanently permanently discontinue TRUDA for discontinueKEY KEYTRUDA forGrade Grade4 4hyperthyroidism. hyperthyroidism.Isolated Isolated hypothyroidism hypothyroidismmay maybebemanaged managed with with replacement replacement therapy therapy without withouttreatment treatmentinterruption interruptionand andwithout withoutcorticosteroids. corticosteroids. • Other • Otherclinically clinicallyimportant importantimmune-mediated immune-mediatedadverse adverse reactions reactions can canoccur. occur.The Thefollowing followingclinically clinicallysignificant significantimmune-mediated immune-mediated adverse adversereactions reactionsoccurred occurredininless lessthan than1% 1%ofofpatients patientstreated treated with withKEYTRUDA: KEYTRUDA:exfoliative exfoliativedermatitis, dermatitis,uveitis, uveitis,arthritis, arthritis,myositis, myositis, pancreatitis, pancreatitis,hemolytic hemolyticanemia, anemia,partial partialseizures seizuresarising arisingininaapatient patient with withinflammatory inflammatoryfoci fociininbrain brainparenchyma, parenchyma,adrenal adrenalinsufficiency, insufficiency, myasthenic myasthenicsyndrome, syndrome,optic opticneuritis, neuritis,and andrhabdomyolysis. rhabdomyolysis.

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

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

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

••Among progression of of disease disease 2.8, 2.8, 2.9, 2.9, and and 8.2 8.2 months months Among the the 21 21 patients patients with with an an objective response, 3 (14%) had progression after after initial initial response. response. •• The durations ranging ranging from from 1.4+ 1.4+ to to 8.5+ 8.5+ months, months,which which The remaining remaining 18 18 patients patients (86%) (86%) had ongoing responses with durations included included 88 patients patients with with ongoing ongoing responses of 6 months or longer. •• One first tumor tumor assessment assessment concurrent concurrentwith withaa Oneadditional additional patient patient developed developed 2 new asymptomatic lesions at the first 75% 75% decrease decrease in in overall overall tumor tumor burden. —KEYTRUDA was durable durable for for 5+ 5+ months. months. —KEYTRUDA was was continued continued and and this reduction in tumor burden was

SELECTED SELECTED SAFETY SAFETY INFORMATION INFORMATION (CONTINUED) common adverse adverse reactions reactions (reported (reported inin at at least least ••For For suspected suspected immune-mediated immune-mediated adverse reactions, ensure • The most common patients) were were fatigue fatigue (47%), (47%), cough cough (30%), (30%), nausea nausea adequate 20% of patients) adequate evaluation evaluation to to confirm confirm etiology or exclude other pruritus (30%), (30%), rash rash (29%), (29%), decreased decreasedappetite appetite(26%), (26%), causes. (30%), pruritus causes.Based Basedon on the the severity severity of of the the adverse reaction, withhold (21%), arthralgia arthralgia (20%), (20%),and anddiarrhea diarrhea(20%). (20%). KEYTRUDA constipation (21%), KEYTRUDA and and administer administer corticosteroids. corticosteroids. Upon improvement of ofthe theadverse adversereaction reaction to to Grade Grade 11 or or less, initiate corticosteroid • It is not known known whether whether KEYTRUDA KEYTRUDA isis excreted excreted ininhuman humanmilk. milk. taper taper and and continue continue to to taper taper over over at least 1 month. Restart drugsare areexcreted excretedin inhuman humanmilk, milk,instruct instructwomen women Because many drugs KEYTRUDA KEYTRUDA ifif the the adverse adverse reaction reaction remains at Grade 1 or less. nursing during during treatment treatmentwith withKEYTRUDA. KEYTRUDA. to discontinue nursing Permanently Permanently discontinue discontinue KEYTRUDA KEYTRUDA for any severe or Grade 3 effectiveness of KEYTRUDA have notbeen been • Safety and effectiveness of KEYTRUDA have not immune-mediated immune-mediated adverse adverse reaction reaction that recurs and for any lifeestablished in pediatric pediatric patients. patients. threatening immune-mediated adverse reaction. threatening immune-mediated adverse ••Based Based on on its its mechanism mechanism of of action, action, KEYTRUDA may cause the Brief Brief Summary Summary of of the the Please see the fetal fetal harm harm when when administered administered to to aa pregnant woman. If used Information on on the the adjacent adjacent pages. pages. Prescribing Information during during pregnancy, pregnancy, or or ifif the the patient patient becomes pregnant during treatment, treatment,apprise apprise the the patient patient of of the the potential hazard to a fetus. Merck Oncology Oncology Advise Advisefemales females of of reproductive reproductive potential potential to use highly effective 2014 Merck Merck Sharp Sharp && Dohme DohmeCorp., Corp., Copyright © 2014 contraception contraception during during treatment treatment and and for 4 months after the last a subsidiary of of Merck Merck & & Co., Co., Inc. Inc. dose doseof ofKEYTRUDA. KEYTRUDA. All rights reserved. reserved. ONCO-1116177-0000 ONCO-1116177-000011/14 11/14 keytruda.com keytruda.com

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

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

Brief Summary of the Prescribing Information for KEYTRUDA® (pembrolizumab) for injection, for intravenous use INDICATIONS AND USAGE KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis: Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development of pneumonitis was 5 months (range 0.3 weeks–9.9 months). The median duration was 4.9 months (range 1 week–14.4 months). Five of eight patients with Grade 2 and the one patient with Grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment of 3 days (range 1–34) followed by a corticosteroid taper. Pneumonitis led to discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with Grade 2–3 pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) pneumonitis. Immune-Mediated Colitis: Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 2.3– 9.8). The median duration was 2.6 months (range 0.6 weeks–3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4–41), followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis. Immune-Mediated Hepatitis: Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. Immune-Mediated Hypophysitis: Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for moderate (Grade 2) hypophysitis, withhold or discontinue KEYTRUDA for severe (Grade 3) hypophysitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hypophysitis. Renal Failure and Immune-Mediated Nephritis: Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3–4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2) nephritis, and permanently discontinue KEYTRUDA for severe (Grade 3), or life-threatening (Grade 4) nephritis. Immune-Mediated Hyperthyroidism and Hypothyroidism: Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5 months (range 0.5–2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with highdose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range 0.7 weeks–19 months). All but two of the patients with hypothyroidism were

treated with long-term thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management of hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold KEYTRUDA for severe (Grade 3) hyperthyroidism, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Other Immune-Mediated Adverse Reactions: Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal insufficiency. Across clinical studies with KEYTRUDA in approximately 2000 patients, the following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. Embryofetal Toxicity: Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PDL-1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with KEYTRUDA and for 4 months after the last dose of KEYTRUDA. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail above. • Immune-mediated pneumonitis. • Immune-mediated colitis. • Immune-mediated hepatitis. • Immune-mediated hypophysitis. • Renal failure and immune-mediated nephritis. • Immune-mediated hyperthyroidism and hypothyroidism. • Immune-mediated adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS and PRECAUTIONS section reflect exposure to KEYTRUDA in Trial 1, an uncontrolled, open-label, multiple cohort trial in which 411 patients with unresectable or metastatic melanoma received KEYTRUDA at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51). The study population characteristics were: median age of 61 years (range 18–94), 39% age 65 years or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for advanced or metastatic disease. KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis. Table 1 presents adverse reactions identified from analyses of the 89 patients with unresectable or metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18–88), 33% were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater than 6 months and 21% for greater than 1 year. KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

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

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

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

Pregnancy: Pregnancy Category D.

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

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

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

Animal Data: Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects General Disorders and Administration Site Conditions on reproduction was provided. A central function of the PD-1/PD-L1 pathway is to preserve Fatigue 47 7 pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 Peripheral edema 17 1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus Chills 14 0 and to result in an increase in fetal loss; therefore, potential risks of administering KEYTRUDA Pyrexia 11 0 during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, Gastrointestinal Disorders there were no malformations related to the blockade of PD-1 signaling in the offspring of Nausea 30 0 these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Constipation 21 0 Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab Diarrhea 20 0 has the potential to be transmitted from the mother to the developing fetus. Based on its Vomiting 16 0 mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing Abdominal pain 12 0 immune-mediated disorders or of altering the normal immune response. Respiratory, Thoracic And Mediastinal Disorders Nursing Mothers: It is not known whether KEYTRUDA is excreted in human milk. No studies Cough 30 1 have been conducted to assess the impact of KEYTRUDA on milk production or its presence in Dyspnea 18 2 breast milk. Because many drugs are excreted in human milk, instruct women to discontinue Skin And Subcutaneous Tissue Disorders nursing during treatment with KEYTRUDA. Pruritus 30 0 Pediatric Use: Safety and effectiveness of KEYTRUDA have not been established in Rash 29 0 pediatric patients. Vitiligo 11 0 Geriatric Use: Of the 411 patients treated with KEYTRUDA, 39% were 65 years and over. Metabolism and Nutrition Disorders No overall differences in safety or efficacy were reported between elderly patients and Decreased appetite 26 0 younger patients. Musculoskeletal and Connective Tissue Disorders Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is Arthralgia 20 0 needed for patients with renal impairment. Pain in extremity 18 1 KEYTRUDA is indicated of patients with pharmacokinetic unresectable Hepatic Impairment: Based on a population analysis, noor dosemetastatic adjustment is Myalgia 14 for the 1 treatment needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN Back pain 12 1 melanoma and disease progression following ipilimumab and, if BRAF V600 mutation and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has Nervous System Disorders not been studied in patients withunder moderate (TB greater than 1.5 to 3 times ULN and anybased AST) positive, a BRAF inhibitor. This indication is approved accelerated approval Headache 16 0 or severe (TB greater than 3 times ULN and any AST) hepatic impairment. on tumor response rate11and durability of response. An improvement in survival or diseaseDizziness 0 Females and Males of Reproductive Potential: Based on its mechanism of action, KEYTRUDA Blood and Lymphatic System Disorders related symptoms has not yet been established. Continued approval this may may cause fetal harm when administered to a pregnant for woman. Adviseindication females of Anemia 14 5 reproductive potential to use highly effective contraception during treatment with KEYTRUDA of clinical benefit in the confirmatory trials. Psychiatric Disordersbe contingent upon verification and description and for at least 4 months following the last dose of pembrolizumab. Insomnia 14 0 OVERDOSAGE Infections and Infestations There is no information on overdosage with KEYTRUDA. Upper respiratory tract infection 11 1 *There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was reported as Grade 4. PATIENT COUNSELING INFORMATION

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

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

All Grades (%)

Grades 3–4 (%)

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

SELECTED SAFETY INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA, including: — Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath. —Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain. —Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding. —Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes. —Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. —Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism. • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests. • Advise women that KEYTRUDA may cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of KEYTRUDA.

pneumonitis, colitis, hepatitis, hypophysitis, • Advise nursing mothers not to breastfeed while taking KEYTRUDA. For more detailed information, please read the Prescribing Information. nephritis, hyperthyroidism, and hypothyroidism. uspi-mk3475-iv-1409r000 Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. Based on the severity of the adverse reaction, Because trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) Revised: 09/2014 assay results, a subset analysis was performed in the patients with a concentration KEYTRUDA should be withheld or ofdiscontinued pembrolizumab below the drug tolerance level of the anti-product antibody assay. In this © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. corticosteroids For moreCopyright information analysis, none of and the 97 patients who were treated with administered. 2 mg/kg every 3 weeks tested All rights reserved. positive for treatment-emergent anti-pembrolizumab antibodies. regarding immune-mediated adverse reactions, please 11/14 read ONCO-1116177-0000 The detection of antibody formation is highly dependent on the sensitivity and specificity of the additional Selected Safety Information on the next page. the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) *Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate aminotransferase, and anemia (one patient each).

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

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

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

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 15

ASH Annual Meeting Hematology

CAR T Cells Impressive in Acute Lymphocytic Leukemia By Alice Goodman

s more experience is gained with the use of genetically engineered chimeric antigen receptor (CAR) T cells in patients with leukemia, the data continue to be highly encouraging. Three different groups using slightly different modifica-

patients with ALL.1 Thirty-six of these patients (92%) have achieved complete remission, and responses are durable. At a median follow-up of 6 months, some patients had a remission of 1 year or more. The 6-month event-free survival

We are seeing pediatric patients who have not responded to other therapies achieve complete remission as a result of treatment with CTL019. —Stephan Grupp, MD

tions of CAR T cells reported positive experiences in treating acute lymphocytic leukemia (ALL) at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.1-3

Pediatric Relapsed/Refractory Acute Lymphocytic Leukemia To date, 130 patients have received CAR T cells (CTL019) at the University of Pennsylvania, including those with ALL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). Stephan Grupp, MD, of Children’s Hospital of Philadelphia Perelman School of Medicine at the University of Pennsylvania, Philadelphia, reported his experience with CTL019 in 39 pediatric

Anti-CD38 Antibodies continued from page 14

leads to enhanced killing of myeloma cells in vitro and is hypothesized to lead to synergistically higher efficacy in the clinical setting,” Dr. Plesner indicated. Patients had received a median of two prior lines of therapy, and three of

Paul Richardson, MD

them were refractory to lenalidomide. The overall response rate was 100% in the dose-escalation phase with median follow-up duration of 13 months

was 70%. The overall survival was 75%. “We are seeing pediatric patients who have not responded to other therapies achieve extended complete remissions as a result of treatment with CTL019,” Dr. Grupp said.

Another important finding is that after the genetically engineered T cells are reinfused into the patient, they continue to persist in vivo for an “extraordinary” length of time, up to 31 months in ongoing responders. Expansion, proliferation, and persistence are accompanied by B-cell aplasia, a pharmacodynamic marker of CTL019 persistence and function, considered an adverse event and managed with intravenous immunoglobulin replacement therapy.

Cytokine Release Syndrome The major toxicity of concern is cytokine release syndrome, which was seen in all responding patients at peak T-cell expansion. Symptoms of cytokine release syndrome include varying degrees of flulike symptoms, with a high fever, nausea, muscle pain, and in some cases low blood pressure and respiratory distress. Treatment of severe cytokine release syndrome was required in 33% of the

CAR T Cells in Children and Adults With Leukemia ■■ Genetically engineered CAR T cells continue to rack up impressive findings in pediatric and adult patients with acute lymphoblastic leukemia (ALL) who have run out of other treatment options. ■■ Complete remissions are frequently observed, and some remissions are durable. ■■ The major toxicity is cytokine release syndrome, which is generally treatable with appropriate supportive care. Treatment of severe cases of the syndrome may involve tocilizumab with or without steroids. ■■ Mild, reversible neurotoxicity has been seen with CAR T cells.

and 87% in the expansion phase of the study with median follow-up duration of 6 months. In patients who were treated for at least 6 months, 75% achieved a very good partial response or better. The majority of patients had at least a 50% reduction in M protein. “The data from part 1 are mature and show an impressive rate of complete response (31%),” Dr. Plesner reported. “And the early results from part 2 are consistent with part 1. Our median follow-up is still less than 6 months and only 2.7 months for the last patient dosed in this analysis.” Of 45 patients, 19 had infusion reactions, but most (86%) occurred during the first infusion only, and all but one patient recovered and were able to continue with subsequent infusions. Phase III clinical development of daratumumab in combination with le-

nalidomide/dexamethasone is ongoing in both the relapsed/refractory and front-line settings. Paul Richardson, MD, Clinical Program Director and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, Boston, who moderated the oral session, called the data “remarkable.” He said, “monoclonal antibodies have activity in high-risk disease and represent truly novel mechanisms of action” and suggested that the combination of monoclonal antibodies and pomalidomide will produce excellent outcomes in the future. n Disclosure: Dr. Martin has received research funding from Sanofi and is on the speakers bureau for Novartis. Dr. Moreau has received honoraria from Janssen and is a member of Janssen’s Board of Directors or advisory committees. Dr. Plesner is a consultant with Genmab and a member of Janssen’s and Celgene’s Board of Directors or

pediatric patients. Fortunately, this syndrome resolves within 1 to 2 days with the use of tocilizumab (Actemra), an interleukin 6–receptor antagonist, Dr. Grupp told listeners. The severity of cytokine release syndrome appears to be related to disease burden at the time of infusion; patients with a higher disease burden are much more likely to develop severe cytokine release syndrome, Dr. Grupp said. Other toxicities include macrophage activation syndrome and neurotoxicity in a small number of patients after the occurrence of cytokine release syndrome. Manufacturing CAR T cells is labor-intensive, involving extracting the patient’s own T cells and genetically engineering them to target the CD19 surface antigen on tumor cells. The T cells are then reinfused into the patient, unleashing cytotoxicity against tumor cells in an antigen-dependent manner. Dr. Grupp said that ongoing research is being devoted to expediting the manufacturing process so that CAR T cells can become more widely available.

Different Version of CAR T Cells Results of a phase I trial using a slightly different version of CAR T cells achieved a 70% complete response rate in 20 patients with ALL (in our intent-to-treat analysis, including 1 patient with lymphoma, the overall complete response rate was 67%), and the continued on page 16

advisory committees. Dr. Richardson reported no potential conflicts of interest.

References 1. Martin TG III, Baz R, Benson DM, et al: A phase 1b dose escalation trial of SAR650984 (anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 83. Presented December 7, 2014. 2. Moreau P, Mateos M-V, Bladé J, et al: An open-label, multicenter, phase 1b study of daratumumab in combination with backbone regimens in patients with multiple myeloma. 2014 ASH Annual Meeting. Abstract 176. Presented December 7, 2014. 3. Plesner T, Arkenau H-T, Lokhorst HM, et al: Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. 2014 ASH Annual Meeting. Abstract 84. Presented December 7, 2014.

The ASCO Post | FEBRUARY 10, 2015

PAGE 16

ASH Annual Meeting CAR T Cells in ALL continued from page 15

vast majority were minimal residual disease–negative,2 reported Daniel “Trey” Lee, MD, of the National Cancer Institute, Bethesda, Maryland. The genetically engineered CD19 T cells used in this trial are developed with a retroviral platform and a different costimulatory domain instead of a len-

These episodes rapidly resolved after treatment with appropriate supportive care or, for more severe cases, tocilizumab and corticosteroids. Other adverse events included mild, reversible neurotoxicity, Dr. Lee said. “Our CAR appears to be less toxic, since our severe cytokine release syndrome rate was 14% in contrast to the 33% seen by Dr. Grupp’s group,” he noted. CAR T cells were found in the cerebrospinal fluid of patients, and the phase I trial has expanded eligibility to include patients with isolated and/or high levels of central nervous system leukemia.

Adult Relapsed/Refractory ALL

Daniel “Trey” Lee, MD

tivirus platform, as is used by the group at University of Pennsylvania and Children’s Hospital of Pennsylvania. The intent-to-treat study was designed to assess the safety and feasibility of CAR T cells in 21 patients, aged 1 to 30 years. Six patents had primary refractory disease and never achieved minimal residual disease–negative status on previous treatments. All were heavily pretreated, and eight had prior stem cell transplants. Regardless of prior transplant, peripheral blood mononuclear cells were collected and CAR T cells manufactured and reinfused into patients 11 days after collection. Patients were lymphodepleted with fludarabine and cyclophosphamide prior to cell infusion. Among minimal residual disease–negative patients, 79% were leukemia-free at at a median follow-up of 10 months. For all patients, overall survival was 52% at a median follow-up of 10 months. As with the University of Pennsylvania experience, Dr. Lee reported a significant frequency of cytokine release syndrome with in vivo proliferation of CAR T cells.

Durable responses have been observed in adult patients with relapsed/ refractory B-cell ALL treated with CAR T cells at Memorial Sloan Kettering Cancer Center in New York. “The prognosis of adult ALL remains poor, with a 5-year overall survival of 7% in patients in first relapse and 3% in those over age 50. Conventional chemotherapy will achieve a response rate of 20% to 37% for patients in first relapse, but the rate is lower in older patients and those with poor-risk cytogenetics. We need to do a better job in adults with relapsed ALL,” said lead author Jae Park, MD, of Memo-

Jae Park, MD

rial Sloan Kettering Cancer Center. Dr. Park and colleagues used CD1928z–directed CAR T cells using a retroviral vector. He reported results of a phase I trial in 33 adult patients older than age 18 with relapsed/refractory B-cell ALL and

EXPERT POINT OF VIEW

“I

’m certainly excited about the promise of CAR T cells for patients with lymphoid leukemia (ALL and CLL). It’s clear from the data presented and published that CAR T cells can induce remissions in patients refractory to multiple lines of therapy,” said Timothy Graubert, MD, Hagler Family Chair in Oncology and Director of the Hematologic Malignancy Program at Massachusetts General Hospital in Boston. Timothy Graubert, MD “The studies are moving beyond the initial phase at a few centers. The process for manufacturing the cells is becoming more efficient. Industry has begun to partner with academic medical centers, and I think we will see a new era, where this treatment will become more widely available than it is right now,” he continued. “The burning question is whether this is a ‘one-trick pony’ or can this type of treatment be applied to other tumors as well,” Dr. Graubert said. “ALL and CLL were logical targets in the initial studies, for a number of reasons. Time will tell whether CAR T cells will find other uses.” n Disclosure: Dr. Graubert reported no potential conflicts of interest.

no central nervous system involvement.3 About 75% were male, the median age was 55 years (range, 23–74 years), 32% were older than age 60, and 46% had minimal disease (< 5% blasts). Two-thirds of patients had two prior lines of therapy, 18% had three prior lines, and the remaining patients had more than three prior therapies. Of 27 patients evaluable for response, 24 had a complete response (89%), and 21 were minimal residual disease–negative (88%). The median time to complete remission was 22.5 days. Complete remission was maintained regardless of prior disease-risk characteristics. At a median follow-up of 6 months (range, 1–38 months), 12 patients remained disease-free (7 without subsequent stem cell transplant) for up to 1 year or more. Ten patients went on to stem cell transplant, and nine relapsed during follow-up. The median overall survival of all pa-

Inotuzumab Ozogamicin Plus Low-Intensity Chemotherapy: A Winner in Older Patients With Leukemia

tients is 8.5 months; at 6 months, 57% were alive. In patients who went on to allogeneic transplant, the median overall survival is 10.8 months; 6-month survival is 68%. In this study, experience regarding cytokine release syndrome and neurotoxicity was similar to that in the other two reports. n

Disclosure: Dr. Grupp is a consultant and has received research funding from Novartis. Dr. Lee reported no potential conflicts of interest. Dr. Park has received research funding from Juno Therapeutics.

References 1. Grupp SA, et al: 2014 ASH Annual Meeting. Abstract 380. Presented December 8, 2014. 2. Lee DW, et al: 2014 ASH Annual Meeting. Abstract 381. Presented December 8, 2014. 3. Park JH, et al: 2014 ASH Annual Meeting. Abstract 382. Presented December 8, 2014. Hematology

By Alice Goodman

notuzumab ozogamicin combined with a low-intensity chemotherapy called mini-hyper-CVD achieved highly encouraging results in older patients with acute lymphoblastic leukemia (ALL) in a phase II study reported at the 56th Annual Meeting of the American Society of Hematology.1 After the presentation, oncologists used words like “phenomenal” and “marvelous” to describe the results.

“This combination is safe and highly effective in newly diagnosed ALL in older patients. The overall response rate was 96%, the early mortality rate was very low, and the 1-year overall survival is 81%. Early results compare favorably with our previous experience using hyper-CVAD,” stated lead author Elias J abbour, MD, of The University of Texas MD Anderson Cancer Cen-

ter, Houston. “This combination may become a new standard for elderly patients with newly diagnosed ALL.”

Regimen Components Mini-hyper-CVD is a lower intensity regimen than conventional hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, Elias Jabbour, MD

continued on page 17

ASCOPost.com | FEBRUARY 10, 2015

PAGE 17

ASH Annual Meeting Inotuzumab Ozogamicin

Study Findings

continued from page 16

Previously reported with hyperCVAD, 1-year survival was 60%, and in this study, with low-intensity chemotherapy and inotuzumab ozogamicin, it was 81%, he said. Inotuzumab ozogamicin is a humanized monoclonal antibody that binds to CD22; is rapidly internalized; and delivers

methotrexate, and cytarabine). Cyclophosphamide and dexamethasone were given at a 50% dose reduction; methotrexate was given at a 75% dose reduction; and cytarabine was given at an 83% dose reduction. No anthracycline was included in the regimen. Inotuzumab ozogamicin was given on day 3 of the first four courses; rituximab (Rituxan) was given on days 2 and 8 for the first four courses for CD20positive patients; and intrathecal chemotherapy was given on days 2 and 8 to prevent CNS relapse.

calicheamicin, a potent cytotoxic agent that binds to DNA and causes doublestrand DNA breaks leading to apoptosis. This is the first study of inotuzumab ozogamicin in ALL patients over the age of 60. These patients typically have worse outcomes, primarily B:7.875” due to poor tolerance to intensive chemotherapy T:7.625” and inability to tolerate full doses of S:6.875”

chemotherapy due to comorbidities. A previous study by Dr. Jabbour and colleagues found that single-agent inotuzumab ozogamicin achieved an overall response rate of 58% and a median survival of 6.3 months in 89 heavily pretreated patients with relapsed ALL.2,3 The present study was designed to look continued on page 18

NOW APPROVED

EXPERT POINT OF VIEW

Yoav Messinger, MD

“T

hese are phenomenal results,” stated Yoav Messinger, MD, a pediatric oncologist at Children’s Hospital and Clinics of Minnesota, Minneapolis, and moderator of the session where these findings were presented. “We knew inotuzumab was coming, but we didn’t know how great it could be. We are very excited.” “The beauty of this is that we know immunotoxins work in ALL. Elderly patients have difficulty tolerating chemotherapy, so giving a gentler chemotherapy with an immunotoxin works,” he continued. “We hope that this drug will be approved by the U.S. Food and Drug Administration for ALL. It has a high chance of success in the treatment of adults with ALL. Pediatric oncologists would also like to have it in their armamentarium, especially for poor-risk patients with B-cell ALL.” Inotuzumab ozogamicin is much easier to administer than blinatumomab (Blincyto), another immunotherapy with encouraging results in ALL, and it has fewer side effects, Dr. Messinger said. n

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

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

The first approved PARP inhibitor LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. • In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/ musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort

FOR MORE INFORMATION VISIT www.LYNPARZA.com Please see next page for Important Safety Information. LYNPARZA is a trademark of the AstraZeneca group of companies. ©2014 AstraZeneca. All Rights Reserved. 3051313 Last updated 11/14

The ASCO Post | FEBRUARY 10, 2015

PAGE 18

ASH Annual Meeting Inotuzumab Ozogamicin continued from page 17

at the combination of inotuzumab ozogamicin with chemotherapy. Results of the phase II study were based on 28 evaluable patients enrolled between April 2012 and September 2014. Patients were at least 60 years of age with untreated Philadelphia chromosome–

negative, B-cell acute lymphoblastic leukemia. The median age was 69 years, and the oldest patient was 79 years old. At the time of the presentation, the overall response rate was 96%; 21 patients were in complete remission, and 5 were in complete remission with incomplete platelet recovery. No deaths were reported in the first 4 weeks of

treatment. Currently, Dr. Jabbour told The ASCO Post, 21 remain alive: 1 post allogeneic stem cell transplantation, 17 on maintenance therapy, and 3 receiving consolidation therapy. Complete cytogenetic response was 100% in 14 patients with an abnormal B:7.875” karyotype; all of theseT:7.625” patients achieved minimal residual diseaseS:6.875” by color flow cy-

tometry. Overall, 77% of patients tested negative for minimal residual disease at complete remission. The median time to platelet recovery was 23 days in cycle 1 and 22 days in subsequent courses of therapy. Grade 3 and 4 toxicities included infections during induction therapy in about 50% of patients; during consolidation therapy, grade 3 and 4 toxicities occurred

IMPORTANT SAFETY INFORMATION There are no contraindications for LYNPARZA. Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been conﬁrmed in 2% of patients enrolled in both a single arm monotherapy trial (6 out of 298) and a randomized placebo controlled trial (3 out of 136). Overall, MDS/AML were reported in <1% of patients (22 out of 2,618) treated with LYNPARZA. The majority of MDS/AML cases were fatal (17 out of 22) and the duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. Monitor complete blood count testing at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. Pneumonitis, including fatal cases, occurred in <1% of patients treated with LYNPARZA. In clinical studies the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Coadministration of drugs which are potent inhibitors or inducers of CYP3A could increase or decrease exposure to LYNPARZA and should be avoided. Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. LYNPARZA is Pregnancy Category D. LYNPARZA is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), moderate renal impairment or severe renal impairment, since safety and efﬁcacy have not been established. Please see adjacent Brief Summary of the full Prescribing Information. LYNPARZA is a trademark of the AstraZeneca group of companies. ©2014 AstraZeneca. All Rights Reserved. 3051313 Last updated 11/14

ASCOPost.com | FEBRUARY 10, 2015

PAGE 19

ASH Annual Meeting in about 75% of patients. One patient in complete remission developed grade 2 venous occlusive disease and was switched to hyper-CVD plus ofatumumab (Arzerra). At a median of 15 months, one death was reported in a patient with primary refractory disease. Two responding patients experienced a relapse and died, and two other patients in complete remission died.

Three patients are receiving consolidation therapy, and 17 are on POMP (mercaptopurine, methotrexate, vincristine, prednisone) maintenance. The median overall survival has not yet been reached. Oneyear median progression-free survival is 88%, and 1-year overall survival is 81%. n Disclosure: Dr. Jabbour has received research grants from Pfizer.

LYNPARZA (olaparib) capsules, for oral use Rx ONLY Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE LYNPARZA is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The indication is approved under accelerated approval based on objective response rate and duration of response [see Clinical Studies (14) in Full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Patient Selection Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/ companiondiagnostics. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Myelodysplastic syndrome/Acute Myeloid Leukemia Myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents. Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza. Pneumonitis Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza. Embryo-Fetal Toxicity Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations]. Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [see Use in Specific Populations].

References 1. Jabbour E, O’Brien S, Thomas DA, et al: Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) as frontline therapy for older patients (≥ 60 years) with acute lymphoblastic leukemia (ALL). ASH Annual Meeting. Abstract 794. Presented December 9, 2014. 2. Kantarjian H, Thomas D, Jorgensen

Table 1 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza Adverse Reaction

3 or more lines of prior chemotherapy Grades 3-4 Grades 1-4 N=223 N=223 % %

Blood and Lymphatic disorders Anemia Gastrointestinal disorders Abdominal pain/discomfort Decreased appetite Nausea Vomiting Diarrhea Dyspepsia General disorders Fatigue/asthenia Infections and infestations Nasopharyngitis/URI Musculoskeletal and Connective Tissue disorders Arthralgia/musculoskeletal pain Myalgia

43 22 64 43 31 25

8 1 3 4 1 0

21 22

0 0

Table 2 presents the frequency of abnormal laboratory ﬁndings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily. Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza

Laboratory Parameter*

3 or more lines of prior chemotherapy Grades 1-4 Grades 3-4 N=223 N=223 % % 90 15

Decrease in hemoglobin (anemia) Decrease in absolute neutrophil count 25 7 (neutropenia) Decrease in platelets (thrombocytopenia) 30 3 Decrease in lymphocytes (lymphopenia) 56 17 Mean corpuscular volume elevation 57 Increase in creatinine* 30 2 *Patients were allowed to enter clinical studies with laboratory values of CTCAE grade 1. The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.

• Pneumonitis [see Warnings and Precautions]

Table 3 presents adverse reactions reported in ≥20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCAmutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.

Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice.

Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.

ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions]

Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy. In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measurable disease) [see Clinical Studies] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.

J, et al: Inotuzumab ozogamicin, an antiCD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia. Lancet Oncol 13:403-411, 2012. 3. Kantarjian H, Thomas D, Jorgensen J, et al: Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 119:2728-2736, 2013.

The ASCO Post | FEBRUARY 10, 2015

PAGE 20

FDA Update

FDA Expands Approved Use of Ibrutinib for Waldenström’s Macroglobulinemia

he U.S. Food and Drug Administration (FDA) today expanded the approved use of ibrutinib (Imbruvica) for patients with Waldenström’s macroglobulinemia, a rare, indolent type of B-cell lymphoma. Ibrutinib is the first therapy indicated specifically

for Waldenström’s macroglobulinemia and previously received Breakthrough Therapy designation for this use. A type of non-Hodgkin lymphoma, Waldenström’s macroglobulinemia usually gets worse slowly over time and causes B lymphocytes to grow

Table 3 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Adverse Reactions

Lynparza N=53 Grades 1-4 %

Blood and Lymphatic disorders Anemia 25 Gastrointestinal disorders Abdominal pain/discomfort 47 Decreased appetite 25 Nausea 75 Vomiting 32 Diarrhea 28 Dyspepsia 25 Dysgeusia 21 General disorders Fatigue (including asthenia, 68 lethargy) Infections and infestations Nasopharyngitis/Pharyngitis/ 43 URI Musculoskeletal and Connective tissue disorders Arthralgia/Musculoskeletal 32 pain Myalgia 25 Back pain 25 Nervous system disorder Headache 25 Respiratory, Thoracic, Mediastinal disorders Cough 21 Skin and Subcutaneous Tissue Dermatitis/Rash 25

Placebo N=43

Pediatric Use The safety and efﬁcacy of Lynparza has not been established in pediatric patients.

Grades 3-4 %

Grades 1-4 %

Grades 3-4 %

Geriatric Use In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged ≥65 years. The safety proﬁle was similar irrespective of age with the exception of AEs of CTCAE ≥3 which were reported more frequently in patients aged ≥65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.

0 0 2 4 4 0 0

58 14 37 9 21 14 9

2 0 0 0 2 0 0

Females of Reproductive Potential Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Speciﬁc Populations]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.

2 6

12 21

0 0

Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial Laboratory parameter*

within the bone marrow, lymph nodes, liver, and spleen. The abnormal B cells also overproduce a protein known as immunoglobulin M or IgM (macroglobulin) that may lead to excess bleeding and problems with vision and the nervous system.

Lynparza N=53 Grades 1-4 Grades 3-4 % % 85 8

Placebo N=43 Grades 1-4 Grades 3-4 % % 58 2

Decrease in hemoglobin Decrease in absolute neutrophil 32 8 23 0 count Decrease in platelets 26 6 19 0 Mean corpuscular volume 85 44 elevation Increase in creatinine* 26 0 5 0 *Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]

Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy. Animal Data In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose). In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence. Nursing Mothers It is not known whether olaparib 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 olaparib, 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.

Ibrutinib works by blocking the Bruton’s tyrosine kinase that allows B cells in Waldenström’s macroglobulinemia to grow and divide. “Today’s approval highlights the importance of development of drugs for supplemental indications,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Continued research has discovered new uses of [ibrutinib].” The FDA initially granted ibrutinib accelerated approval in November 2013 for use in patients with mantle cell lymphoma who received one prior therapy. In February 2014, the FDA granted accelerated approval to ibrutinib for use in patients with previously treated chronic

Hepatic Impairment The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT ≥2.5 X ULN (≥5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology]. Renal Impairment Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [see Clinical Pharmacology]. OVERDOSAGE There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death. PATIENT COUNSELING INFORMATION SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE) Dosing Instructions Inform patients on how to take Lynparza [see Dosage and Administration]. Lynparza should be taken twice daily. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges. MDS/AML Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions. This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza [see Warnings and Precautions]. Pneumonitis Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing [see Warnings and Precautions]. Pregnancy and Females of Reproductive Potential Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least one month after receiving the last dose of Lynparza [see Warnings and Precautions and Use in Specific Populations]. Nursing Mothers Advise patients not to breastfeed while taking Lynparza [see Use in Special Populations]. Nausea/vomiting: Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

Manufactured for: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 By: Patheon Pharmaceuticals, Inc. Cincinnati, OH 45237 Issued: 12/2014 ©AstraZeneca 2014

3051313 last updated 12/14

lymphocytic leukemia (CLL), and then in July 2014, expanded its use to include initial treatment of CLL patients who carry a deletion in chromosome 17p.

Phase II Study The new approval was based on data from a phase II multicenter study of 63 previously treated patients with Waldenström’s macroglobulinemia. All study participants received a daily 420mg dose of ibrutinib until disease progression or side effects became intolerable. Results showed 62% of participants had their cancer shrink after treatment (overall response rate). Nearly 51% of patients achieved a partial response, and 11% achieved a very good partial response. No complete responses were reported. At the time of the study, the duration of response ranged from 2.8 months to approximately 18.8 months. The most common side effects associated with the drug are thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. Health-care professionals should inform patients of the risk for hemorrhage, infections, atrial fibrillation, second primary malignancies tumor lysis syndrome, and embryo-fetal toxicity associated with the use of ibrutinib. According to the National Cancer Institute, approximately 70,800 Americans were diagnosed and 18,990 died from non-Hodgkin lymphomas in 2014. n

ASCOPost.com | FEBRUARY 10, 2015

PAGE 21

American College of Surgeons Clinical Congress Gastrointestinal Oncology

Minimally Invasive Techniques Used to Address Small GIST Lesions By Caroline Helwick

urgeons at the cutting edge are offering minimally invasive resection to patients with small gastrointestinal stromal tumors (GISTs) deemed to be lowrisk, according to panelists at a session of the American College of Surgeons 2014 Clinical Congress in San Francisco. “We are seeing more small GISTs due to increased screening, and they will be amenable to hybrid resection [endoscopy/laparoscopy] or pure endoscopic resection,” said Lee L. Swanstrom, MD, FACS, Clinical Professor of Surgery at Oregon Health Sciences University and Director of GI and Minimally Invasive Surgery for Legacy Health System in Portland. Dr. Swanstrom is also Chief Innovations Officer at the IHU Stras-

Lee L. Swanstrom, MD, FACS

intervals can be considered, according to the guidelines of the National Comprehensive Cancer Network (NCCN). Surgery is indicated when GISTs increase in size or become symptomatic, he said. Field F. Willingham, MD, MPH, Director of Endoscopy and Assistant Professor of Medicine at Emory University School of Medicine, Atlanta, agreed that the patient with a submucosal mass < 2 cm and no suspicious features on endoscopic ultrasound can be considered for surveillance. “The NCCN has adopted this, and we think it’s a reasonable way to go for these small lesions,” he said. “We need to figure out who will progress,” Dr. Raut added. Radiology,

Chandrajit P. Raut, MD, MSc

bourg in Strasbourg, France. “Endoscopic resection is demanding, but it has been shown to be safe and feasible for the right indications. Improvements in flexible endoscopic tools will make such resections quicker and easier in the near future,” Dr. Swanstrom said.

Not All GISTs Require Resection Chandrajit P. Raut, MD, MSc, Associate Professor of Surgery at Harvard Medical School and Surgery Director of Sarcoma at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, noted that GISTs are “exceedingly common, but most are clinically irrelevant.” He said that about 5,000 GIST cases are diagnosed in the United States each year, but submucosal microscopic lesions (ie, those < 1 cm) occur more frequently. Submucosal microscopic GISTs have been identified in 35% of stomachs removed for gastric cancer and in more than 20% of autopsy specimens. “Certainly, they don’t all require surgery,” Dr. Raut noted. Among GISTs < 2 cm, resection is recommended for lesions that are symptomatic, ulcerated, and enlarging. For those < 2 cm without high-risk features—irregular borders, cystic spaces, ulceration, echogenic foci, and heterogeneity—endoscopic surveillance at 6- to 12-month

Field F. Willingham, MD, MPH

endoscopy, histopathology, and molecular diagnostics all have shortcomings in determining which small lesions are aggressive, he added. “Endoscopic biopsy using standard biopsy forceps is not usually helpful for submucosal tumors. Mitotic count can help identify which to resect but cannot be accurately assessed on endoscopic ultrasound–guided fine-needle aspiration specimens. Tumors < 2 cm vs those > 2 cm have an excess of wildtype cases, compared with known mutations, so they appear to be a different

The use of endoscopy for lower-risk tumors would be a great advantage over our standard approach, which is to remove a big portion of the stomach. If we can do this minimally invasively, as these speakers have described, and adhere to oncologic principles, this will optimize treatment. —David A. Kooby, MD

subpopulation with less proliferation potential,” Dr. Raut suggested.

Minimally Invasive Resections For small tumors that warrant resection, laparoscopic and endoscopic approaches are emerging, although they are still highly experimental in North America. Dr. Willingham described a “hybrid” technique that partners endoscopic with laparoscopic techniques and that succeeds in obtaining negative margins in GISTs not amenable to standard laparoscopic wedge resection. He and his colleagues at Emory developed this approach as part of their aim to offer a less invasive treatment to GIST patients. Dr. Willingham noted that standard GIST surgery can involve a major gastric resection, especially for lesions at the gastroesophageal junction and in the proximal cardia, which are difficult locations for wedge resection (Fig. 1). “This led us to think of ways we could work together [with surgeons] to offer less invasive therapy in this area, especially for small, nonaggressive tumors,” he said. Their technique, which they call a

Fig. 1: Retroflexed endoscopic view of a gastric submucosal gastrointestinal stromal tumor in the proximal cardia. Courtesy of Field F. Willingham, MD, MPH.

“push-pull endoscopic and laparoscopic full-thickness resection,” addresses the deep margins of the tumor in a minimally invasive way. In a study of four patients with challenging disease, they found that endoscopic resection alone was associated with a positive deep margin, but a negative margin was achieved after a laparoscopic, full-thickness resection that accompanied the endoscopy.1 “The advantages of this technique are that it is minimally invasive, does not require major organ resection, and provides a full-thickness resection of the involved deep margin,” he explained. Endoscopic submucosal dissection is another emerging minimally invasive approach to GIST. This procedure is still emerging in the United States but is in widespread use in Asia, where more than 50% of foregut digestive cancers are treated via flexible endoscopy rather than surgical resection, Dr. Swanstrom reported. He predicted that the trend will grow in the Western world as well. He cautioned that endoscopic resection of GISTs is only indicated for lesions that are small (< 5 cm), located in the esophagus or stomach, and demonstrate low-risk characteristics. “As our instrumentation in flexible endoscopy becomes more sophisticated, with better ways to control energy and with oncologic tools such as specimen retrieval sacs, we will see an expansion of endoscopic submucosal dissection,” Dr. Swanstrom predicted. “We no longer fear doing full-thickness resections in the gut, as we once did.” Dr. Raut added a note of caution. “Ultimately, GIST is a cancer, and oncologic principles trump whatever observational or operative approach we use. We need to do what’s most appropriate oncologically.” Dr. Raut does not advocate for a pure endoscopic excision, and continued on page 24

Introducing the first an FDA-approved treatme

patients with polycythemia ve inadequate response to or are In a phase 3 trial of Jakafi® (ruxolitinib) vs best available therapy: 21% of patients receiving Jakafi achieved the primary composite end point of hematocrit (Hct) control and spleen volume reduction compared with <1% of patients on best available therapy at week 32 (P < 0.0001)*

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly

Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk‐benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent

nd only ent for

era who have had an e intolerant of hydroxyurea

Visit www.jakafi.com/HCP illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non‐hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

to see Full Prescribing Information and learn more about Jakafi for use in PV

* A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both Hct control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value). Reference: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.

The ASCO Post | FEBRUARY 10, 2015

PAGE 24

American College of Surgeons Clinical Congress Small GIST Lesions continued from page 21

this is not routinely performed at his institution. Instead, he favors a laparoscopic or combined laparoendoscopic approach, which allows removal of the tumor with a margin of normal tissue. David A. Kooby, MD, Professor of Surgery, Emory University School of

Medicine, Atlanta, called the minimally invasive approaches to GIST, “innovative, wonderful stuff.” “Where we are now and where we will be in 5 to 10 years are very different. The use of endoscopy for lowerrisk tumors would be a great advantage over our standard approach, which is to remove a big portion of the stom-

ach,” Dr. Kooby noted. “If we can do this minimally invasively, as these speakers have described, and adhere to oncologic principles, this will optimize treatment.”n

Fractyl, and Apollo. Drs. Willingham, Raut, and Kooby reported no potential conflicts of interest.

Reference 1. Reynolds PT, et al: Hybrid push-pull endoscopic and laparoscopic full-thickness resection for the minimally invasive management of gastric gastrointestinal stromal tumors. Gastroenterology 146(5 suppl 1):S1051–S-1052, Abstract Su1847, 2014.

Disclosure: Dr. Swanstrom has received research and education support and/or consulted for Boston Scientific, Olympus, Aponos, Covidien, Cardica, Endogastric Solutions, Titan, Stryker,

Description of Selected AdverseAdverse Drug Reactions Anemia Anemia In the twoInPhase 3 clinical Description of Selected Drug Reactions the two Phase 3studies, clinicalmedian studies, median time to onset CTCAE Grade 2 orGrade higher2 anemia approximately 6 weeks. 6One patient discontinued timeoftofirst onset of first CTCAE or higherwas anemia was approximately weeks. One(<1%) patient (<1%) discontinued treatmenttreatment because of anemia.of Inanemia. patientsIn receiving Jakafi, mean decreases in hemoglobin reached areached nadir ofa nadir of because patients receiving Jakafi, mean decreases in hemoglobin approximately 1.5 to 2.01.5 g/dL below baseline 8 toafter 12 weeks therapyofand then and gradually recoveredrecovered to approximately to 2.0 g/dL below after baseline 8 to 12ofweeks therapy then gradually to reach a new steady thatstate was approximately 1.0 g/dL below baseline. This pattern observed in patientsin patients BRIEF SUMMARY: For Full Prescribing Information, see package reach a newstate steady that was approximately 1.0 g/dL below baseline. Thiswas pattern was observed BRIEF SUMMARY: For Full Prescribing Information, see insert. package insert. regardlessregardless of whether had they received transfusions during therapy. the randomized, placebo-controlled of they whether had received transfusions during In therapy. In the randomized, placebo-controlled CONTRAINDICATIONS None. None. CONTRAINDICATIONS of patients Jakafi 38%and of patients placebo received red bloodredcellblood cell study, 60% of treated patientswith treated withandJakafi 38% of receiving patients receiving placebo received WARNINGS AND PRECAUTIONS Thrombocytopenia, AnemiaAnemia and Neutropenia TreatmentTreatment with study, WARNINGS AND PRECAUTIONS Thrombocytopenia, and Neutropenia with 60% during randomized treatment.treatment. Among transfused patients, patients, the median units transfused during randomized Among transfused thenumber medianofnumber of units transfused Jakafi canJakafi causecanthrombocytopenia, anemia and neutropenia. [see Dosage Administration (2.1) in Full cause thrombocytopenia, anemia and neutropenia. [see and Dosage and Administration (2.1) transfusions in Full transfusions per monthperwas 1.2 inwas patients Jakafi andJakafi 1.7 inand placebo Thrombocytopenia In month 1.2 intreated patientswith treated with 1.7 intreated placebopatients. treated patients. Thrombocytopenia In Prescribing Information]. Manage thrombocytopenia by reducing the dose the or temporarily interrupting Jakafi. Jakafi. Prescribing Information]. Manage thrombocytopenia by reducing dose or temporarily interrupting two Phase 3 clinical patientsinwho developed Grade 3 orGrade 4 thrombocytopenia, the median to time to the two Phase 3studies, clinicalinstudies, patients who developed 3 or 4 thrombocytopenia, thetime median Platelet transfusions may be necessary [see Dosage Administration (2.1.1) and(2.1.1) Adverse (6.1) in Full(6.1)the Platelet transfusions may be necessary [seeand Dosage and Administration andReactions Adverse Reactions in Full approximately 8 weeks.8Thrombocytopenia was generally reversiblereversible with dosewith reduction or dose or dose was approximately weeks. Thrombocytopenia was generally dose reduction Prescribing Information]. Patients developing anemia may require transfusions and/or dose modifications of onsetofwasonset Prescribing Information]. Patients developing anemia mayblood require blood transfusions and/or dose modifications The median to recovery plateletofcounts 50above X 109/L50was Thetime median time to of recovery plateletabove counts X 10149/Ldays. was Platelet 14 days.transfusions Platelet transfusions Jakafi. Severe (ANC less(ANC thanless 0.5 than X 1090.5 /L) Xwas reversiblereversible by withholding Jakafi until Jakafi.neutropenia Severe neutropenia 109generally /L) was generally by withholding Jakafiinterruption. until interruption. to 5% oftopatients Jakafi and to 4% control regimens. were administered 5% of receiving patients receiving Jakafi andoftopatients 4% of receiving patients receiving control regimens. recovery [see Adverse (6.1)]. Perform pre-treatment completecomplete blood count (CBC) and(CBC) monitor recovery [seeReactions Adverse Reactions (6.1)].aPerform a pre-treatment blood count andCBCs monitorwere CBCsadministered Discontinuation of treatment because because of thrombocytopenia occurred occurred in <1% ofin patients Jakafi andJakafi and Discontinuation of treatment of thrombocytopenia <1% of receiving patients receiving every 2 toevery 4 weeks dosesuntil aredoses stabilized, and then and as clinically [see Dosage Administration 2 to 4until weeks are stabilized, then as indicated. clinically indicated. [seeand Dosage and Administration 9 9 9 <1% of patients control regimens. Patients with a platelet of 100 10100 /L toX200 10200 /L before <1% ofreceiving patients receiving control regimens. Patients with acount platelet countX of 10 /LX to X 109/L before (2.1.1) and Adverse (6.1) in Full Information]. Risk ofRisk Infection Serious bacterial, (2.1.1) and Reactions Adverse Reactions (6.1)Prescribing in Full Prescribing Information]. of Infection Serious bacterial, starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious 9 count greater 200than X 10200 /L (17% Neutropenia In the twoIn Phase clinical3studies, of 1% of countthan greater X 109versus /L (17%7%). versus 7%). Neutropenia the two3 Phase clinical 1% studies, infectionsinfections have resolved. Observe patients Jakafi forJakafi signs for andsigns symptoms of infection and manage have resolved. Observe receiving patients receiving and symptoms of infection and manage patients reduced stopped of neutropenia. Table 2 provides the frequency and severity patients or reduced or Jakafi stoppedbecause Jakafi because of neutropenia. Table 2 provides the frequency and ofseverity of promptly.promptly. Tuberculosis Tuberculosis infection infection has beenhas reported patientsin receiving Jakafi. Observe Tuberculosis Tuberculosis been in reported patients receiving Jakafi. patients Observe patients clinical hematology abnormalities reported for patients treatmenttreatment with Jakafiwith or placebo the placeboclinical hematology abnormalities reported forreceiving patients receiving Jakafi orinplacebo in the placeboreceiving receiving Jakafi forJakafi signs for andsigns symptoms of active of tuberculosis and manage Prior to initiating and symptoms active tuberculosis and promptly. manage promptly. Prior to Jakafi, initiating Jakafi, study. study. patients should evaluated for tuberculosis risk factors, thoseand at higher should testedbefortested latent forcontrolled patientsbeshould be evaluated for tuberculosis riskand factors, those atriskhigher riskbeshould latent controlled a a Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study infection. infection. Risk factors are notbutlimited prior residence in or travelintoorcountries with a highwith prevalence Riskinclude, factorsbut include, are notto,limited to, prior residence travel to countries a high prevalence Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study of tuberculosis, close contact a person activewith tuberculosis, and a history active or of tuberculosis, closewith contact with awith person active tuberculosis, and of a history of latent active tuberculosis or latent tuberculosis Jakafi Jakafi PlaceboPlacebo where anwhere adequate course ofcourse treatment cannot becannot confirmed. For patients evidence of active ofor active latent or latent an adequate of treatment be confirmed. For with patients with evidence (N=155)(N=155) (N=151)(N=151) tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision b b 3 Laboratory All Grades Grade Grade All 4Grades Grade 3 Grade Grade All Grades Grade 3 4 Grade All Grades 3 4 Grade 4 to continuetoJakafi during treatment of active tuberculosis should beshould based be on based the overall risk-benefit determination. continue Jakafi during treatment of active tuberculosis on the overall risk-benefit determination. Laboratory Parameter (%) Parameter (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) PML Progressive multifocalmultifocal leukoencephalopathy (PML) has(PML) occurred with ruxolitinib treatmenttreatment for myelofibrosis. PML Progressive leukoencephalopathy has occurred with ruxolitinib for myelofibrosis. If PML is Ifsuspected, stop Jakafistop andJakafi evaluate. Herpes Zoster Advise early signsearly andsigns symptoms of Thrombocytopenia PML is suspected, and evaluate. Herpes Zosterpatients Adviseabout patients about and symptoms of Thrombocytopenia 70 70 9 9 4 4 31 31 1 1 0 0 herpes zoster andzoster to seek as early asaspossible suspected [see Adverse (6.1)]. Symptom herpes andtreatment to seek treatment early asifpossible if suspected [seeReactions Adverse Reactions (6.1)]. Symptom Anemia Anemia 96 34 11 87 16 3 96 34 11 87 16 3 Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Exacerbation Following Interruption or Discontinuation of Treatment with Following Jakafi Following Neutropenia 19 discontinuation of Jakafi,ofsymptoms from myeloproliferative neoplasmsneoplasms may returnmay to pretreatment levels overlevels a over 19 5 5 2 2 4 4 <1 <1 1 1 discontinuation Jakafi, symptoms from myeloproliferative return to pretreatment a Neutropenia period ofperiod approximately one week.oneSome myelofibrosis have experienced one or more of the values arevalues worst Grade values regardless of baselineof baseline of approximately week.patients Some with patients with myelofibrosis have experienced one or more aofPresented the a Presented are worst Grade values regardless b following following adverse events discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ adverseafter events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ NationalbCancer Institute Criteria forCriteria AdverseforEvents, version 3.0version 3.0 National CancerCommon Institute Terminology Common Terminology Adverse Events, failure. If one or more afteroccur discontinuation of, or whileof,tapering dose of and for failure. If oneoforthese moreoccur of these after discontinuation or whilethe tapering theJakafi, dose ofevaluate Jakafi, for evaluate and Additional Additional Data from thefrom Placebo-controlled Study 25% of patients Jakafiwith andJakafi 7% ofand patients Data the Placebo-controlled Study 25% oftreated patientswith treated 7% of patients treat any treat intercurrent illness andillness consider restartingrestarting or increasing the dose the of Jakafi. to treated any intercurrent and consider or increasing dose ofInstruct Jakafi.patients Instruct not patients not to with placebo newly occurring or worsening Grade 1 abnormalities in alanineintransaminase treated with developed placebo developed newly occurring or worsening Grade 1 abnormalities alanine transaminase interrupt interrupt or discontinue Jakafi therapy their physician. When discontinuing or interrupting or discontinue Jakafi without therapyconsulting without consulting their physician. When discontinuing or interrupting (ALT). The(ALT). incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no 3 and no The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade therapy with Jakafiwith forJakafi reasons thanother thrombocytopenia or neutropenia [see Dosage Administration (2.5) Grade therapy forother reasons than thrombocytopenia or neutropenia [seeand Dosage and Administration (2.5)4 ALT elevations. 17% of patients Jakafi andJakafi 6% ofand patients placebo Grade 4 ALT elevations. 17% oftreated patientswith treated with 6% oftreated patientswith treated withdeveloped placebo developed in Full Prescribing Information], consider tapering dose of rather thanrather discontinuing abruptly. abruptly. in Full Prescribing Information], considerthe tapering theJakafi dose gradually of Jakafi gradually than discontinuing newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The(AST). incidence of Grade 2of Grade 2 newly occurring or worsening Grade 1 abnormalities in aspartate transaminase The incidence Non-Melanoma Skin Cancer Non-melanoma skin cancers basal cell,basal squamous cell, and Merkel Non-Melanoma Skin Cancer Non-melanoma skinincluding cancers including cell, squamous cell, and Merkel AST elevations was <1%was for Jakafi with no Grade 3 orGrade 4 AST3 elevations. 17% of patients Jakafi andJakafi and AST elevations <1% for Jakafi with no or 4 AST elevations. 17% oftreated patientswith treated with cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. <1% of patients placebo newly occurring or worsening Grade 1 elevations in cholesterol. <1% oftreated patientswith treated withdeveloped placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail inThe other incidence of Grade 2ofcholesterol elevationselevations was <1%was for Jakafi with no Grade 3 orGrade 4 cholesterol elevations.elevations. The incidence Grade 2 cholesterol <1% for Jakafi with no 3 or 4 cholesterol sections ofsections the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] Clinical of the •labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] Clinical Trial Experience in Polycythemia Vera In aVera randomized, open-label, active-controlled study, study, Trial Experience in Polycythemia In a randomized, open-label, active-controlled • Risk of•Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation FollowingFollowing Interruption or 110 or Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Interruption patients polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi andJakafi 111 patients 110 with patients with polycythemia vera resistant to or intolerant of hydroxyurea received and 111 patients Discontinuation of Treatment with Jakafiwith [seeJakafi Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer Discontinuation of Treatment [see Warnings and Precautions (5.3)] • Non-Melanoma Skin[see Cancer [see best received available therapy [see Clinical in Full Information]. The mostThe frequent received best available therapy [seeStudies Clinical(14.2) Studies (14.2)Prescribing in Full Prescribing Information]. most frequent WarningsWarnings and Precautions (5.4)]. Because are trials conducted under widely adverse adverse and Precautions (5.4)]. clinical Becausetrials clinical are conducted undervarying widelyconditions, varying conditions, adverse drug reaction anemia. 3 presents the most the frequent treatmenttreatment emergentemergent adverse drug was reaction was Table anemia. Table 3 presents most non-hematologic frequent non-hematologic reaction rates observed in the clinical of atrials drug ofcannot directlybecompared to rates intothe clinical of trials reaction rates observed in thetrials clinical a drugbecannot directly compared rates in thetrials clinical of adverse events up to Week Discontinuation for adverse of causality, was adverseoccurring events occurring up to32.Week 32. Discontinuation for events, adverseregardless events, regardless of causality, was another drug anddrug mayand not may reflectnotthereflect ratestheobserved in practice. ClinicalClinical Trials Experience in observed another rates observed in practice. Trials Experience in observed in 4% of patients Jakafi. in 4% oftreated patientswith treated with Jakafi. Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration Table 3: Polycythemia Vera: Treatment EmergentEmergent Adverse Adverse Events Occurring in ≥ 6% ofinPatients on Table 3: Polycythemia Vera: Treatment Events Occurring ≥ 6% of Patients on of follow-up of 10.9 months, 301 patients myelofibrosis in two Phase 3 studies. these two Phasetwo 3 Phase of follow-up of 10.9including months, including 301with patients with myelofibrosis in two Phase 3Instudies. In these Jakafi3 inJakafi the Open-Label, Active-controlled Study upStudy to Week 32Week of Randomized Treatment in the Open-Label, Active-controlled up to 32 of Randomized Treatment studies, patients a median exposure to Jakafi of months 0.5(range to 17 0.5 months), with 89%with 89% studies,had patients had aduration medianofduration of exposure to 9.5 Jakafi of 9.5(range months to 17 months), Jakafi Jakafi Best Available TherapyTherapy Best Available of patientsoftreated more than 6 months 25% and treated more than 12 months. hundred elevenand eleven patientsfortreated for more than 6and months 25%fortreated for more than 12 One months. One and hundred (N=110)(N=110) (N=111)(N=111) (111) patients at 15 mgattwice dailytwice and daily 190 patients 20 mgattwice daily. In patients (111)started patientstreatment started treatment 15 mg and 190started patientsatstarted 20 mg twice daily. In patients 9 a 9 mg twice starting treatment with 15 mg dailytwice (pretreatment platelet counts 100 to of200 /L) and Events Events All Grades (%) aGrade (%) 3-4All (%) 3-4 (%) starting treatment withtwice 15 mg daily (pretreatment plateletofcounts 100X 10 to 200 X 1020 /L) and 20 mg Adverse twice Adverse All Grades (%) 3-4 Grade (%)Grades All (%) GradesGrade (%) 3-4 Grade daily (pretreatment platelet counts 200 than X 109200 /L), 65% 25% and of patients, required arequired daily (pretreatment plateletgreater countsthan greater X 109and /L), 65% 25% of respectively, patients, respectively, a Headache 16 <1 19 <1 Headache 16 <1 19 <1 dose reduction below thebelow starting within thewithin first 8the weeks therapy.ofIntherapy. a double-blind, randomized, placebo- placebodose reduction thedose starting dose firstof8 weeks In a double-blind, randomized, b b Abdominal Pain 15 <1 15 <1 Abdominal Pain 15 <1 15 <1 controlledcontrolled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia Table[see 2 ].Table Thrombocytopenia, anemia and neutropenia are dose related DiarrheaDiarrhea 15 0 7 <1 were thrombocytopenia and[see anemia 2 ]. Thrombocytopenia, anemia and neutropenia are dose related 15 0 7 <1 effects. The three most frequent adverse reactions were bruising, and headache [see Dizziness c effects. The three most non-hematologic frequent non-hematologic adverse reactions were dizziness bruising, dizziness and headache [see Dizziness c 15 0 13 0 15 0 13 0 Table 1]. Table Discontinuation for adverse of causality, was observed in 11% ofinpatients 1]. Discontinuation forevents, adverseregardless events, regardless of causality, was observed 11% oftreated patientswith treated with Fatigue Fatigue 15 0 15 3 0 15 3 15 Jakafi andJakafi 11% and of patients placebo. 1 presents most common adverse reactions occurringoccurring 11% oftreated patientswith treated with Table placebo. Table 1 the presents the most common adverse reactions in patientsinwho received in the double-blind, placebo-controlled study during randomized treatment.treatment. Pruritus Pruritus 14 <1 23 4 patients who Jakafi received Jakafi in the double-blind, placebo-controlled study during randomized 14 <1 23 4 Table 1: Myelofibrosis: Adverse Adverse ReactionsReactions OccurringOccurring in Patients on JakafioninJakafi the Double-blind, Table 1: Myelofibrosis: in Patients in the Double-blind, Dyspnead 13 3 4 0 Dyspnead 13 3 4 0 Placebo-controlled Study During Randomized Treatment Placebo-controlled Study During Randomized Treatment Muscle Spasms 12 <1 5 0 Muscle Spasms 12 <1 5 0 Jakafi Jakafi PlaceboPlacebo Nasopharyngitis 9 0 8 0 (N=155)(N=155) (N=151)(N=151) Nasopharyngitis 9 0 8 0 a 8 0 3 0 Constipation 8 0 3 0 Gradea 3 Grade Grade All Grades Grade 3 Grade Grade AdverseAdverse Reactions All Grades 3 4 Grade 4 All Grades 3 4 GradeConstipation 4 Reactions All Grades (%) 8 0 5 0 (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)Cough Cough 8 0 5 0 BruisingbBruisingb

c c DizzinessDizziness Headache Headache

18 15

d Urinary Tract Infections Urinary Tract Infections9d

a b

c d

e f

23 <1 18 <1

<1 0 <1 0

0 15 0 7

15 0 7 0

0 0 0 0

0Edema Edemae 0ArthralgiaArthralgia

15 0 9 0

0 0 0 0 <1 0

0 5 0 5 0 1

5 0 5 <1 1 <1

0 0 <1 <1 <1 0

0AstheniaAsthenia <1EpistaxisEpistaxis f 0Herpes Zoster Herpes Zosterf

0 0 0 0

0 <1 0 <1

<1 0 <1 0

0 0 0 0

6 0 4 0 0Nausea Nausea 6 0 4 Institute Criteria forCriteria AdverseforEvents (CTCAE), 3.0version 3.0 0a NationalaCancer National CancerCommon Institute Terminology Common Terminology Adverse Eventsversion (CTCAE),

e Weight Gain Weight Gaine

Flatulence Flatulence f Herpes Zoster Herpes Zosterf

7 <1 5 0

2 0

includesbabdominal pain, abdominal pain lower,pain andlower, abdominal pain upperpain upper includes abdominal pain, abdominal and abdominal NationalaCancer Institute Criteria forCriteria AdverseforEvents (CTCAE), 3.0version 3.0 National CancerCommon Institute Terminology Common Terminology Adverse Eventsversion (CTCAE), c cdizziness and vertigo includes includes dizziness and vertigo includesb contusion, ecchymosis, hematoma,hematoma, injection site hematoma, periorbitalperiorbital hematoma,hematoma, vessel puncture site d site includes contusion, ecchymosis, injection site hematoma, vessel puncture includesddyspnea dyspnea includesand dyspnea andexertional dyspnea exertional hematoma,hematoma, increased increased tendency to bruise, petechiae, purpura purpura tendency to bruise, petechiae, e includeseedema andedema peripheral edema edema includes and peripheral includescdizziness, postural dizziness, vertigo, balance Disease, labyrinthitis includes dizziness, postural dizziness, vertigo,disorder, balanceMeniere’s disorder, Meniere’s Disease, labyrinthitis f includesf herpes zoster andzoster post-herpetic neuralgia neuralgia includes herpes and post-herpetic includesdurinary tract infection, urosepsis, urinary tract infection infection, bacteria includes urinary tractcystitis, infection, cystitis, urosepsis, urinary tractbacterial, infectionkidney bacterial, kidneypyuria, infection, pyuria,urine, bacteria urine, Other clinically importantimportant treatmenttreatment emergentemergent adverse events in less than 6% than of patients bacteria urine identified, nitrite urinenitrite present Other clinically adverseobserved events observed in less 6% of patients bacteria urine identified, urine present treated with Jakafi Weight hypertension, and urinary infections includeseweight increased, abnormal weight gainweight gain treated withwere: Jakafi were:gain, Weight gain, hypertension, andtract urinary tract infections includes weight increased, abnormal ClinicallyClinically relevant laboratory abnormalities are shown Table 4. includesf herpes zoster andzoster post-herpetic neuralgia neuralgia relevant laboratory abnormalities areinshown in Table 4. includes herpes and post-herpetic b

ASCOPost.com | FEBRUARY 10, 2015

PAGE 25

Announcements

FDA Appoints Robert Califf, MD, Deputy Commissioner for Medical Products and Tobacco

.S. Food and Drug Administration (FDA) Commissioner Margaret A. Hamburg, MD, has appointed Robert Califf, MD, as the FDA Deputy Commissioner for Medi-

cal Products and Tobacco. Dr. Califf is a leader in cardiology, clinical research, and medical economics, who is currently serving as Vice Chancellor of Clinical and Translational Research

at Duke University in Durham, North Carolina. Dr. Califf will provide executive leadership to the Center for Drug Evaluation and Research, the Cen-

9 9 50 X 10950 Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled /L and X 10150 /L, Xa dose is recommended. A dose reduction is also is also count between X 10150 Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlledcount between /L and 109/L,reduction a dose reduction is recommended. A dose reduction a Study upStudy to Week 32Week of Randomized Treatment recommended for patients polycythemia vera and vera hepatic [see Dosage Administration up to 32 of Randomized Treatmenta recommended for with patients with polycythemia andimpairment hepatic impairment [seeand Dosage and Administration (2.4) in Full Prescribing Information]. (2.4) in Full Prescribing Information]. Jakafi Jakafi Best Available TherapyTherapy Best Available OVERDOSAGE There is no known overdoses with Jakafi. doses up doses to 200upmgtohave beenhave been OVERDOSAGE There is noantidote knownfor antidote for overdoses withSingle Jakafi. Single 200 mg (N=110)(N=110) (N=111)(N=111) given withgiven acceptable acute tolerability. Higher than recommended repeat doses aredoses associated with increased with acceptable acute tolerability. Higher than recommended repeat are associated with increased b b 3 Laboratory Grade Grade All Grades Grade 3 Grade Grade including including leukopenia, anemia and thrombocytopenia. Appropriate supportivesupportive treatmenttreatment Laboratory All Grades All Grades Grade 3 4 Grade 4 All Grades 3 4 Grademyelosuppression 4 myelosuppression leukopenia, anemia and thrombocytopenia. Appropriate Parameter (%) given. be Hemodialysis is not expected to enhance elimination of ruxolitinib. Parameter (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)should beshould given. Hemodialysis is not expected to the enhance the elimination of ruxolitinib. Hematology Hematology

Anemia Anemia

72 <1 27 5

<1 <1 5 <1

<1 58 <1 24

58 0 24 3

0 <1

<1 10

10 <1

Hypercholesterolemia 35 Hypercholesterolemia ElevatedElevated ALT 25 ALT

35 0 25 <1

ElevatedElevated AST AST 23 Hypertriglyceridemia Hypertriglyceridemia15

23 0 15 0

0 0 <1 0 0 0

0 16 0 23

8 0 16 0 23 <1

0 13

13 0

Thrombocytopenia Thrombocytopenia 27 Neutropenia 3 Neutropenia Chemistry Chemistry

a b

3 <1 <1 0

<1 0 0 0

a values are worst Grade values regardless of baseline Presented Presented values are worst Grade values regardless of baseline NationalbCancer Institute Criteria forCriteria AdverseforEvents, version 3.0version 3.0 National CancerCommon Institute Terminology Common Terminology Adverse Events,

DRUG INTERACTIONS Drugs That Inhibit Induce Cytochrome P450 Enzymes RuxolitinibRuxolitinib DRUG INTERACTIONS Drugs That or Inhibit or Induce Cytochrome P450 Enzymes is metabolized by CYP3A4byand to a lesser by extent CYP2C9. The Cmax and is metabolized CYP3A4 and toextent a lesser by CYP3A4 CYP2C9. inhibitors: CYP3A4 inhibitors: TheAUC Cmax ofandruxolitinib AUC of ruxolitinib increasedincreased 33% and33% 91%,and respectively following following concomitant administration with the strong 91%, respectively concomitant administration with theCYP3A4 strong inhibitor CYP3A4 inhibitor ketoconazole in healthyinsubjects. Concomitant administration with mildwith or moderate CYP3A4 inhibitors did not did not ketoconazole healthy subjects. Concomitant administration mild or moderate CYP3A4 inhibitors result in result an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong consider dose reduction [see Dosage Information]. When administering Jakafi withCYP3A4 strong inhibitors, CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Information]. Fluconazole: The AUC The of ruxolitinib is predicted to and Administration (2.3)Prescribing in Full Prescribing Information]. Fluconazole: AUC of ruxolitinib is predicted to increase increase by approximately 100% to 100% 300% tofollowing concomitant administration with the combined CYP3A4 CYP3A4 by approximately 300% following concomitant administration with the combined and CYP2C9 at doses ofat 100 mgofto100 400mg mgtoonce respectively [see Pharmacokinetics andinhibitor CYP2C9fluconazole inhibitor fluconazole doses 400 daily, mg once daily, respectively [see Pharmacokinetics (12.3) in (12.3) Full Prescribing Information]. Avoid theAvoid concomitant use of Jakafi with fluconazole doses of doses greaterof greater in Full Prescribing Information]. the concomitant use of Jakafi with fluconazole than 200than mg daily [seedaily Dosage Administration (2.3) in Full Information]. CYP3A4 inducers: 200 mg [seeand Dosage and Administration (2.3)Prescribing in Full Prescribing Information]. CYP3A4 inducers: The Cmax The and CAUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration max and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong healthyinsubjects. No dose adjustment is recommended; however,however, with theCYP3A4 stronginducer CYP3A4rifampin inducer inrifampin healthy subjects. No dose adjustment is recommended; monitor patients and adjustandtheadjust Jakafithedose based safetyonandsafety efficacy Pharmacokinetics monitor frequently patients frequently Jakafi doseonbased and [see efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. (12.3) in Full Prescribing Information]. USE IN USE SPECIFIC POPULATIONS Pregnancy Pregnancy CategoryCategory C: Risk Summary There areThere are IN SPECIFIC POPULATIONS Pregnancy Pregnancy C: Risk Summary no adequate and well-controlled studies ofstudies Jakafi inof pregnant women. Inwomen. embryofetal toxicity studies, no adequate and well-controlled Jakafi in pregnant In embryofetal toxicitytreatment studies, treatment with ruxolitinib resulted inresulted an increase late resorptions and reduced weights maternally toxic doses. with ruxolitinib in an in increase in late resorptions and fetal reduced fetalatweights at maternally toxic doses. Jakafi should used during only if theonly potential benefit justifies potential risk to theriskfetus. Jakafibeshould be usedpregnancy during pregnancy if the potential benefit the justifies the potential to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits theduring periodthe of period organogenesis, Animal Data Ruxolitinib was administered orally to pregnant rats orduring rabbits of organogenesis, at doses of 30ofor15, 60 30 mg/kg/day in rats andin 10, 60 30 mg/kg/day in rabbits.inThere wasThere no evidence of at 15, doses or 60 mg/kg/day rats30 andor10, or 60 mg/kg/day rabbits. was no evidence of teratogenicity. However,However, decreasesdecreases of approximately 9% in fetal9%weights noted in rats at intherats highest teratogenicity. of approximately in fetalwere weights were noted at theand highest and maternallymaternally toxic dosetoxic of 60dose mg/kg/day. This doseThis results an exposure (AUC) that(AUC) is approximately 2 times the of 60 mg/kg/day. dosein results in an exposure that is approximately 2 times the clinical exposure at the maximum recommended dose of 25dose mgoftwice daily. In rabbits, fetallower weights clinical exposure at the maximum recommended 25 mg twice daily. Inlower rabbits, fetalofweights of approximately 8% and increased late resorptions were noted the highest maternally toxic dosetoxic of dose of approximately 8% and increased late resorptions wereat noted at theand highest and maternally 60 mg/kg/day. This doseThis is approximately 7% the clinical at the maximum recommended dose. In adose. In a 60 mg/kg/day. dose is approximately 7% theexposure clinical exposure at the maximum recommended pre- and post-natal development study in rats, animals were dosed with ruxolitinib from implantation pre- and post-natal development studypregnant in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation doses up to 30 mg/kg/day. There were no drug-related adverse findings pups forinfertility through at lactation at doses up to 30 mg/kg/day. There were no drug-related adverseinfindings pups for fertility indices orindices for maternal or embryofetal survival, growth and development parameters at the highest or for maternal or embryofetal survival, growth and development parameters at the dose highest dose evaluatedevaluated (34% the(34% clinicaltheexposure at the maximum recommended dose of 25 mgoftwice daily). Nursing clinical exposure at the maximum recommended dose 25 mg twice daily). Nursing MothersMothers It is not known is excretedis in humaninmilk. Ruxolitinib and/or itsand/or metabolites were were It is notwhether knownruxolitinib whether ruxolitinib excreted human milk. Ruxolitinib its metabolites excreted in the milkinofthelactating with arats concentration that was 13-fold maternal plasma. Because excreted milk of rats lactating with a concentration that wasthe 13-fold the maternal plasma. many Because many drugs aredrugs excreted humaninmilk and because the potential seriousforadverse in nursingininfants are in excreted human milk and of because of the for potential seriousreactions adverse reactions nursing infants from Jakafi, decisiona should made be to discontinue nursing ornursing to discontinue the drug, the taking intotaking account froma Jakafi, decisionbeshould made to discontinue or to discontinue drug, into account the importance of the drug mother. Use TheUse safetyThe andsafety effectiveness of Jakafi of in pediatric the importance of to thethe drug to thePediatric mother. Pediatric and effectiveness Jakafi in pediatric patients have not have been not established. GeriatricGeriatric Use Of the myelofibrosis patients inpatients clinicalin clinical patients been established. Usetotal Of number the totalofnumber of myelofibrosis studies with Jakafi, were52% 65 years of age andof older. Noolder. overallNodifferences in safety in or safety effectiveness of studies with52% Jakafi, were 65 years age and overall differences or effectiveness of Jakafi were observed between between these patients younger Renal Impairment The safetyTheandsafety and Jakafi were observed these and patients and patients. younger patients. Renal Impairment pharmacokinetics of single dose Jakafi (25Jakafi mg) were evaluated in a studyininahealthy 72-164 pharmacokinetics of single dose (25 mg) were evaluated study insubjects healthy[CrCl subjects [CrClmL/min 72-164 mL/min (N=8)] and in subjects mildwith [CrClmild 53-83 mL/min [CrCl 38-57 mL/min severeor severe (N=8)] and in with subjects [CrCl 53-83(N=8)], mL/minmoderate (N=8)], moderate [CrCl 38-57(N=8)], mL/minor(N=8)], renal impairment [CrCl 15-51 (8) Eight additional subjects subjects with endwith stageendrenal disease renal impairment [CrClmL/min 15-51 (N=8)]. mL/min Eight (N=8)]. (8) additional stage renal disease requiring requiring hemodialysis were alsowere enrolled. The pharmacokinetics of ruxolitinib was similar subjects hemodialysis also enrolled. The pharmacokinetics of ruxolitinib wasinsimilar in with subjects with various degrees renal impairment and in those normal function. However,However, plasma AUC values various ofdegrees of renal impairment andwith in those withrenal normal renal function. plasma AUCof values of ruxolitinibruxolitinib metabolites increasedincreased with increasing severity ofseverity renal impairment. This was This mostwas marked the in the metabolites with increasing of renal impairment. mostinmarked subjects with end with stageend renal disease hemodialysis. The change the pharmacodynamic marker, marker, subjects stage renalrequiring disease requiring hemodialysis. Theinchange in the pharmacodynamic pSTAT3 inhibition, was consistent with the corresponding increase increase in metabolite exposure.exposure. RuxolitinibRuxolitinib is not is not pSTAT3 inhibition, was consistent with the corresponding in metabolite removed removed by dialysis; the removal some active metabolites by dialysisbycannot ruled out. Whenout. When by however, dialysis; however, the ofremoval of some active metabolites dialysisbecannot be ruled administering Jakafi toJakafi patients myelofibrosis and moderate (CrCl 30-59 or severeorrenal administering to with patients with myelofibrosis and moderate (CrClmL/min) 30-59 mL/min) severe renal 9 X 109/L, a dose impairment (CrCl 15-29 mL/min) a platelet between X 109/L50and 150 is impairment (CrCl 15-29 with mL/min) with acount platelet count 50 between X 10 /L and 150 X 109/L,reduction a dose reduction is recommended. A dose reduction is also recommended for patients polycythemia vera and vera moderate recommended. A dose reduction is also recommended for with patients with polycythemia and moderate (CrCl 30-59 or severeorrenal impairment (CrCl 15-29 In all patients end with stageend renal (CrClmL/min) 30-59 mL/min) severe renal impairment (CrClmL/min). 15-29 mL/min). In all with patients stage renal disease ondisease dialysis, dose reduction is recommended [see Dosage Administration (2.4) in Full Prescribing onadialysis, a dose reduction is recommended [seeand Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluatedevaluated in a studyin ina healthy (N=8) and(N=8) in subjects with mildwith [Child-Pugh A (N=8)],Amoderate study insubjects healthy subjects and in subjects mild [Child-Pugh (N=8)], moderate [Child-Pugh B (N=8)],Bor(N=8)], severeorhepatic [Child-Pugh C (N=8)].CThe meanThe AUCmean for ruxolitinib was [Child-Pugh severeimpairment hepatic impairment [Child-Pugh (N=8)]. AUC for ruxolitinib was increasedincreased by 87%, 28% and 28% 65%,and respectively, in patientsinwith mild,with moderate and severe by 87%, 65%, respectively, patients mild, moderate andhepatic severeimpairment hepatic impairment comparedcompared to patientstowith normal The terminal half-life was prolonged in patientsin patients patients withhepatic normalfunction. hepatic function. Theelimination terminal elimination half-life was prolonged with hepatic comparedcompared to healthytocontrols versus hours). change the in the withimpairment hepatic impairment healthy (4.1-5.0 controls hours (4.1-5.0 hours2.8versus 2.8The hours). Theinchange pharmacodynamic marker, pSTAT3 was consistent with the corresponding increase increase in ruxolitinib pharmacodynamic marker, inhibition, pSTAT3 inhibition, was consistent with the corresponding in ruxolitinib exposureexposure except in except the severe C) hepaticC)impairment cohort where thewhere pharmacodynamic activity activity in the(Child-Pugh severe (Child-Pugh hepatic impairment cohort the pharmacodynamic was morewas prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to Jakafi patientsto with myelofibrosis and any degree hepaticofimpairment and with and a platelet administering patients with myelofibrosis and anyofdegree hepatic impairment with a platelet

Jakafi is aJakafi registered trademarktrademark of Incyte. of AllIncyte. rights reserved. is a registered All rights reserved. U.S. PatentU.S. Nos. 7598257; 8415362;8415362; 8722693;8722693; 8822481;8822481; 8829013 8829013 Patent Nos. 7598257; © 2011-2014 Incyte Corporation. All rights reserved. © 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428 Issued: December 2014 RUX-1428

Robert Califf, MD

ter for Biologics Evaluation and Research, the Center for Devices and Radiological Health, and the Center for Tobacco Products. He will also oversee the Office of Special Medical Programs in the Office of the Commissioner. Dr. Califf will play a critical role in providing high-level advice and policy direction on the agency’s medical product and tobacco priorities, and he will manage clinical, scientific and regulatory initiatives in several key areas for the agency, including personalized medicine, orphan drugs, pediatric science, and the advisory committee system. “I am delighted to announce this important addition to the FDA’s senior leadership team,” said Dr. Hamburg. “Dr. Califf ’s deep knowledge and experience in the areas of medicine and clinical research will enable the agency to capitalize on, and improve upon, the significant advances we’ve made in medical product development and regulation over the past few years.”

Landmark Clinical Studies In addition to his current position at Duke University, Dr. Califf has served in other prominent roles during his tenure at Duke, including Director of the Duke Translational Medicine Institute (DTMI) and Professor of Medicine in the Division of Cardiology at the Duke University Medical Center. Before serving as Director of DTMI, he was the Founding Director of the Duke Clinical Research Institute. During his career, Dr. Califf has led many landmark clinical studies and is a widely recognized expert in cardiovascular medicine, health outcomes research, health-care quality, and clinical research. He is a leader in the field of translational research, which is key to ensuring that advances in science translate into medical care. Dr. Califf will join the FDA in late February 2015. n

The ASCO Post | FEBRUARY 10, 2015

PAGE 26

In the Clinic Hematology

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

n December 4, 2014, ruxolitinib ( Jakafi) was approved for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.1,2 Ruxolitinib was initially approved in November 2011 for treatment of patients with intermediate-risk or highrisk myelofibrosis.

Supporting Trial Approval was based on findings in an open-label phase III trial in which 222 patients with polycythemia vera resistant to hydroxyurea or who could not tolerate hydroxyurea were randomly assigned to receive oral ruxolitinib at a starting dose of 10 mg twice daily (n = 110) or best available care (n = 112). The ruxolitinib dose could be increased to 25 mg twice daily. Patients had to require phlebotomy, had to have splenomegaly, and had to have hematocrit control between 40% and 45% prior to randomization.

OF NOTE Ruxolitinib carries warnings/precautions for thrombocytopenia, anemia, neutropenia, infection, and risk of nonmelanoma skin cancer.

Patients ranged in age from 33 to 90 years (30% > 65 years), and 66% were male. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (Vercyte) (2%), lenalidomide (Revlimid)/thalidomide (Thalomid) (5%), and observation (15%).

Ruxolitinib was superior to best available therapy in achieving the composite endpoint of durable hematocrit control (absence of phlebotomy eligibility beginning at week 8 and maintained thereafter) and spleen volume reduction (≥ 35% reduction) at week 32 (21% vs 1%, P < .0001) and at week 48 (19% vs 1%, P < .0001). Complete hematologic remission at week 32 was achieved in 24% vs 9% (P = .0034). At week 32, 60% vs 20% of patients had hematocrit control and 38% vs < 1% had spleen volume reduction ≥ 35%.

How It Works Ruxolitinib inhibits Janus kinases ( JAKs) JAK1 and JAK2, which mediate signaling of cytokines and growth factors involved in hematopoiesis and immune function. JAK signaling involves

vere renal impairment, and those with hepatic impairment. Doses may be titrated based on safety and efficacy evaluations. Complete blood counts and platelet counts must be performed before starting therapy,

OF NOTE Ruxolitinib inhibits JAK1 and JAK2, which, when dysregulated, are associated with polycythemia vera.

every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Serious infections should have resolved before ruxolitinib treatment is started. Detailed recommendations for dose modifications and interruptions based on hemoglobin, platelet count, and neutrophil count are provided in prod-

Expanded Indication for Ruxolitinib ■■ Ruxolitinib (Jakafi) has been approved for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. ■■ The recommended starting dose of ruxolitinib in polycythemia vera is 10 mg twice daily.

recruitment of STATs to cytokine receptors and activation and localization of STATs to the nucleus, leading to modulation of gene expression. Polycythemia vera is associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2-mutant myeloproliferative neoplasms, ruxolitinib prevented splenomegaly, preferentially decreased JAK2 mutant cells in the spleen, and decreased circulating inflammatory cytokines.

How It Is Given The recommended starting dose of ruxolitinib in polycythemia vera is 10 mg twice daily. The starting dose is 5 mg twice daily in patients taking strong CYP3A4 inhibitors (eg, ritonavir, idinavir, clarithromycin, ketoconazole, itraconazole), those with moderate to se-

uct labeling. In patients with insufficient response who have adequate platelet, hemoglobin, and neutrophil counts, doses may be increased in increments of 5 mg twice daily to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks. In patients restarting ruxolitinib after treatment interruption, except interruption due to phlebotomy-associated anemia, doses may be increased to a maximum total daily dose not exceeding 5 mg less than the dose resulting in interruption.

Safety Profile The most common hematologic adverse events of any grade in the ruxolitinib group in the phase III trial were

More on Rare Cancers See pages 87-89

anemia (72%, including < 1% grade 3 and < 1% grade 4, vs 58% in the control group, with no grade 3 or 4 events) and thrombocytopenia (27%, including 5% grade 3 and < 1% grade 4, vs 24%, including 3% grade 3 and < 1% grade 4). The most common nonhematologic adverse events of any grade were headache (16% vs 19%), abdominal pain (15% vs 15%), diarrhea (15% vs 7%), dizziness (15% vs 13%), and fatigue (15% vs 15%). The only grade 3 or 4 adverse event occurring in > 1% of ruxolitinib patients was dyspnea (3% vs 0%). Ruxolitinib treatment was discontinued due to adverse events in 4% of patients. Ruxolitinib carries warnings/precautions for thrombocytopenia, anemia, and neutropenia; infection; symptom exacerbation following treatment interruption or discontinuation; and risk of nonmelanoma skin cancer. n References 1. U.S. Food and Drug Administration: Ruxolitinib. Available at www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm425732.htm. Accessed December 23, 2014. 2. Jakafi® (ruxolitinib) tablets prescribing information, Incyte Corporation, December 2014. Available at www. incyte.com/sites/default/files/Jakafi_ PI.pdf?time=20141215104415. Accessed December 23, 2014.

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

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

In appropriate patients with advanced melanoma

KEYTRUDA:

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

11%% 23 23%%

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

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

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

KEYTRUDA responded KEYTRUDA provided provided ongoing responses in patients who responded

86%

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

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

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

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

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

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

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

Pregnancy: Pregnancy Category D.

Adverse Reaction

KEYTRUDA: All Grades (%)

Grade 3* (%)

ANTI–PD-1 EFFICACY

TO HELP FIGHT TUMORS

All Grades (%)

Grades 3–4 (%)

SELECTED SAFETY INFORMATION

on the adjacent pages.

The Merck Access Program for KEYTRUDA for Injection Visit

merckaccessprogram-keytruda.com OR

Call

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

• Ask to be contacted by a field reimbursement associate.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 27

State of the Art Genitourinary Oncology

Treating Bladder Cancer in 2015 A Conversation With Derek Raghavan, MD, PhD, FACP, FRACP, FASCO By Ronald Piana

reatment of advanced bladder cancer continues to prove challenging, and therapies that offer long-term survival remain elusive. The ASCO Post recently spoke with Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, President of the Levine Cancer Center, Charlotte, North Carolina, about the current state of bladder cancer treatment and what the future clinical picture might look like in this persistently difficult disease.

Next Generation of Inquiry Immunotherapy is having a renaissance of sorts. Please talk about the role of immunotherapy in bladder cancer. Bladder cancer is a very interesting disease in that for more than 40 years, we’ve known that immunology is intimately involved in how bladder cancer grows and regresses. In the 1970s, Drs. Paul Lange and Catherine Limas did some elegant studies showing that the prognosis of noninvasive bladder cancer—or what used to be called superficial bladder cancer—was associated with the elaboration of blood group antigens on the surface of the bladder cancer cells. In the 1980s, Dr. Alvaro Morales and others postulated that you could stimulate the immunity of the mucosa of the bladder to help reject tumor cells. It was found that in noninvasive bladder cancer, administering intravesical bacillus Calmette-Guérin (BCG) would delay tumor recurrence, and some studies suggested that BCG actually improves survival. As we gained more knowledge, we saw that the ABO blood group determinants were expressed in bladder cancer, and the heavy presence of those substances correlated with a good prognosis. Although we thought that the more favorable prognosis had something to do with the differentiation of the tumor cells, we also realized that it easily could have been produced by an immunologic reaction.

With the passage of time, it became clear that mutations in a number of genes such as RAS and TP53 were associated with different types of bladder cancer. So, when you put this together, it indicates that immunologic function could play an important role in the defense against bladder cancer. As we fast-forward to the present, we have identified PD-L1 (programmed cell death ligand 1), which puts the brake on T-cell function, and therefore an anti–PD-L1 would release the brake. PD-L1 is expressed heavily in lung cancer, and researchers are looking at a whole series of PD-L1 activations that might stimu-

More Sophisticated Diagnostic Technologies The diagnosis of bladder cancer has relied on cystoscopy and brush biopsy. Is our ability to evaluate bladder cancer moving forward with the advent of more sophisticated technologies? Yes. Some years ago, flexible cystoscopy replaced rigid cystoscopy, which was the first important step in moving our diagnostics ahead. Flexible cystography allows a much better view of the whole bladder. Subsequently, we developed the technique of random biopsy, understanding that the changes that beget urothelial carcinoma represent a field effect in the disease. For instance, you might discover a

The standard of care for deeply invasive bladder cancer should remain neoadjuvant chemotherapy with MVAC. Adjuvant chemotherapy, with any regimen, remains unproven, with only modestly improved survival trends despite decades of study. —Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

late an immune response that would reject lung cancer. We also know that PD-L1 is heavily expressed in urothelial malignancy, which gives a basis for some immunotherapy trials in invasive and metastatic bladder cancers. Early studies in PD-L1 in bladder cancer that were presented at the 2014 ASCO Annual Meeting were interesting, but they need to be validated. I certainly see immunotherapy as a promising next generation of inquiry. Although chemotherapy has been a mainstay of treatment for metastatic disease for decades, there have not been major improvements since the development of the MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) and GC (gemcitabine/cisplatin) regimens, so it is time for a new approach.

tumor on the left ureteric orifice, but if you multisite biopsy, you might discover other patches of carcinoma in situ or noninvasive disease. In addition, the flexible cystoscopy can be done as an office procedure and used with the patient under anesthesia to biopsy unique sites. Moreover, we now know that the whole urothelium is at risk, so with flexible cystoscopy, we look at the prostatic urethra and the ureters. In terms of technologic advances, there’s a new type of fluorescence cystoscopy that uses light to identify mossy patches on the mucosal lining of the bladder, which frequently connotes a tumor site. Another recent advance is narrow-band imaging cystoscopy, in which light of specific blue and green wavelengths is used to enhance the detail of certain aspects of the surface of the mucosa.

Finally, we now have an array of antibody tests that measure antigens released from noninvasive bladder cancers. They come as antibody kits, which allow you to look at gene expression or protein expression, reasoning that the urine is a concentrated soup that could reflect anything sitting in the bladder. This new era of antigen tests is improving the sensitivity and specificity of diagnostic tests.

Adjuvant Chemotherapy Adjuvant chemotherapy is standard treatment in breast, colon, and prostate cancers. What is the role of adjuvant chemotherapy in bladder cancer following cystectomy? There have been myriad trials in this area over the past 20 years. Unfortunately, many of the trials were flawed in their design, being underpowered or having early stopping rules and using disease-free survival instead of overall survival as the endpoint. If you give any type of adjuvant therapy that works, by definition you have to improve disease-free survival, simply because you’ve dropped the tumor load. And in breast and colon cancers, the results show that overall survival at all time points is statistically better with adjuvant therapy. Unfortunately, all the bladder cancer trials have a statistically significant increment in progression-free survival and a trend in terms of overall survival, but we don’t know what would have happened, because they all closed too early, had design flaws, or had inadequate powering. The biggest study was done by the European Organisation for Research and Treatment of Cancer, which was a randomized trial of adjuvant MVAC or GC or high-dose MVAC vs observation after cystectomy for invasive bladder cancer. Unfortunately, the trial closed after years of insufficient accrual. As predicted, because MVAC and continued on page 28

The ASCO Post | FEBRUARY 10, 2015

PAGE 28

State of the Art Derek Raghavan, MD, PhD, FACP, FRACP, FASCO continued from page 27

GC work in bladder cancer, there was a statistically significant improvement in disease-free survival, but overall survival was seen as just a nonsignificant trend toward improved outcome. The other problem was that the impact was seen in locally extensive tumors without node involvement, suggesting that suboptimal surgery may have been a contributing factor.

‘Slow to Adopt Neoadjuvant Chemotherapy’ Please discuss the role of neoadjuvant chemotherapy in bladder cancer. There has been a clinically relevant, statistically significant increase in survival from the use of neoadjuvant chemotherapy. Dr. Mark Soloway and I published the first two neoadjuvant single-agent cisplatin trials back in 1984, and we presented the data the next year at the ASCO Annual Meeting.1 The results looked way better than anything we’d seen before, so neoadjuvant chemotherapy was studied in a randomized phase III trial. Although the trial did not show an increment in survival, we found that all the patients had done better. After looking more deeply into this finding, we realized our neoadjuvant studies were conducted at the time that computed tomography was introduced

into routine clinical practice for bladder cancer. Therefore, in our phase II studies, we’d inadvertently ruled out patients who had hitherto undetected abdominal nodal metastases, so, of course, the results were better. That said, there was no survival increment from singleagent cisplatin. Subsequently, we designed an international randomized trial looking at the CMV (cisplatin/methotrexate/vinblastine) regimen followed by cystectomy or radiotherapy. We wanted to see a 10% survival increment, and in the first trial, we had a 6% increment, so we didn’t meet the requirement; therefore, it was published as a negative study. However, the long-term follow-up showed a statistically significant improvement in outcome.2 Later on in the United States, we showed a median 3-year increase in survival and a 7% increase in cure rate in a Southwest Oncology Group trial. The results were published in The New England Journal of Medicine,3 and it should have been a practice-changing paper, but subsequent reports indicated that the urology community had been very slow to adopt neoadjuvant therapy. However, the urology community is now embracing the use of neoadjuvant chemotherapy with greater frequency.

‘Game-Changer in Surgery’ What surgical advances have increased outcomes for bladder cancer patients?

The original surgical approach was radical cystectomy, which meant excising the bladder and lymph nodes and leaving the patient with an external bag to collect urine. The real game-changer in surgery has been a technique called the Kock Pouch, developed by Dr. Nils Koch and colleagues. The Pouch is an internal vessel into which the ureters drain under the skin of the abdomen, so the patient would be catheterized several times a day. Naturally, not having to walk around with an external plastic bag full of urine markedly improves one’s quality of life. The next advance was doing a cystectomy with reconstruction, in which the surgeon took bowel tissue and turned it inside out, creating an artificial bladder that could contain urine. The first iteration required a catheter, but later iterations allowed patients to pass urine naturally.

Final Thoughts Please share some closing thoughts on the treatment of bladder cancer with the readers. I think it’s important to note that the neoadjuvant story illustrates the phenomenon of stage migration, which showed that effectively used chemotherapy does alter the natural history in both metastatic and invasive disease. However, it has left us with a conundrum: If it works in neoadjuvant chemotherapy, why not

in adjuvant therapy? And this conundrum tells us that we need to put more emphasis in designing better, well-powered studies. It’s fitting to close by mentioning the development of the MVAC regimen by the late Dr. Alan Yagoda, which was truly practice-changing. The standard of care for deeply invasive bladder cancer should remain neoadjuvant chemotherapy with MVAC, which has been validated in well-powered clinical trials. As mentioned, adjuvant chemotherapy, with any regimen, remains unproven, with only modestly improved survival trends despite decades of study. n

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

References 1. Raghavan D, Pearson B, Duval P, et al: Initial intravenous cisplatinum therapy: Improved management for invasive high-risk bladder cancer? J Urol 133:399402, 1985. 2. Griffiths G, Hall R, Sylvester R, et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial. J Clin Oncol 29:21712177, 2011. 3. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003.

Announcements

University of Pittsburgh Appoints Director of Stem Cell Transplantation

arren Shlomchik, MD, has been named Director of Stem

Warren Shlomchik, MD

Cell Transplantation and Cell Therapies for the University of Pittsburgh’s Division of Hematology-Oncology and the University of Pittsburgh Cancer Institute (UPCI). His appointment is effective March 1, 2015. He also will serve as UPCI’s Scientific Director of Hematopoietic Malignancies, as well as Professor of Medicine and ImEdward Chu, MD munology at the University of

Pittsburgh School of Medicine. Dr. Shlomchik previously served on the senior faculty at Yale Cancer Center at the Yale University School of Medicine.

Immunology Research Dr. Shlomchik’s research has focused on the immunologic mechanisms underlying graft-vs-host disease (GVHD). “Dr. Shlomchik’s work has been invaluable in helping researchers under-

stand more about the mechanisms of GVHD,” said Edward Chu, MD, Chief of the Division of Hematology/Oncology and Deputy Director of UPCI. “His main priorities will be to continue to conduct innovative, groundbreaking laboratory-based science and to oversee the translation of that science into investigator-initiated clinical trials, which will be a huge advance for our transplant and hematopoietic malignancies clinical research program.” n

ASCOPost.com | FEBRUARY 10, 2015

PAGE 31

Journal Spotlight Genitourinary Oncology

Novel Genomic Signature Predicts Postcystectomy Recurrence in High-Risk Bladder Cancer By Matthew Stenger

s reported in the Journal of the National Cancer Institute, Anirban P. Mitra, MD, PhD, of the University of Southern California, and colleagues identified a novel genome-based signature that improves prediction of postcystectomy recurrence in patients with highrisk bladder cancer.1 Use of the signature could help to guide selection of patients for adjuvant therapy in this setting. Dr. Mitra is the corresponding author for the Journal of the National Cancer Institute article. Siamak Daneshmand, MD, of the University of Southern California, and Peter C. Black, MD, of the University of British Columbia, contributed equally to the work.

Study Details This study involved a generation of transcriptome-wide expression profiles using 1.4 million feature arrays on archival tumors from 225 patients with muscle-invasive or node-positive bladder cancer who had undergone radical cystectomy. Genomic classifiers and clinicopathologic classifiers for predicting tumor recurrence were developed in a discovery set (n = 133). The predictive performances of genomic classifiers, clinicopathologic classifiers (individual features and an optimized prognostic model developed in the discovery set including age, gender, pathologic stage, and lymphovascular invasion status), the independent clinical nomogram of the International Bladder Cancer Nomogram Consortium, and combined genomic-clinicopathologic classifiers were assessed in the discovery and independent validation (n = 66) sets. In the discovery set, patients had a median age of 68.5 years (interquartile range = 63.6–75.6 years), median follow-up was 9.3 years, 51% of patients had tumor recurrence, and 58% of patients had died at last follow-up. In the validation set, median age was 69.8 years (interquartile range = 63.1–74.3 years), median follow-up was 10.8 years, 50% of patients had tumor recurrence, and 68% of patients had died at last follow-up.

Genomic Markers In the discovery set, 15 genomic markers were identified, corresponding to RNAs from genome regions that were differentially expressed in tumor

recurrence. Associated genes included those involved in cell proliferation/cellcycle regulation/apoptosis, cell differentiation, transcription regulation, and signaling pathways and transduction (FOXO6, HSD17B7, ARID4B, ENAH, MAP4K3, MARCH7, MECOM, LRBA, MUT, CRCP, SYPL1, ARFGEF1, EHF, METTL7A, and PPP1R12A).

Findings in the Discovery Set In the discovery set, area under the standard receiver-operating characteristic curve values were 0.88 for the genomic classifiers compared with 0.70 for nodal status, 0.69 for lymphovascular invasion, 0.58 for tumor stage, 0.53 for age, 0.47 for gender, 0.73 for International Bladder Cancer Nomogram Consortium,

was the best predictor of tumor recurrence (hazard ratio [HR] = 1.42, P = .005); other significant predictors were nodal status (P = .017), lymphovascular invasion (P = .045), and interaction of the genomic signature and nodal status (P = .03), whereas age, gender, race, tumor stage, and receipt of adjuvant therapy were not independent predictors. Multivariate analysis of the predictive models showed an independent predictive effect when the genomic signature was added to the International Bladder Cancer Nomogram Consortium model (HR = 1.18, P = .016) compared with the International Bladder Cancer Nomogram Consortium model alone (HR = 1.04, P = .62) and when the genomic signature was added to the clinicopatho-

The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This [novel genomic signature] may be used to better identify patients who need more aggressive management. —Anirban P. Mitra, MD, PhD, and colleagues

0.89 for genomic–International Bladder Cancer Nomogram Consortium, 0.81 for the clinicopathologic model, and 0.93 for genomic-clinical classifiers.

Predictive Ability in the Validation Set In the validation set, the genomic signature had a survival receiver-operating characteristic curve value of 0.77, higher than the values for the individual clinical parameters of nodal status (0.71), lymphovascular invasion (0.68), tumor stage (0.57), age (0.50), and gender (0.44) and similar to those for the International Bladder Cancer Nomogram Consortium (0.73) and the clinicopathologic model (0.78). The survival receiver-operating characteristic curve value was increased with the addition of the genomic signature to both the International Bladder Cancer Nomogram Consortium (0.82) and the clinicopathologic model (0.86). On multivariate analysis adjusting for demographic, clinicopathologic, and treatment factors, the genomic signature

logic model (HR = 1.18, P = .008) compared with the clinicopathologic model alone (HR = 1.10, P = .30).

Reclassification and Decision-Curve Analyses An analysis in the validation set categorizing patients as high-risk or low-risk based on genomic-clinicopathologic scoring and adjusting for competing risks showed a 4-year probability of tumor recurrence of 81.5% vs 20.6% (P < .001). Further, addition of the genomic signature to the International Bladder Cancer Nomogram Consortium model reclassified 18 patients into different risk categories, with 12 (67%) correctly reclassified based on outcome. The genomic-clinicopathologic model reclassified 12 patients from initial International Bladder Cancer Nomogram Consortium risk categories, with 10 (83%) correctly reclassified. Decision-curve analysis for decision to treat based on the specificity and sensitivity of predictive models at different thresholds of probability for

postcystectomy recurrence showed a greater overall benefit for genomebased classifiers. Thus, for example, for a 50% threshold probability of postcystectomy recurrence, compared with “treat none” and “treat all” options, the genomic–International Bladder Cancer Nomogram Consortium model resulted in a reduction in unnecessary treatment (ie, in low-risk patients) by 27%, compared with 17% for the International Bladder Cancer Nomogram Consortium model alone, and the genomic-clinicopathologic model resulted in a reduction in overtreatment in 28%, compared with 20% for the clinicopathologic model alone.

External Validation In the validation cohort, the genomic signature showed better survival predictive ability (survival receiver-operating characteristic curve value = 0.77) than seven other previously reported genomic signatures for muscle-invasive or nodepositive disease (receiver-operating characteristic curve values = 0.51–0.72). Finally, the genomic signature was validated in four additional external bladder urothelial carcinoma data sets (n = 341). For overall survival (all four data sets), hazard ratios ranged from 2.26 to 7.57, with P values of .016 to < .001 and concordance indices of 0.65 to 0.80. For cancer-specific survival (one dataset), the hazard ratio was 2.23, P = .001, and the concordance index was 0.65. For recurrence-free survival (one dataset), the hazard ratio was 3.33, P < .001, and the concordance index was 0.67. The investigators concluded: “The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This [novel genomic signature] may be used to better identify patients who need more aggressive management.” n

Disclosure: This study was supported by Genome British Columbia. For full disclosures of the study authors, visit jnci.oxfordjournals.org.

Reference 1. Mitra AP, Lam LL, Ghadessi M, et al: Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer. J Natl Cancer Inst 106(11):dju290, 2014. See commentary by Cora N. Sternberg, MD, FACP, on page 32.

The ASCO Post | FEBRUARY 10, 2015

PAGE 32

Perspective

Molecular Classification Predicts Postcystectomy Recurrence in High-Risk Bladder Cancer By Cora N. Sternberg, MD, FACP

adical cystectomy is the standard therapeutic option for patients with muscle-invasive bladder cancer. However, 5-year overall survival for high-risk patients with pT3, pT4, pN-negative, and pN-positive M0 bladder cancer after radical cystectomy is only about 50% and ranges from 32% in patients with lymph node involvement to 75% in those without lymph node involvement. Optimal removal of adequate numbers of pelvic lymph nodes is fundamental.1 Recurrence is mainly due to systemic occult disease that was present at the time of cystectomy. Neoadjuvant or adjuvant systemic chemotherapy has been recommended in this setting for patients at high risk of recurrence based mainly upon clinical and pathologic features. There is more level 1 evidence from meta-analyses for the use of neoadjuvant than adjuvant chemotherapy, but in most countries, immediate cystectomy is usually the preferred option.2 Identifying those patients who would derive the most benefit from these therapies is of utmost importance. As reviewed in this issue of The ASCO Post, Mitra and colleagues have reported identification of a genomic signature that predicts postcystectomy recurrence in high-risk patients.3 This study was performed at the University of Southern California in collaboration with a molecular diagnostics company. Two-thirds of the patients were allocated to a discovery set, and one-third was placed in the validation set. Patients underwent radical cystectomy and lymph node dissection at the same university hospital between 1998 and 2004, and all patients had a minimum of 2 years of follow-up. In the discovery set of 141 patients, Dr. Sternberg is Chief of Medical Oncology at San Camillo-Forlanini Hospital in Rome, Italy.

54 patients (41%) received adjuvant chemotherapy as per physician and patient preference, as did 34 (52%) of the 66 patients in the internal validation set. The clinical endpoint for discovery was recurrence-free survival, defined as the time from cystectomy to local recurrence or recurrence at distant soft-tissue sites.

Genomic Classifier Helps Predict Recurrence Formalin-fixed paraffin-embedded cystectomy specimens were evaluated for histopathology, RNA extraction, and gene-expression profiling. The investigators iden-

The prognostic ability of the genomic classifier was compared with two clinical nomograms for predicting risk of recurrence: that of the International Bladder Cancer Nomogram Consortium (IBCNC) and the investigators’ own clinical classifier, which included age, gender, pathologic stage, and lymphovascular invasion. Their work suggested that combining the genomic classifier with the clinical and pathologic classifiers was best at predicting relapse-free survival, outperforming the clinical nomograms. Validation of the genomic classifier was also performed on 341 patients from 4 external datasets obtained

The data from Mitra and colleagues are of great interest if they can differentiate those patients who are really at high risk and require treatment while avoiding chemotherapy for those patients at low risk for relapse. —Cora N. Sternberg, MD, FACP

tified a novel 15-marker gene-expression signature, a genomic classifier, which when added to clinical and pathologic prognostic features could help to predict high- and low-risk patients for recurrence following radical cystectomy. The genomic classifier is composed of biologically important RNA sequences that are involved in cell proliferation and differentiation, apoptosis, cellcycle and transcriptional regulation, and signal transduction. All of these processes are associated with tumor development and progression. Four of the transcripts within the genomic classifier had been previously described.

through The Cancer Genome Atlas and the National Center for Biotechnology Information–Gene Expression Omnibus. The patients received consistent surgical management at the same center, but adjuvant chemotherapy was given on an individual basis. Adjuvant chemotherapy trials have been fraught with difficulties in accrual, and results have been inconsistent as to which patients benefit. Recent meta-analyses seemed to suggest an advantage with adjuvant chemotherapy, but the patient population to benefit still requires further c larification.4,5 The data from Mitra and colleagues are of great interest if they can differ-

entiate those patients who are really at high risk and require treatment while avoiding chemotherapy for those patients at low risk for relapse. The fact that this test can be performed on paraffin-embedded tissue renders it practical. Since this signature was determined in a single institution, where surgical treatment was consistent, with many patients receiving adjuvant chemotherapy, further prospective validation on a multi-institutional basis is warranted. n

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

References 1. Yafi FA, Aprikian AG, Chin JL, et al: Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: A Canadian multicentre experience. BJU Int 108:539-545, 2010. 2. Sternberg CN, Bellmunt J, Sonpavde G, et al: ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for urothelial carcinoma-neoadjuvant and adjuvant settings. Eur Urol 63:58-66, 2013. 3. Mitra AP, Lam LL, Ghadessi M, et al: Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer. J Natl Cancer Inst 106(11):dju290, 2014. 4. Leow JJ, Martin-Doyle W, Rajagopal PS, et al: Adjuvant chemotherapy for invasive bladder cancer: A 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 66:42-54, 2014. 5. Sternberg CN, Skoneczna I, Kerst JM, et al: Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): An intergroup, openlabel, randomised phase 3 trial. Lancet Oncol. December 11, 2014 (early release online).

Visit The ASCO Post website at ASCOPost.com

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%). The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%). Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions. To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)]. 5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. 5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. 5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. 5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. 5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent. In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination. Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness. Gastrointestinal Disorders: Stomatitis, pancreatitis. General Disorders and Administration Site Conditions: Asthenia. Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular. Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma. Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension. Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. 7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)]. Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight. MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)]. Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals. 8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients. Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)]. Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)]. MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal. TAFINLAR is a registered trademark of GlaxoSmithKline. MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

ASCOPost.com | FEBRUARY 10, 2015

PAGE 41

Direct From ASCO

Cornerstone Spotlight: Frank M. Muller, Jr

rank M. Muller, Jr, the newest member of the Conquer Cancer Foundation (CCF) Cornerstone Planned Giving Society, has a 40-year history of successfully leading investment and high-tech corporations. He served 8 years on active duty in tours to Vietnam. It is rare for him to experience a challenge that cannot be overcome with hard work and perseverance. Yet,

cancer was a much more lethal foe. When his wife was diagnosed, he traveled as far as China and Korea, searching for a cure. He was told that the best care could be received much closer to their home in Galveston, Texas. Sharon underwent most of her treatment at The University of Texas MD Anderson Cancer Center. Despite receiving excellent care, Sharon succumbed to her disease

A person who has the experience of finality with cancer should attempt to direct his or her dollars to those organizations that are thrifty and focused on funding quality, innovative, state-of-the-art research…. I believe that CCF and ASCO have that as a mantra. —Frank M. Muller, Jr

Mr. Muller encountered such a challenge when his beloved wife Sharon was diagnosed with pancreatic cancer in 2011.

A Life-Changing Experience This was not the first time Mr. Muller had been impacted by cancer. His father developed prostate cancer in his 70s, followed by leukemia that took his life 10 years later. Mr. Muller knew that pancreatic

11 months after she was diagnosed. The loss was incalculable. “Sharon was the happiest person I ever knew,” he reflected. “She was exuberant and a loving mother and fantastic soul mate.” The experience for Mr. Muller was life-changing. “I probably spend an hour a day on the Internet, looking at every article written on pancreatic cancer,” he said. It has led Mr. Muller, who is president of a medical technology/

high technology investment company, to new business ventures. “I recently acquired a company owned by a doctor in Germany who is researching stem cells, wound healing, and pancreatic cancer using embryonic stem cells,” he shared.

Investing in the Next Generation of Cancer Research Nora Janjan, MD, MBA, MPSA, FASCO, suggested Mr. Muller contact ASCO. At the time, Dr. Janjan was a member of the Conquer Cancer Foundation Board of Directors. “Dr. Janjan introduced me to key people at ASCO and CCF, and in 2013 I made my first trip to ASCO headquarters. Since then I’ve made more trips to visit the Foundation to help in any way I can. I was impressed that nearly 87% of dollars raised go toward research and other programs,” he shared. As an entrepreneur, Mr. Muller was also impressed that CCF invests in developing the next generation of cancer researchers. “I think the focus

should be on giving research dollars to younger researchers who can think out of the box and still believe they can do anything,” he said. “They are more passionate about thinking in different ways. This is true in business as well. That resonated with me a great deal.” By joining Cornerstone, Mr. Muller is helping to build a strong future for cancer research. “A person who has the experience of finality with cancer should attempt to direct his or her dollars to those organizations that are thrifty and focused on funding quality, innovative, state-of-the-art research,” he remarked. “I believe that CCF and ASCO have that as a mantra…as long as CCF and ASCO continue to spend 87% on programs and research, they will be premier organizations.” For information about Cornerstone, please visit www.conquercancerfoundation.org/cornerstone. n © 2015. American Society of Clinical Oncology. All rights reserved.

Five Organizations Awarded 2015 International Innovation Grants to Improve Cancer Care in Low- and Middle-Income Countries

he Conquer Cancer Foundation of ASCO has announced the five recipients of the 2015 International Innovation Grant. This grant supports novel and innovative projects that may improve diagnosis, prevention, and treatment of cancer in low- and middle-income countries. For 2015, the 1-year grants of up to $20,000 will support projects in India, Mexico, Nigeria,

Romania, and Uganda. Roughly two-thirds of cancer deaths occur in low- and middle-income countries, where 5-year survival rates are lower than in high-income countries.1 By reducing barriers to cancer control, these projects have the potential to reduce the cancer burden in the communities where the grantees live and work, as well as in other low-

The development of novel, resource-appropriate, sustainable, and transferrable programs aimed at improving cancer control in low- and middle-[income countries] is the mission of the Conquer Cancer Foundation International Innovation Grants. —Matthew D. Galsky, MD

or middle-income settings. “The development of novel, resource-appropriate, sustainable, and transferrable programs aimed at improving cancer control in low- and middle-[income countries] is the mission of the Conquer Cancer Foundation International Innovation Grants. The research studies proposed by the five awardees are perfect exemplars of this mission,” said International Innovation Grant Subcommittee Chair Matthew D. Galsky, MD. The recipients of the 2015 Conquer Cancer Foundation of ASCO International Innovation Grants are: • College of Medicine, University of Ibadan (Nigeria) Principal Investigator: Olutosin Alaba Awolude, MBBS, MS Cervical cancer screening techniques like visual inspection with acetic acid are often not accessible

to patients in developing countries such as Nigeria due to a shortage of trained nurses and midwives, especially in hard-to-reach communities. Based on the success of HIV programs in Africa, Dr. Awolude will implement community-level intervention strategies to recruit and train local health providers to prevent, detect, and treat cervical cancer. • Uganda Cancer Institute/Fred Hutchinson Cancer Research Center Clinic and Training Institute (Uganda) Principal Investigator: Noleb Mugume Mugisha, MPH, MBChB Dr. Mugisha will conduct a 9-month pilot study to test the impact and acceptability of an integrated screening program on identifying earlystage invasive cervical cancer in a high-volume HIV clinic in Kampala, continued on page 42

The ASCO Post | FEBRUARY 10, 2015

PAGE 42

Direct From ASCO

ASCO Names Advance of the Year, Reviews Top Research Trends

n just a year’s time, four new therapies have been approved for patients with chronic lymphocytic leukemia (CLL), treatments that are highly effective and far easier for patients to tolerate. These therapies are a major step forward, bringing renewed hope to nearly 120,000 people living with CLL in the United States. This standout achievement—the transformation of treatment for CLL—is ASCO’s Advance of the Year.

Big Gains in the Treatment of CLL: Targeted and Immunotherapies Patients whose cancer becomes resistant to or relapses after standard CLL treatments have thus far had very limited options. But new, targeted

International Innovation Grants continued from page 41

Uganda. By coordinating efforts between traditionally siloed HIV and cancer care programs, this innovative study will evaluate the success of offering cervical cancer screening services in HIV clinics overseen by cancer specialists. • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Mexico) Principal Investigator: Yanin ChávarriGuerra, MD, MSc Mexican women with breast cancer present at more advanced stages than those in developed countries due to delays in diagnosis and poor

This year’s Clinical Cancer Advances report continues its emphasis on the unique and vital role of federally

funded research in advancing progress against cancer.1 In the United States, cancer research is critically dependent on federal funding, which supports research that the private sector typically does not pursue. Roughly one-third of the advances featured in the 2015 report were supported in whole or in part by federal research dollars. Among the most significant are: • Adding generic chemotherapy to standard advanced prostate cancer treatment yields one of the biggest survival gains ever seen in this disease • Adding a generic, low-cost, hormone treatment to standard chemotherapy helps preserve fertility of young women with breast cancer

access to information. Dr. ChávarriGuerra plans to implement a breast health educational program for rural adolescents that he hypothesizes will increase knowledge of breast health and promote help-seeking behaviors. • Tata Medical Center (India) Principal Investigator: Tanuj Chawla, MD, MBBS More than a million patients are diagnosed with cancer in India each year, and most of them experience toxicity during chemotherapy, for which they must travel long distances to receive help. Dr. Chawla hypothesizes that Short Message Service (SMS) alerts may improve chemotherapy protocol compli-

ance and reduce toxicity in patients. The first of its kind in a developing country, Dr. Chawla’s randomized controlled trial will test the success of text-message intervention on reducing emergency room visits, among other indicators, for patients who are beginning a chemotherapy regimen. • The Oncology Institute “Prof. Dr. Ion Chiricuta” (Romania) Principal Investigator: Alexandru Eugen Eniu, MD, PhD Despite having access to many standard therapies for breast cancer, patients in Romania have worse outcomes than patients in developed countries who receive the same treatments. Dr. Eniu plans to imple-

drugs such as ibrutinib (Imbruvica) and idelalisib (Zydelig) are so effective they are poised to transform CLL care, potentially eliminating the need for chemotherapy. For patients with newly diagnosed, previously untreated CLL, obinutuzumab (Gazyva) and ofatumumab (Arzerra) have been shown to delay disease progression by roughly a year. These agents are immunotherapy drugs that help the body’s own immune system find and attack cancer cells.

Federal Research Dollars Support Key Advances

undergoing chemotherapy and extend their lives • Combining standard radiation therapy with chemotherapy adds years of life to patients with low-grade glioma • Identifying ways to maximize benefits and reduce potential risks from low-dose computed tomography (CT) lung cancer screening • New, molecularly targeted drugs help overcome treatment resistance in lung cancer

ASCO Calls for Strong Federal Investment in Cancer Research But despite this record of success, the future of the U.S. federal cancer research enterprise faces critical continued on page 43

ment a telemedicine web-based platform that will enable an experienced multidisciplinary breast tumor board to review cases and improve treatment decisions for patients in small, remote cancer centers. The 2015 International Innovation Grants were made possible by the generous support of ASCO International, AstraZeneca, and Roche. n Reference 1. Patel JD, Galsky MD, Chagpar AB, et al: Role of American Society of Clinical Oncology in low- and middle-income countries. J Clin Oncol 29:3097-3102, 2011.

Save the Date Best of ASCO® Boston

Best of ASCO® San Francisco

Best of ASCO® Chicago

July 31–August 1, 2015

August 7–8, 2015

August 28–29, 2015

Renaissance Boston Waterfront Hotel

San Francisco Marriott Marquis

Swissotel Chicago

Boston, Massachusetts

San Francisco, California

Chicago, Illinois

ASCOPost.com | FEBRUARY 10, 2015

PAGE 43

Direct From ASCO Clinical Cancer Advances continued from page 42

challenges that must be addressed by policymakers, together with the cancer community, so that the pace of research progress can continue well into the future. In the report, ASCO is calling on Congress to provide a strong investment to the National Institutes of Health in 2015 to sustain the search for cancer cures.

the report’s introduction, and “The 10 Year Horizon,” which previews trends likely to shape the next decade of cancer care, such as genomic technology, nanomedicine, and information technology. Clinical Cancer Advances 2015: ASCO’s Report on Progress Against Cancer was published in the Journal of Clin-

ical Oncology (www.jco.org) on January 20. To access the full-color report and additional resources, visit www .cancerprogress.net/cca. Clinical Cancer Advances 2015 is funded in part by the Conquer Cancer Foundation of the American Society of Clinical Oncology Mission Endowment Fund. n

© 2015. American Society of Clinical Oncology. All rights reserved. Reference 1. Masters GA, Krilov L, Bailey HH, et al: Clinical Cancer Advances 2015: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol. January 20, 2015 (early release online).

About the CCA Clinical Cancer Advances 2015 was developed through a peer-review process, under the direction of an 18-person editorial board comprising prominent experts in a wide range of oncology specialties. The editors reviewed research published in peerreviewed journals or presented at major scientific meetings over a 1-year period (October 2013–September 2014). The report covers a broad range of cancer types and features a selection of recent trends and achievements across the entire continuum of cancer care, from prevention and screening to treatment and survivorship. In addition to announcing the Advance of the Year, special features in this 10th anniversary issue include “A Decade in Review,” which recounts the biggest changes in cancer care since

Help Your Patients Understand the Importance of Phase I Clinical Trials

WHAT DOES THE BLOOD-BRAIN BARRIER HAVE TO DO WITH ALK+ NSCLC? In up to 46% of ALK+ NSCLC patients, the CNS is the first site of progression while receiving an ALK-directed therapy1 • The blood-brain barrier, composed of numerous efflux transporters, forms a sanctuary for metastatic disease by actively preventing some therapeutic molecules from entering the CNS2 • Therapies with minimal exposure in the CNS may be unable to inhibit progression in the CNS1,2 • Patients with CNS metastases often experience poor outcomes and significant morbidity3

Discover more at ResearchALK.com

ncourage your patients to consider participating in clinical trials, including phase I clinical trials. Direct your patients to www.cancer.net/ clinicaltrials for detailed information about the purpose and advantages of clinical trials and why today’s phase I studies are different. On the Cancer.Net blog, your patients can also listen to a new podcast with Jeffrey S. Weber, MD, PhD, on why it’s important to talk about phase I clinical trials and the misconceptions that are associated with clinical trials. n © 2015. American Society of Clinical Oncology. All rights reserved.

ALK=anaplastic lymphoma kinase; CNS=central nervous system; NSCLC=non-small cell lung cancer. References: 1. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. 2. Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. 3. Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137. © 2014 Genentech USA, Inc. All rights reserved. BIO/100814/0053 Printed in USA.

The ASCO Post | FEBRUARY 10, 2015

PAGE 44

Direct From ASCO

ASCO Policy Statement Urges Removal of Barriers to Patient Participation in Phase I Clinical Trials

SCO has released a policy statement calling for greater access to and education about phase I clinical trials, the first-in-human studies of new agents designed to fight cancer. In “The Critical Role of Phase I Trials in Cancer Research and Treatment” ASCO policy statement, the Society stresses the critical importance of phase I clinical trials in cancer research and treatment. The statement emphasizes that this research offers greater potential as a treatment option for many patients than was the case in the past, due to development of molecularly targeted agents, biomarker tests to identify patients likely to respond to treatments, and innovative clinical trial designs. The ASCO policy statement reviews evidence that shows patients who participate in phase I trials may experience improved quality of life,

psychological advantages, and direct medical benefits. Yet, according to the Society, significant barriers, including insurance coverage, discourage patient enrollment in research.

and contribute to knowledge about their disease,” said the statement’s lead author, Jeffrey S. Weber, MD, PhD, a member of the ASCO Cancer Research Committee. “[The Centers for Medicare &

The uneven laws and regulations create disparities in patient access to phase I trials and deny many patients the opportunity to try a novel therapy and contribute to knowledge about their disease. — Jeffrey S. Weber, MD, PhD

“The uneven laws and regulations create disparities in patient access to phase I trials and deny many patients the opportunity to try a novel therapy

Medicaid Services] should address these disparities and fix these gaps.” Phase I clinical trials are an important step in translating basic research

into clinical practice. Researchers use these studies to determine the recommended dose and schedule of an investigational agent, observe its therapeutic effect, and assess its safety profile. Additional phase I studies, called phase Ib, may also be used to evaluate new schedules of existing agents or combinations of new agents with established agents or radiation. In addition to specifically focusing on the special issues related to conducting phase I trials in children, the ASCO policy statement recommends concrete steps be taken to creating a health-care delivery and payment system and expanding educational efforts that support decisions by patients to participate in these trials. n © 2015. American Society of Clinical Oncology. All rights reserved.

Accelerating Breakthroughs Launching Careers Improving Cancer Care

ConquerCancerFoundation.org

ASCOPost.com | FEBRUARY 10, 2015

PAGE 45

In the Clinic Thoracic Oncology

Ramucirumab in Metastatic Non–Small Cell Lung Cancer By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n December 12, 2014, ramucirumab (Cyramza) was approved for use in combination with docetaxel for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.1,2 Patients with EGFR or ALK genomic tumor aberrations should have disease progression on approved therapy for these aberrations prior to receiving ramucirumab.

Supporting Trial Approval was based on the finding of superior overall survival in a doubleblind phase III trial (REVEL) in which 1,253 patients with previously treated metastatic NSCLC were randomized to receive ramucirumab (10 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 every 3 weeks) on day 1 of a 21-day cycle (n = 628) or matching placebo plus docetaxel (n = 625).2,3 Patients had a median age of 62 years, 67% were men, 84% were white and 12% were Asian, 33% had an Eastern Cooperative Oncology Group performance status of 0, and 74% had a nonsquamous histology and 25% had a squamous histology. Patients received a median of 4.5 doses of ramucirumab, the median duration of exposure was 3.5 months, and 31% received ramucirumab for at least 6 months. The median overall survival was 10.5 months in the ramucirumab group vs 9.1 months in the control group (hazard ratio [HR] = 0.86, P = .024). The median progression-free survival was also significantly longer in the ramucirumab group (4.5 vs 3.0 months, HR = 0.76, P < .001).

How It Works Ramucirumab is a recombinant human immunoglobulin 1 monoclonal antibody that acts as a vascular endothelial growth factor receptor 2

( VEGFR2) antagonist. It specifically binds VEGFR2 and blocks the binding of the VEGFR ligands VEGF-A, VEGFC, and VEGF-D. As a result of receptor blockade, ramucirumab inhibits ligandstimulated activation of VEGFR2, thus inhibiting ligand-induced proliferation and migration of endothelial cells. Ramucirumab inhibited angiogenesis in animal models.

How It Is Given The recommended dose of ramucirumab in metastatic NSCLC is 10 mg/ kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Treatment should be continued until disease progression or unacceptable toxicity. All patients should be premedicated with an intravenous

OF NOTE Ramucirumab acts as a VEGFR2 antagonist and blocks the binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D.

histamine (H1) antagonist (eg, diphenhydramine hydrochloride) prior to each infusion, and patients who have a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or its equivalent) and acetaminophen. The infusion rate should be reduced by 50% for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 infusion-related reactions. Treatment should be interrupted in patients with severe hypertension, urine protein levels ≥ 2 g/24 hours, and prior to surgery until wounds are fully healed. It should be permanently discontinued in those with severe hypertension that cannot be managed with

OF NOTE Ramucirumab carries a boxed warning for hemorrhage, including fatal bleeding.

antihypertensive therapy, proteinuria of > 3 g/24 hours or nephrotic syndrome, arterial thromboembolic events, gastrointestinal perforation, grade 3 or 4 bleeding, or reversible posterior leukoencephalopathy syndrome.

Safety Profile In the phase III trial, the most common adverse events of any grade occurring in the ramucirumab/docetaxel group at a rate at least 30% and at least 2% higher than in the docetaxel/placebo group were neutropenia (55% vs 46%), fatigue/asthenia (55% vs 50%), and stomatitis/mucosal inflammation (37% vs 19%). The most common grade 3 or 4 adverse events in the ramucirumab group were neutropenia (49% vs 40%), febrile neutropenia (16% vs 10%), and fatigue/asthenia (14% vs 11%), and the most common serious adverse events were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). Granulocyte colony-stimulating factor treatment was used in 42% of the ramucirumab group and 37% of the control group. Pulmonary hemorrhage occurred in 7% (grade ≥ 3 in 1%) vs 6% (grade ≥ 3 in 1%) of patients with a nonsquamous histology and 10% (grade ≥ 3 in 2%) vs 12% (grade ≥ 3 in 2%) of patients with a squamous histology. Adverse events led to discontinuation of treatment in 9% vs 5%, with the most common reasons in the ramucirumab group consisting of infusionrelated reaction (0.5%) and epistaxis (0.3%). Death on treatment or within

Combination Treatment With Ramucirumab in NSCLC ■■ Ramucirumab was approved for use in combination with docetaxel for the treatment of patients with metastatic non–small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. ■■ The recommended dose of ramucirumab in metastatic NSCLC is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion.

30 days of discontinuing treatment occurred in 8% vs 4% of patients older than age 65 and in 3% vs 6% of patients younger than age 65. Ramucirumab carries a boxed warning for hemorrhage, including fatal bleeding. It also has warnings/precautions for arterial thromboembolic events (sometimes fatal), hypertension, infusion-related reactions, gastrointestinal perforation, impaired wound healing, clinical deterioration in patients with cirrhosis (including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome), and reversible posterior leukoencephalopathy syndrome. Ramucirumab may cause fetal harm, and nursing mothers should discontinue nursing or discontinue ramucirumab. n References 1. U.S. Food and Drug Administration: Approved drugs. Ramucirumab (Cyramza). Available at www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm426735.htm. Accessed January 7, 2015. 2. Cyramza (ramucirumab) injection, for intravenous use, prescribing information, Eli Lilly and Company, December 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s007lbl. pdf. Accessed January 7, 2015. 3. Garon EB, Ciuleanu TE, Arrieta O, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, doubleblind, randomised phase 3 trial. Lancet 384:665-673, 2014.

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

After failure of first-line VEGFR-TKIs sunitinib or sorafenib in aRCC,

CHANGE THEIR COURSE AFINITOR® (everolimus) Tablets is the first and only oral mTOR inhibitor indicated for the treatment of adult patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib

Abbreviations: aRCC, advanced renal cell carcinoma; BSC, best supportive care; mTOR, mammalian target of rapamycin; PFS, progression-free survival; VEGFR-TKI, vascular endothelial growth factor receptor-tyrosine kinase inhibitor.

Proven experience1 • AFINITOR is now approved in 5 indications, with experience in aRCC • A safety profile based on data in 274 patients with aRCC

3x antitumor effect1-3 • AFINITOR inhibits angiogenesis, growth and proliferation, and metabolism in in vitro and/or in vivo studies

More than 2x median PFS1,4* • AFINITOR (n=277): 4.9 months (95% CI, 4.0-5.5); placebo (n=139): 1.9 months (95% CI, 1.8-1.9) (HR=0.33; 95% CI, 0.25-0.43; log-rank P<0.0001)

*In the RECORD-1 trial, AFINITOR + BSC (n=277) extended PFS vs placebo + BSC (n=139) after progression on sunitinib or sorafenib (4.9 months [95% CI, 4.0-5.5] vs 1.9 months [95% CI, 1.8-1.9]; log-rank P<0.0001).1,4

Important Safety Information AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • Monitor for clinical symptoms or radiological changes • Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis • Manage noninfectious pneumonitis by dose reduction or discontinuation until symptoms resolve, and consider the use of corticosteroids • For patients who require use of corticosteroids, prophylaxis for PJP may be considered • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment • PJP has been reported in patients who received everolimus, sometimes with a fatal outcome. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents; consider prophylaxis for PJP when concomitant use of these agents is required

Continued on next page

Important Safety Information (cont) Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Impaired Wound Healing: • Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma • These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period Laboratory Tests and Monitoring: • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Monitoring of complete blood count is recommended prior to treatment and periodically thereafter Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less Hepatic Impairment: • Exposure to everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman • Advise female patients of reproductive potential to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%) • The most common grade 3/4 adverse reactions (incidence ≥5%) were infections (10%), dyspnea (7%), stomatitis (5%), and fatigue (5%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%, all grades) were: decreased hemoglobin (92%) and lymphocytes (51%); and increased cholesterol (77%), triglycerides (73%), glucose (57%), and creatinine (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥5%) were decreased hemoglobin (13%), lymphocytes (18%), and phosphate (6%), and increased glucose (16%) Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. AFINITOR [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014. 2. Yuan R, Kay A, Berg W, Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol. 2009;2:45. 3. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs. 2005;14:313-328. 4. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116(18):4256-4265.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

8/14

AFI-1095434

The ASCO Post | FEBRUARY 10, 2015

PAGE 48

San Antonio Breast Cancer Symposium Fulvestrant Plus Bortezomib continued from page 13

tle grade 3 and no grade 4 toxicity due to treatment, suggesting the regimen is well tolerated. “The study provides proof of principle that targeting the proteasome may prevent and/or delay the emergence of acquired resistance to endocrine

therapy with fulvestrant,” Dr. Adelson suggested.

25-Gene Panel Offers More Thorough Screening Use of a 25-gene gene panel in community oncology practices could greatly increase the detection of hereditary breast cancer mutations, according to

a study by US Oncology investigators.3 In their study, the 25-gene hereditary cancer panel increased the identification of deleterious mutations by almost 70% over testing for hereditary breast and ovarian cancer or Lynch syndrome alone, reported Sami Diab, MD, of Rocky Mountain Care Centers and Colorado Integrative Care in Aurora.

AFINITOR® (everolimus) tablets for oral administration AFINITOR® DISPERZ (everolimus tablets for oral suspension) Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 noninfectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jiroveci pneumonia (PJP) and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required. 5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of

Sami Diab, MD

patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)]. 5.4 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring (5.7)]. 5.5 Impaired Wound Healing Everolimus delays wound healing and increases the occurrence of woundrelated complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period. 5.7 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.8 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions (7.2)]. 5.9 Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 5.10 Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines

ASCOPost.com | FEBRUARY 10, 2015

PAGE 49

San Antonio Breast Cancer Symposium “We found that almost 10% of highrisk patients had a mutation that could have been causing their cancer. If we limited our testing to the BRCA genes or Lynch syndrome genes, we would have identified only 60%. There are 40% of patients with other genes that could be identified,” Dr. Diab said. The 25-gene panel, which is based on

next-generation sequencing, targets 8 cancers: breast, ovarian, colorectal, endometrial, pancreatic, melanoma, prostate, and stomach. The panel assays for mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, CDKN2A, CDK4, PALB2, CHEK2, SMAD4, BMPR1A, STK11, TP53, CHD1, PTEN, ATM, NBN,

prior to the start of therapy. An accelerated vaccination schedule may be appropriate. 5.11 Embryo-fetal Toxicity Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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)]. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.6)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label [see Warnings and Precautions (5)]: • Non-infectious pneumonitis [see Warnings and Precautions (5.1)]. • Infections [see Warnings and Precautions (5.2)]. • Oral ulceration [see Warnings and Precautions (5.3)]. • Renal failure [see Warnings and Precautions (5.4)]. • Impaired wound healing [see Warnings and Precautions (5.5)]. Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. 6.3 Clinical Study Experience in Advanced Renal Cell Carcinoma The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving AFINITOR and 60 days (range 21-295 days) for those receiving placebo. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 6 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 6: Adverse Reactions Reported in at Least 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274 All grades % Any adverse reaction

Grade 3 Grade 4 % %

Placebo N=137 All grades %

Grade 3 Grade 4 % %

Gastrointestinal disorders 44 Stomatitisa Diarrhea 30 Nausea 26 Vomiting 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and infestationsb

0 (continued)

BARD1, BRIP1, RAD51C, and RAD51D. U.S. Oncology clinicians performed the test on 997 individuals, of whom 773 (77.5%) had a personal history of at least one of the eight panel cancers. Almost all met the National Comprehensive Cancer Network guidelines for testing for hereditary breast and ovarian cancer, Lynch syndrome, or both.

Table 6: Adverse Reactions Reported in at Least 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274 All grades %

Grade 3 Grade 4 % %

Placebo N=137 All grades %

General disorders and administration site conditions Asthenia 33 3 <1 23 Fatigue 31 5 0 27 Edema peripheral 25 <1 0 8 Pyrexia 20 <1 0 9 Mucosal inflammation 19 1 0 1

Grade 3 Grade 4 % % 4 3

0 <1

<1 0

0 0

Respiratory, thoracic and mediastinal disorders Cough 30 <1 0 Dyspnea 24 6 1 Epistaxis 18 0 0 Pneumonitisc 14 4 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and subcutaneous tissue disorders Rash 29 1 0 Pruritus 14 <1 0 Dry skin 13 <1 0

7 7 5

0 0 0

Metabolism and nutrition disorders Anorexia 25 1

Nervous system disorders Headache 19 Dysgeusia 10

<1 0

9 2

<1 0

0 0

Musculoskeletal and connective tissue disorders Pain in extremity 10 1 0 7

Median duration of treatment (d)

<1 0

141

Grading according to CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%) Vascular disorders: Hypertension (4%), deep vein thrombosis (< 1%) Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key laboratory abnormalities are presented in Table 7.

The test identified 83 mutations in 79 patients. Of those with a personal history of cancer, 72 (9.3%) had a pathogenic mutation. Mutations were identified in 15 different genes. Only 59% of these genes were among the six genes that are included in single-syndrome hereditary breast and ovarian cancer (BRCA1, continued on page 50

The ASCO Post | FEBRUARY 10, 2015

PAGE 50

San Antonio Breast Cancer Symposium 25-Gene Panel continued from page 49

BRCA2) and Lynch syndrome (MSH6, MLH1, MSH2, PMS2) testing, Dr. Diab reported. “A significant portion of mutations were found in genes not traditionally associated with hereditary breast and ovarian cancer or Lynch syndrome,” he said.

somerase 1 inhibitor, etirinotecan pegol, in patients with previously treated metastatic breast cancer and target-specific biomarkers in circulating tumor cells, according to Edith Perez, MD, of the Mayo Clinic in Jacksonville, Florida.4 Topoisomerase 1 is a nuclear enzyme that plays an essential role in DNA replication, transcription, recom-

The next step is to better understand the clinical spectrum of the deleterious mutations identified in this 25-gene panel in order to provide appropriate screening recommendations.

Novel Topo-1 Inhibitor The international phase III BEACON trial will evaluate a novel topoi-

Table 7: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory parameter

AFINITOR 10 mg/day N=274 All grades %

Hematologya Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased

Grade 3 Grade 4 % %

Placebo N=137 All grades %

Grade 3 Grade 4 % %

Clinical chemistry Cholesterol increased 77 4 0 35 0 0 Triglycerides increased 73 <1 0 34 0 0 Glucose increased 57 15 <1 25 1 0 Creatinine increased 50 1 0 34 0 0 Phosphate decreased 37 6 0 8 0 0 Aspartate transaminase (AST) increased 25 <1 <1 7 0 0 Alanine transaminase (ALT) increased 21 1 0 4 0 0 Bilirubin increased 3 <1 <1 2 0 0 Grading according to CTCAE Version 3.0 a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. 6.6 Postmarketing Experience The following adverse reactions have been identified during post approval use of AFINITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events and reflex sympathetic dystrophy. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. 7.1 Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions (5.8)]. Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions (5.8)]. 7.2 Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered.

bination, and repair. Etirinotecan pegol is a long-acting topoisomerase 1 inhibitor designed for prolonged tumor cell exposure. In a previous phase II trial of 70 patients, the response rate to etirinotecan pegol was 29%, the median progressionfree survival was 4.7 months, and the median overall survival was 10.3 months.

St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. 7.3 Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions (5.11)]. Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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. 8.5 Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions (5.6) in the full prescribing information]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients

ASCOPost.com | FEBRUARY 10, 2015

PAGE 51

San Antonio Breast Cancer Symposium

Edith Perez, MD

Based on these results, the phase III BEACON trial was designed; it will compare single-agent etirinotecan pegol with physicians’ choice of treatment in 852 previously treated patients. Patients must have received an anthracycline, taxane, and capecitabine, “so they are truly refractory patients,” she said. One of the exciting aspects of the

were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Females and Males of Reproductive Potential Contraception Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology (13.1) in the full prescribing information]. Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology (13.1) in the full prescribing information]. 8.7 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

trial is that it is biomarker-driven, Dr. Perez emphasized. The investigators will analyze circulating tumor cells obtained at baseline and throughout treatment and correlate these findings with clinical outcomes. BEACON is employing the ApoStream system for isolation of circulating tumor cells. This technique, which is based on dielectro-

8.8 Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (ChildPugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2014-66 July 2014

Select Studies on Breast Cancer From SABCS ■■ The EPO-ANE-3010 study, mandated by the FDA to evaluate the safety of epoetin alfa in 2,100 metastatic breast cancer patients, did not meet the protocol-defined noninferiority criteria, and thus the findings uphold the black box warning. Patients in the epoetin alfa arm, vs supportive care alone, had a 9% increased risk of disease progression or death. Transfusion remains the preferred approach to correcting anemia in cancer patients. ■■ Bortezomib, added to fulvestrant in metastatic patients refractory to aromatase inhibitors, significantly improved progression-free survival. ■■ A 25-gene panel may identify 40% of individuals at risk for breast cancer who would not be identified through testing for mutations associated with hereditary breast and ovarian cancer or Lynch syndrome alone. ■■ The international BEACON trial is evaluating a novel topoisomerase 1 inhibitor, etirinotecan pegol, in patients with previously treated metastatic breast cancer and target-specific biomarkers in circulating tumor cells.

phoresis and microfluidic technology and is antibody-independent, reportedly yields higher numbers of circulating tumor cells than the first-generation EpCAM-dependent methods. “We were happy to have access to novel technology that can detect many more circulating tumor cells than EpCAM-dependent technology,” she said. Top-line results—the endpoint being overall survival—are expected in the first quarter of 2015. n

Disclosure: Dr. Leyland-Jones has served as a consultant for Genentech, Roche, Bristol-Myers Squibb, Janssen, Xoma, Genta, NewBiotics, GlaxoSmithKline, and Hospira. He also has contracts with Roche, AstraZeneca, Insmed, Arius, and Nanocarrier. Dr. Adelson is a speaker for Genomic Health. Drs. Diab and Perez reported no potential conflicts of interest.

References 1. Leyland-Jones B, Bondarenko I, Nemsadze G, et al: A randomized, open-label, multicenter, phase 3 study of epoetin alfa plus standard supportive care versus standard supportive care in anemic patients with metastatic breast cancer receiving continued on page 52

The ASCO Post | FEBRUARY 10, 2015

PAGE 52

San Antonio Breast Cancer Symposium Breast Cancer

Four-Gene Panel Predicts Response to Letrozole By Caroline Helwick

t the 2014 San Antonio Breast Cancer Symposium, a research team led by Michael Dixon, MD, of Western General Hospital in Edinburgh, shed light on the development of endocrine resistance and presented a four-gene messenger RNA (mRNA) profile that can predict response

HER2-enriched—have been associated with poor outcomes. To improve outcomes for patients who become resistant to endocrine therapies, it would be helpful to identify key mutations and how they interact with molecular subtypes. The dynamic profiling of the same tumor,

In our 17 patients, we could detect at 14 days who would not do well. This test appears to have clinical utility. —Michael Dixon, MD

to letrozole with a high degree of accuracy.1 Mutations in certain genes have previously been shown to confer resistance to aromatase inhibitors, and certain molecular subtypes—especially luminal B and

at baseline and throughout neoadjuvant endocrine therapy, could be a unique opportunity to identify important genomic changes, Dr. Dixon pointed out. “What we need is a better test to

predict who will respond to endocrine therapy and to help us better understand endocrine resistance,” Dr. Dixon said. He believes their research may have accomplished just this. Dr. Dixon and his team evaluated postmenopausal women with estrogen receptor–rich tumors treated with neoadjuvant letrozole, including 73 from Edinburgh and 44 from the Royal Marsden Hospital in London. Fresh tissue taken at baseline and at 14 days was used to develop a predictive test based on mRNA expression. To understand endocrine resistance, they evaluated 17 patients, a cohort enriched for nonresponse, who had multiple biopsies at baseline, 14 days, and 6 months to 3 years. Serial sampling meant that tumors were evaluated while sensitive to endocrine therapy and upon de novo or acquired resistance to it. This gives a dynamic picture of how the genetic makeup changes as resistance develops, Dr. Dixon explained.

Key Findings Based on what the researchers observed on the molecular profiling of serial biopsies, they reached these conclusions: • Molecular subtypes change according to response to treatment: nonresponders are more likely to be luminal B at the start or to end treatment with luminal B status; responders are more likely to be luminal A at the start or to become luminal A. • Responders demonstrate a loss of genetic mutations. • New mutations develop in nonresponding tumors; these changes suggest that clonal selection is occurring. • Baseline analysis is insufficient to predict response to endocrine therapy. • A four-gene model can predict response to letrozole with accuracy.

Study Details Of the 17 patients, 13 progressed continued on page 53

EXPERT POINT OF VIEW

atthew J. Ellis, MB, BChir, PhD, Director of the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston, commented on endocrine resistance and the potential of the four-gene panel for assessing resistance for The ASCO Post. Endocrine response and resistance is a research focus of Dr. Ellis’. “Dr. Dixon’s presentation highlights some very important principles that are emerging regarding the use of endocrine agents in breast cancer,” he said. First, is the key idea of profiling tumors not just at baseline, which is routine, but after endocrine treatment has been started. Estrogen receptor–positive tumors that do not demonstrate a dramatic decline in gene-expression patterns associated with cell growth are clearly resistant to endocrine intervention, and multiple groups have shown that persistent proliferation despite an aromatase in-

News Roundup continued from page 51

standard chemotherapy. 2014 San Antonio Breast Cancer Symposium. Abstract S5-07. Presented December 12, 2014. 2. Adelson KB, Ramaswamy B, Sparano JA, et al: Randomized phase II trial of

hibitor or tamoxifen portends a poor outcome, even when chemotherapy is administered, he noted. Second, neoadjuvant endocrine therapy can be used to discern mutations that drive resistance, according

at baseline. Equally, mutant allele dropout might signal the presence of mutations/clones that are highly sensitive to therapy and help identify mutations that are not associated with resistance,” he continued.

Dr. Dixon’s study is currently too small to alter clinical practice. His four-gene signature, while promising, needs to be taken into rigorous assay development, and much larger studies are needed. —Matthew J. Ellis, MB, BChir, PhD

to Dr. Ellis. “As we shift to genomedriven oncology, treatment with an aromatase inhibitor may become a way to detect the presence of uncommon clones harboring resistance mutations that were not detectable

fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: A New York Cancer Consortium trial. 2014 San Antonio Breast Cancer Symposium. Abstract S603. Presented December 12, 2014.

Finally, biomarker models can be developed to predict outcomes based on the presence or absence of a gene signature in treated samples, he said. When fully developed, these tests could drive change in the neoadjuvant

3. Diab S, Rodriguez P, Leininger A, et al: Experience in the community oncology practice with a 25-gene hereditary cancer panel. 2014 San Antonio Breast Cancer Symposium. Abstract P1-03-03. Presented December 10, 2014. 4. Perez EA, Caygill K, Hannah AL, et

approach, rather than leave patients on inadequately effective neoadjuvant endocrine therapy when other options are readily available. “In the final analysis, Dr. Dixon’s study is currently too small to alter clinical practice. His four-gene signature, while promising, needs to be taken into rigorous assay development, and validation efforts and much larger studies are needed,” according to Dr. Ellis. The ALTERNATE trial is one such ongoing example in the United States, where patients with high levels of proliferation (based on Ki67) despite neoadjuvant endocrine therapy (anastrozole, fulvestrant [Faslodex], or the combination) are taken off neoadjuvant endocrine therapy after just 1 month and offered a switch to neoadjuvant chemotherapy (NCT01953588). n Disclosure: Dr. Ellis has received royalties from patents related to Nanostring’s Prosigna Breast Cancer Prognostic Test.

al: Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study. 2014 San Antonio Breast Cancer Symposium. Abstract P3-10-03. Presented December 11, 2014.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 53

San Antonio Breast Cancer Symposium Response to Letrozole continued from page 53

on treatment or initially responded and then developed resistance, whereas 4 patients responded well. Their dynamic clinical response was assessed via threedimensional ultrasound measurements obtained during treatment. Fresh tissue was taken before treatment and after resistance developed. RNA and DNA were extracted from the tumor, and normal DNA was obtained from matched blood or normal lymphatic tissue. The researchers used UNCeqR, which integrates RNA and DNA sequencing, to improve mutation detection. This technology is particularly valuable if there is low tumor cellularity or a low variant allele fraction of mutations. The intrinsic subtype results across time showed that some luminal B tumors at baseline became luminal A by the time of the last biopsy, whereas some “hopped” from luminal A to luminal B and back to luminal A, depending on the status of response. “We saw that nonresponders were much more heterogeneous than responders, but there was a tendency to maintain their luminal B status, although some luminal Bs did change to luminal A,” he said. There were 12 patients with multiple samples and normal DNA, based on UNCeqR analysis. Somatic mutations were comparable to those found by the Cancer Genome Atlas, although some genes were mutated more frequently than expected. Only two “passed the test” of being significant on multiple tests: GATA3 (a transcriptional factor in luminal epithelial differentiation) and SMCP (sperm mitochondria-associated cysteine-rich protein). Counting the mutations in the tumor, and associating them with re-

sponse status, the researchers observed that responders had a high level of mutations at baseline that “appeared to fall dramatically” with treatment. Nonresponders did not demonstrate an obvious pattern. This loss of mutation was not explained by changes in tumor cellularity, he added. Genetic heat maps of the resistant patients showed that muta-

tions remain present throughout treatment, although their composition and allele frequency change over time.

Four-Gene Model Dr. Dixon and his team determined that measuring mRNA from four genes B:7.875 in could predict response to letrozole: two T:7.625 in of which were measured at diagnosis and

■■ Measuring mRNA from a fourgene panel developed by the authors predicted, with a high degree of accuracy, whether patients would respond to treatment with letrozole.

continued on page 54

CLINICAL EVIDENCE INDICATES...

THERE ARE DISTINCT WAYS TO HELP MANAGE ADVANCED PROSTATE CANCER * INHIBIT ANDROGEN PRODUCTION

BLOCK THE ANDROGEN RECEPTOR

Predicting Endocrine Resistance With Genomic Analysis ■■ In-depth genomic analysis of estrogen receptor– positive tumors treated with neoadjuvant letrozole revealed that molecular subtype often changes over the course of treatment and that responding tumors lose mutations.

S:6.625 in

two proliferation genes that were measured on day 14 of treatment. At baseline, mRNA levels of IL6ST, which functions as a transmembrane signal transducer, and mRNA from NGFRAP, which is thought to be involved in apoptosis, predicted response. At day 14, mRNA from MCM4, which is essential for eukaryotic

EACH PLAYS AN IMPORTANT ROLE 1-3 Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Schulze H, Senge T. Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990;144(4):934-941. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 10/14 016538-140607

The ASCO Post | FEBRUARY 10, 2015

PAGE 54

Journal Spotlight Gynecologic Oncology

Moffitt Cancer Center Reports on Faculty Participants in International Discovery of Genetic Risk Factors for Ovarian Cancer

esearchers from Moffitt Cancer Center in Tampa, Florida have participated in a global effort that has identified six new regions of the genome that increase risk of epithelial ovarian cancer, according to a news release from Moffitt. The collaborative study was published recently in Nature Genetics.1 The study is unique in that it includes a combined analysis of two groups of women who had their genetic profiles completed as part of a large international collaboration.

Combined Analysis of Study Participants The first group of women in the study included those with and without ovarian cancer who had inherited a mutation in BRCA1 or BRCA2, which are gene mutations already known to increase risk of ovarian cancer. The women were recruited to 54 studies in 27 countries. The second group included women with ovarian cancer who did not have a BRCA mutation and women who were cancer-free but involved in

Response to Letrozole continued from page 53

genome replication, and ASPM, which is involved in mitotic spindle function, were predictive. Although the concept has been that “apoptosis is important after treatment,” he said the study shows that “apoptotic genes at diagnosis matter as to whether the cancer will be responsive to letrozole.” He added, “Potentially, at 14 days, the mRNA levels of these proliferation genes predict outcome. Unless letrozole ‘switch-

the Ovarian Cancer Association Consortium of 26 individual studies. Altogether, DNA from approximately 69,700 women, including more than 18,400 women with ovarian cancer, was extensively analyzed for genetic changes called single-nucleotide polymorphisms (SNPs). SNPs found on six different regions on chromosomes 1, 4, 6, 9 and 17 are linked to epithelial ovarian cancer.With this most recent investigation, the number of SNPs that influence ovarian cancer risk has increased to 18. This information can be used to stratify patients according to their risk of developing cancer and enable primary prevention efforts.

This study gets us closer to the ability to identify women with a 10% lifetime risk of ovarian cancer, which is the generally accepted target for clinical intervention to lower risk. —Thomas A. Sellers, PhD, MPH

Thomas A. Sellers, PhD, MPH, Center Director at Moffitt, explained, “This study gets us closer to the ability to identify women with a 10% lifetime risk of ovarian cancer, which is the generally accepted target for clinical intervention to lower risk. Given that there is

no early detection test, most women are diagnosed at late stage and outcomes are less than optimal. Thus, identification of women at high risk to try and prevent the disease is really appealing and an important goal to pursue.”  A total of seven Moffitt researchers participated in this international study, including Dr. Sellers, Catherine M. Phelan, PhD, MD, MMS, Jenny Permuth-Wey, PhD, Alvaro N.A. Monteiro, PhD, Y. Ann Chen, PhD, Hui-Yi Lin, PhD, and Zhihua Chen. Georgia Chenevix-Trench, MD, is the corresponding author. For a complete list of

es off’ proliferation, you don’t appear to get the benefit in the long run from endocrine therapy. In responding tumors, once proliferation ‘switches off,’ it stays off.” With the application of mRNA from this four-gene profile, he said, “Every patient gets an indication of mRNA whether she will respond or not respond.” The test was highly accurate, both the training set of 73 tumors (96%) and the validation set of 44 (93%). Its application to the 17-patient cohort enriched for poor response showed it to

be 100% accurate in predicting patients who achieved a “quick stable response,” those who were “static then progressed,” and those who “progressed.” It was 83% accurate in predicting which patients would respond and then progress, missing only one of these six patients. “In our 17 patients, we could detect at 14 days who would not do well. We only got one wrong,” he said. “This test appears to have clinical utility.” Dr. Dixon said this research shows that “baseline analysis is not sufficient

Identifying Women at Risk of Ovarian Cancer

For more information, visit http://www.siog.org/

authors, visit Nature.com. An estimated 22,000 new cases of ovarian cancer are diagnosed each year in the United States. It is the fifth most common cause of cancer-related death in women, with approximately 14,000 deaths each year and a 5-year survival rate of only 44%. n Reference 1. Kuchenbaecker KB, Ramus SJ, Tyrer J, et al: Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Gen. January 12, 2015 (early release online).

to predict response to endocrine or any other treatment. We need to analyze the cancer during treatment, because it will change.” n Disclosure: Dr. Dixon reported no potential conflicts of interest.

Reference 1. Dixon JM, Turnbull AK, Fan C, et al: Indepth genomic analysis of ER+ breast cancers during development of endocrine resistance. 2014 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 10, 2014.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 55

ASH Annual Meeting Hematology

New Choosing Wisely List, Leukemia Quick-Takes From ASH By Alice Goodman and Caroline Helwick

early 5,000 scientific abstracts were presented at the 2014 American Society of Hematology (ASH) Annual Meeting and Exhibition in San Francisco. Along with our targeted coverage of the meeting’s key newsmakers, The ASCO Post provides you with these brief reports of other interesting presentations.

mains the standard of care for upfront treatment of medically fit CLL patients, withstanding a challenge from BR (bendamustine [Treanda] and rituximab) in a head-to-head phase

III study.2 However, BR may be a better choice than FCR in elderly and/or less medically fit patients with regard to B:7.875 in the toxicity profile, according to the authors of the GermanT:7.625 CLLinStudy Group

(GCLLSG) CLL10 study. CLL10 was designed to show noninferiority of front-line BR vs FCR in patients with active CLL without del

S:6.625 in

continued on page 56

Choosing Wisely List ASH announced its second list of five tests, treatments, and procedures in hematology that should be questioned for routine use as part of the Choosing Wisely campaign, an initiative of the American Board of Internal Medicine Foundation. The first list from ASH was published in 2013; the new list was published just prior to the 2014 ASH meeting.1 The new Choosing Wisely recommendations include: • Do not treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor. • Do not routinely transfuse patients with sickle cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication. • Do not perform baseline or routine surveillance computed tomography (CT) scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia (CLL). • Do not test or treat for suspected heparin-induced thrombocytopenia in patients with a low pretest probability of heparin-induced thrombocytopenia. • Don’t treat patients with immune thrombocytopenic purpura in the absence of bleeding or a very low platelet count. The goal of the campaign is to reduce unnecessary spending while maintaining evidence-based quality care. Since the launch of the campaign in April 2012, more than 100 national and state medical specialty societies, regional health collaborative organizations, and consumer partners have climbed aboard. Studies are underway to determine the impact of these recommendations. The recommendations, as well as the evidence supporting them, are available at www.hematology.org/choosingwisely.

Upfront Treatment of CLL FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) re-

IN ADVANCED PROSTATE CANCER…

DO YOUR PATIENTS HAVE

MORE ANDROGEN THAN YOU CAN CATCH WITH ANDROGEN RECEPTOR BLOCKADE?

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 10/14 016539-140607

The ASCO Post | FEBRUARY 10, 2015

PAGE 56

ASH Annual Meeting New Choosing Wisely List continued from page 55

(17p) who were deemed medically fit. Patients were randomly assigned to six cycles of FCR (n = 284) or BR (n = 280), with the primary endpoint of progression-free survival. Front-line FCR was significantly superior to BR on several measures. Median progression-free survival was 55.2 months for FCR vs 41.7 months for BR (P < .001). In younger patients (≤ 65), progression-free survival with FCR was also significantly superior to BR: 53.6 months vs 38.5 months, respectively (P < .001). The difference in progression-free survival favoring FCR was not statistically significant in patients older than 65 years. The rate of complete remission was significantly better in the FCRtreated group: 39.7% vs 30.8% for BR (P = .034). Overall response rate was similar between the two arms, and there was no difference in overall survival between groups at 3 years: 90.6% vs 92.2%, respectively. Final results of CLL10 were presented by lead author Barbara Eichhorst, MD, of University Hospital in Cologne, Germany.

7-Year Follow-up With Dasatinib in CML After 7 years of follow-up, collective data on safety and efficacy continue to support the use of dasatinib (Sprycel) in patients with chronic-phase chronic myeloid leukemia (CML) who are resistant to or intolerant of first-line imatinib (Gleevec).3 “This is the longest follow-up for safety and efficacy of any second-generation BCR-ABL tyrosine kinase inhibitor,” said lead author Neil P. Shah, MD, PhD, University of California, San Francisco. Study CA180-034 was designed to compare four different doses of dasatinib in patients with chronic-phase CML resistant to or intolerant to imatinib; 662 patients were randomly assigned to 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. After 2 years, patients randomized to twice-daily dosing were allowed to switch to once-daily dosing. The primary endpoint of the study was molecular cytogenetic remission. Over 7 years of follow-up, the dose of 100 mg was generally well tolerated. Cumulative rates of drug-related pleural effusion increased over time. Cardiovascular events occurred at low

rates in all four groups, and most occurred during the first year of therapy. “Dasatinib at 100 mg daily continues to demonstrate durable efficacy in second-line therapy in a proportion of patients,” Dr. Shah said. More than 20% of heavily pretreated patients continued therapy for at least 7 years. No newly described BCR-ABL mutations were reported over the followup period. In patients who achieved BCR-ABL expression ≤ 10%, overall survival and progression-free survival were significantly improved at 3 years compared with patients who did not reach that milestone. Deaths due to disease progression occurred in 12% of patients across all four dosage groups.

Novel Regimen in T-Cell Lymphoblastic Lymphoma The phase II open-label GRAALLLYSA LL-03 study is one of the largest ever conducted in adults with T-cell lymphoblastic lymphoma, enrolling 131 patients to evaluate an adapted

of lactate dehydrogenase, were the strongest prognostic indicators for treatment outcome. “The study confirms the good response rate and outcomes achieved in these patients when using a pediatric-like ALL chemotherapy,” said lead author Stephane Lepretre, MD, of Henri Becquerel Center in Rouen, France.

Predicting Relapse After Stopping Imatinib CML patients treated with first-line imatinib achieve a complete cytogenetic response in more than 70% of cases and a major molecular response in 18% to 58%. However, a quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay is unable to ensure eradication of disease, even in the setting of undetectable BCR-ABL. The newer digital polymerase chain reaction (dPCR) can detect one BCR-ABL–positive cell out of 107 cells and is 100 times more sensitive than quantitative RTPCR. The use of dPCR could potentially

Dasatinib at 100 mg daily continues to demonstrate durable efficacy in second-line therapy in a proportion of patients. —Neil P. Shah, MD, PhD

pediatric-inspired GRAALL treatment, which has yielded good results in adults with acute lymphoblastic leukemia (ALL). Outcomes with this protocol were reported by French investigators.4 The pediatric-inspired ALL treatment included a corticosteroid prephase, a five-drug induction with sequential cyclophosphamide, high-dose consolidation, late intensification, central nervous system prophylaxis and cranial irradiation, and a 2-year maintenance phase. Allogeneic stem cell transplantation was offered to complete responders with high-risk disease. Of 131 patients, 119 (91%) reached a complete or unconfirmed complete response; 30 patients needed a salvage course, and 34 relapsed. At 3 years, event-free survival was 63%, diseasefree survival was 72%, and overall survival was 69%. The four-gene profile of NOTCH1/ FBXW7/RAS/PTEN, as well as level

separate patients with minimal residual disease from those in whom CML has been completely eradicated. The global Imatinib Suspension and Validation study aimed to evaluate relapse after discontinuation of imatinib and to validate the capability of dPCR to predict these relapses in CML patients with negative quantitative RTPCR results.5 The study included 112 patients treated with imatinib for more than 2 years who were in complete molecular remission at the time of enrollment for at least 18 months. The median duration of imatinib treatment was 103 months, median time from first evaluation of complete molecular remission to imatinib discontinuation was 26 months, and median time from CML diagnosis to imatinib discontinuation was 108 months. At a median follow-up of 22 months, 48% of patients relapsed after discontinuing imatinib. Of these, 68% were dPCR-positive and 43% were dPCR-

negative. Of the 108 patients analyzed by dPCR, 23% were dPCR-positive and 77% were dPCR-negative (33% of relapsed patients were dPCR-positive and 67% were dPCR-negative). More than 73% of the relapses occurred within the first 9 months after imatinib discontinuation. Age younger than 45 and dPCR positivity were significantly associated with relapses. No case of CML progression was observed. The authors concluded that dPCR positivity and young age are predictive of relapse. The presence of patients whose quantitative RT-PCR remained positive but at levels < 0.1% “remains scientifically unexplained and requires particular clinical attention,” said Silvia Mori, PhD, of the University of Milano-Bicocca in Monza, Italy. n

Disclosure: Drs. Lepretre and Mori reported no potential conflicts of interest. Dr. Eichhorst is on the advisory boards of and receives honoraria from Janssen, Gilead, Mundipharma, GlaxoSmithKline, has received scientific grants from Roche and Mundipharma, and has received honoraria from Roche.

References 1. Hicks LK, Bering H, Carson KR, et al: Five hematologic tests and treatments to question. Blood. December 4, 2014 (early release online). 2. Eichhorst B, Fink AM, Busch R, et al: Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) shows superior efficacy in comparison to bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German GLL Study Group (GCLLSG) (CLL10 study). 2014 ASH Annual Meeting. Abstract 19. Presented December 6, 2014. 3. Shah NP, Rousselot P, Schiffer C, et al: Seven-year follow-up of patients with imatinib-resistant or –intolerant chronic phase chronic myeloid leukemia receiving dasatinib in study CA180-034, final study results. 2014 ASH Annual Meeting. Abstract 520. Presented December 8, 2014. 4. Lepretre S, Touzart A, Vermeulin T, et al: Pediatric ALL-like therapy for adults with T-cell lymphoblastic lymphoma: Results of the Graall-Lysa LL03 study. 2014 ASH Annual Meeting. Abstract 371. Presented December 8, 2014. 5. Mori S, Vagge E, le Coutre P, et al: The risk of relapse in CML patients who discontinued imatinib can be predicted based on patients age and the results of dPCR analysis. 2014 ASH Annual Meeting. Abstract 813. Presented December 9, 2014.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 57

FDA Update

CPX-351 Receives Fast Track Designation for Secondary Acute Myeloid Leukemia in Elderly Patients

he U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Celator Pharmaceuticals’ investigational agent CPX-351, a liposomal formulation of

The FDA established the Fast Track designation process to facilitate the development and expedite the review of drugs intended to treat serious or lifethreatening conditions and that dem-

onstrate the potential to address unmet medical needs. A phase III studyB:7.875 comparing CPXin 351 to the current standard of care T:7.625 in has completed enrollment. Induction S:6.625 in

response rate data are expected to be available in the second quarter of 2015, and overall survival data, the primary endpoint of the study, are expected in early 2016. n

cytarabine:daunorubicin, for the treatment of elderly patients with secondary acute myeloid leukemia.

Supplemental New Drug Application for Carfilzomib

mgen and its subsidiary Onyx Pharmaceuticals, Inc, announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) carfilzomib (Kyprolis) to seek approval for the treatment of patients with relapsed multiple myeloma who have received at least one prior therapy. The sNDA is designed to support the conversion of accelerated approval to full approval and expand the current approved indication. Carfilzomib, a proteasome inhibitor, was granted accelerated approval by the FDA in 2012.

ASPIRE Trial The submission is based on data from the phase III ASPIRE trial of carfilzomib, lenalidomide (Revlimid), and dexamethasone vs lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma, and other relevant data. “Multiple myeloma is an incurable blood cancer that often becomes resistant to treatment, underscoring the need for new therapeutic options that provide deep and durable responses to extend the time patients live without their disease progressing,” said Pablo J. Cagnoni, MD, President of Onyx Pharmaceuticals. n

In mCRPC, is it appropriate to

INHIBIT ANDROGEN PRODUCTION BEFORE BLOCKING THE ANDROGEN RECEPTOR?* THIS APPROACH IS AN OPTION FOR TREATMENT IN ADVANCED PROSTATE CANCER.1,2 Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, prospective clinical study data on treatment sequencing in mCRPC. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Sartor AO, Tangen CM, Hussain MHA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112(11):2393-2400. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 10/14 016540-140607

The ASCO Post | FEBRUARY 10, 2015

PAGE 58

Expert’s Corner Health-Care Policy

Transitioning From Volume to Value in Cancer Care A Conversation With Thomas A. Gallo, MS By Ronald Piana Whether the care is delivered in a cancer center or a community practice, having the infrastructure in place to collect data is paramount to driving success with the various value-based programs that are emerging.

Administrative Burden

Thomas A. Gallo, MS

n an oncology health-care system that is increasingly changing its delivery and payment models, how do busy oncologists successfully bridge the transition from a volume- to value-based, patientcentric model? This, and other topics on value fueled a robust discussion at the Association of Community Cancer Centers (ACCC) second annual Institute for the Future of Oncology forum. At the ACCC meeting, Thomas A. Gallo, MS, Executive Director of the Richmond-based Virginia Cancer Institute, a large medical oncology community practice, facilitated a conversation among oncology care experts about how programs “communicate quality” in cancer care, especially as we shift from a volume-based to valuebased system. The ASCO Post spoke with Mr. Gallo about this rapidly evolving issue.

Defining Value In order to move from volume to value, we need to come to a consensus about the definition of value. Should that be on a national cancer community level, or can it be defined on an institution-by-institution level? I think there have to be some common value-of-care criteria that are established at a national level, which are based on consensus-driven standards, particularly when it comes to treatment protocols and practice guidelines. To that end, it’s important to have an impartial organization to help set those tools based on evidence. However, individual institutions and practices can set quality-care goals for themselves by using national standards as their baseline. And these institution-based practices will generally modify the way they measure value and deliver care to meet the specific needs of the communities and regions they serve.

You made a key point that having the infrastructure in place to collect data is paramount to driving success with the various value-based programs that are emerging. There are, however, current challenges with efficient collection and sharing of information from electronic health records needed for quality assessment and reporting to help oncology staff use the information to improve quality and patient outcomes. In the meantime, practices and providers must continue to rely on classic retrospective chart abstraction to assess and report on quality. While this approach does present an administrative burden for already stressed practices, it is important to stay engaged until more efficient processes are available. Can

Lively Roundtable At the ACCC meeting, you facilitated a forum to garner consensus and progress in measuring and communicating excellence in cancer care. Please share some of the salient points from the forum. We had a diverse group of about 20 professionals from the cancer community participating in the forum. There were physicians, administrators, pharmacists, social workers, and even a few cancer survivors. Our central purpose was to explore topics that are in the forefront of what’s going on in the cancer community across the nation. Obviously, one of the prime topics is assessing and communicating quality and value in care. It was a lively roundtable forum, which resulted in a white paper that I hope will be widely received. We all agreed that defining quality in oncology care is challenging, because it’s not like scoring a test or a certification; it’s a process of self-examination and im-

[I]t is essential for cancer care providers to successfully bridge the transition from a volume-based care model to one that is value based. The way we currently measure and communicate quality is not comprehensive or well aligned, especially for whom it matters most: our patients. —Thomas A. Gallo, MS

you comment on this with regards to transitioning from volume to value? Well, as a result of all of the external pressures on smaller practices, including administrative costs in time and labor to participate in various quality reporting programs, such as the Physician Quality Reporting System (PQRS), meaningful use, and clinical/quality data registries, we have seen a trend in which smaller practices are merging with larger practices or hospital systems. Equally important, I think this trend is also driven by the recognition that as we make the inevitable transition from volume-based care to value-based care, providers will need to have the infrastructure in place to gather data and measure value, and larger institutions provide that infrastructure. And I agree with you, that the electronic health record systems will need to improve their capabilities to capture and share data needed for quality and value measurement and reporting.

provement that needs to be integrated into your practice model (see sidebar). And it’s important to imbed quality and value into the culture of your practice by emphasizing improvement, not nec-

essarily punishment—people have to look at every complaint or failure as a learning opportunity used to improve care. We also discussed how organizations are measuring quality in a number of ways, which was highlighted by an ACCC trend survey in which 110 cancer programs submitted their results. The metrics cited to measure and track quality were largely based on patient satisfaction scores, American College of Surgeons Commission on Cancer standards, ASCO’s Quality Oncology Practice Initiative (QOPI) data, and guidelines by our own program. We looked at quality improvement initiatives that addressed issues such as time of referral to time of appointment, time of appointment to start of treatment, imaging wait times, chemotherapy and radiation therapy during the last weeks of life, and palliative care standards and shared-cost models. As mentioned, due to the shrinking levels of reimbursement and growing administrative costs, we looked at participation rates in accountable care organizations and found that 24% of respondents are currently involved in an accountable care organization that has an oncology component, which is up from 5% in the previous survey. We also found that 22% of practices plan to participate in an accountable care organization in the future.

Cost-Effective Care The consensus among the oncology community is that delivering high-value care reduces cost. Did you have a discus-

Consensus Points at the ACCC Institute for the Future of Oncology Forum

orum participants agreed that:

• Defining quality in cancer care is challenging. • Each stakeholder group—practitioners, payers, patients—has its own definition of quality. • Given the growing number of accrediting/quality improvement organizations/standards and reporting requirements, some streamlining or consolidating of these programs would be beneficial. • Patients often define quality by nonclinical parameters, such as environment of care and communication with provider. • The current reimbursement climate does not incentivize many of the approaches that improve quality. • Cost and quality must be considered in tandem when determining value.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 59

Expert’s Corner

sion that was centered on cost-effective delivery of care? We spoke about cost and quality as a uniform measure, in that it has become necessary to intertwine cost and value in the same equation. But one thing we emphasized was that value cannot be a code word for cost reduction. We need to make sure that we are getting the best outcomes for our patients for the money that is spent.

ing the topic of costs into their care. They want the best care possible, and cost is something hard to process when you’re battling cancer. That said, there’s been quite a bit published in the literature over the past several years detailing the financial toxicity of cancer treatment that burdens. We’ve found that many cancer

programs offer financial assistance programs to help ease the pressure on their patients. So, evaluating cost-effectiveness in cancer care is based on the perspectives of the patient, payer, and provider. One thing we all agree on is that in our shifting health-care environment, it is essential for cancer care providers to

Now Lee N. Newcomer, MD

For instance, Lee N. Newcomer, MD, led a 3-year alternative reimbursement pilot program at UnitedHealthcare, with five medical oncology practices covering patients with breast, colon, and lung cancers. They found significant cost savings while improving patient care. It’s important to note, that in cost and value discussions, the great majority of patients are afraid of bring-

The ASCO Post

OAK

successfully bridge the transition from a volume-based care model to one that is value based. The way we currently measure and communicate quality is not comprehensive or well aligned, especially for whom it matters most: our patients. n Disclosure: Mr. Gallo reported no potential conflicts of interest.

Enrolling

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

MPDL3280A1 Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

(an engineered anti-PDL1 antibody)

N=850

Randomized 1:1

Docetaxel

Primary Endpoint:

Secondary Endpoints:

• Objective survival

• Safety: incidence of adverse events • Overall response rate • Progression-free survival • Duration of response

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Locally advanced or metastatic NSCLC • • • •

• History of autoimmune disease

(stage IIIB, stage IV, or recurrent) Representative FFPE tumor specimens Disease progression during or following platinum-containing treatment regimen Measurable disease, defined by RECIST v1.1 ECOG performance status of 0-1

@ASCOPost

• Active hepatitis B or hepatitis C • Prior treatment with docetaxel, CD137 agonists,

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

For more information Visit: clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only)

E-mail: global.rochegenentechtrials@roche.com

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

The ASCO Post | FEBRUARY 10, 2015

PAGE 60

Conference on Clinical Cancer Research Friends of Cancer Research Holds Annual Conference on Clinical Cancer Research By Margot J. Fromer

riends of Cancer Research, in conjunction with the Engelberg Center for Health Care Reform at Brookings, recently held the seventh annual Conference on Clinical Cancer Research in Washington, DC. The panels that comprised the daylong meeting discussed a future that has already begun. The most salient point was that a potential new role is emerging for singlearm trials. Traditionally, large randomized clinical trials, with overall survival as the primary endpoint, have been the best—and often only acceptable—way to conduct new research. They require years of time and millions of dollars but for many years were the only way a new product could get through the U.S. Food and Drug Administration (FDA) for full approval. Now, mostly because of the advent of molecular therapy and the problems of accruing large numbers of participants, single-arm trials can provide alternative ways of looking at and interpreting evidence. As Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “In the 1970s and 1980s, we tested highly toxic drugs that mostly didn’t work. Now, with these new agents, because response rates are so good, we have to ask two entirely different questions: not

Richard Pazdur, MD

whether we should approve a drug but how quickly we can approve it, and does a trial answer a meaningful question for a good reason?”

Off-Label Use Off-label use in oncology is more common than ever and is often supported by varying types of evidence: reports in the medical literature as well as information from clinical trials, practice guidelines, and therapeutic standards. Reasons to go off-label with an agent can be compelling, especially when its use can be applied with great precision. Some patients have tumors with dis-

tinct biomarker signatures that do not align with abnormalities found in other cancers of the same histology, and others may have exhausted multiple lines of approved treatment. An agent that has efficacy in a biomarker-defined population may also have activity in another cancer expressing the same biomarker. If this is proven to be true, it means that off-label use will become more important. However, off-label use is not without challenges. Data about clinical effectiveness are sometimes limited, and the costs and side effects may be high. In addition, insurers may not reimburse unless the proposed use is in a major drug compendium, and there is no system to capture outcomes data when a drug is prescribed off-label. Off-label uses with enough supporting evidence to be listed in a major drug compendium are now covered by Medicare and some private payers. Some plans will reimburse when all other treatment options have been exhausted.

agents have shown that certain subsets of patients are most likely to respond, thus obviating the need for as many patients as once might have been required in a single trial. And more often than not, response rate reflects clinical benefit. “It may also be ethically and logistically challenging to enroll patients in a placebo-controlled or active-controlled randomized trial when they and their physicians are aware of the potential for benefit with the experimental agent. Moreover, because of crossover, [interpretation of overall survival data] has become increasingly difficult.” Two other situations render a randomized controlled trial inadvisable: if a new drug demonstrates an unprecedented overall response rate when there is no other treatment available, and when an approved molecularly targeted agent is tested in a rare tumor histology expressing the appropriate biomarker.

Role of Nonrandomized Trials Deborah Armstrong, MD, Professor of Oncology, Gynecology, and Obstetrics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, noted that randomized controlled trials

Deborah Armstrong, MD

with overall survival have long been the gold standard, with single-arm trials reserved for accelerated approval. “The overall response rate of a drug can be easily measured in a single-arm trial because, absent the therapy, it is extremely unusual for a tumor to regress spontaneously,” she said. “But overall survival requires a randomized controlled trial, because only many patients and enough time can provide those data. In view of new types of therapy, it is time to re-evaluate which trials are appropriate for which patients.” Dr. Armstrong added that several highly effective molecularly targeted

Josh Sommer

Josh Sommer, Executive Director of the Chordoma Foundation and a chordoma survivor, added, “For patients with no good standard treatment options, the idea of enrolling in a randomized trial in which they take a risk of not receiving the experimental therapy could be less than appealing.” The median survival for chordoma is 8 years, he said, so it is difficult to do a trial that measures overall survival. “Though we don’t know the preferences of chordoma patients as a whole, I frequently hear from patients that, if forced to make a choice, they would rather have better quality of life than more years with poor quality of life.”

Role of Single-Arm Trials Can single-arm trials support FDA approval? This is the big question, and the answer is, in many circumstances, they can—and should. Mace Rothenberg, MD, Senior Vice President for Clinical Develop-

ment/Medical Affairs and CMO of Pfizer Oncology, talked about when large effects are seen in early clinical studies or in rare cancers. Since 2003, he said, the FDA has granted traditional approval for a number of agents, notably the 2006 approval of imatinib (Gleevec) for several rare, life-threatening malignancies (chronic myelogenous leukemia and gastrointestinal stromal tumors) that express imatinib-sensitive

Mace Rothenberg, MD

tyrosine kinases. The 2012 approval of vismodegib (Erivedge) for metastatic and locally advanced basal cell carcinomas was based on a strong mechanistic rationale and the fact that it produced durable tumor responses. These approvals over the past decade can generate a set of standards to determine whether a single-arm trial is robust enough to support traditional approval: • The mechanism of action is supported by strong scientific rationale and/ or preclinical data. • The drug is intended for well-defined patient populations. • It produces substantial durable responses that exceed those of existing therapy. • The benefits outweigh the risks.

Translating Tumor Response Into Clinical Benefit Tumor response rates have been used to assess therapeutic efficacy for more than 50 years and can translate to historic controls in single-armed trials, said Gideon Blumenthal, MD, Clinical Team Leader, FDA Office of Hematology Oncology Products. He described a meta-analysis of 26 randomized controlled trials in ovarian cancer published between 1975 and 1989, which found that large improvements in response rates meant significant improvement in overall survival. Another meta-analysis, this one in non–small cell lung cancer, found that continued on page 62

Take a bite out of G-CSF acquisition costs Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

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

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

For more information, visit GRANIXhcp.com. Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

The ASCO Post | FEBRUARY 10, 2015

PAGE 62

Conference on Clinical Cancer Research Friends of Cancer Research continued from page 60

treatment effect on overall response rate was strongly correlated with treatment effect on progression-free survival but not between overall response rate and overall survival. “Response rate is not just a surrogate measure, it is a real-world clinical tool for patient assessment. Significant and

prolonged reduction of tumor burden is clinically meaningful and could be used for regulatory approval. Using response rate as an endpoint would shorten the time to final analysis compared with progression-free survival or overall survival,” he added. There are caveats, though. Clinical relevance depends on the nature of the disease, tumor location, and asso-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

ciated symptoms. Moreover, whether a tumor response is clinically meaningful depends on the depth, duration, and type of response. Even more critical is the existence of competing therapies, especially in rare or fastgrowing malignancies.

able for FDA approval, its outcome has to be clearly superior to that obtainable with currently available treatments, said Richard Simon, DSc, Chief of the Biometric Research Branch at the National Cancer Institute. The following factors should be considered:

Designing Single-Arm Trials For a single-arm trial to be accept-

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40503 December 2014 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Richard Simon, DSc

• Sufficient historic control data and how they will be selected and analyzed • Enough participants to assure that an improved outcome is not due to chance alone • Information about the prognostic impact of the biomarker used to select participants

Two Pathways to Evidence Development ASCO has outlined an approach to better evidence through a national “facilitated access program” and study of cancer patients receiving off-label targeted agents. It’s called the Targeted Agent and Profiling Utilization Registry (TAPUR), which will enroll patients with advanced cancer who have been on standard treatment and who have an “actionable” genomic alteration that can be targeted with an FDA-approved drug. “One of the major challenges to implementing personalized medicine is the lack of information about the risks and benefits of targeted drugs that are used off label to treat patients whose tumor harbors a genomic abnormality,” said Richard L. Schilsky, MD, FACP, FASCO, ASCO Chief Medical Officer. “Other difficulties are lack of access to these agents and interpretation of complex genomic test results. The ASCOled trial will address both challenges.” It has two primary objectives: to describe the antitumor activity and toxicity of commercially available targeted cancer drugs used off label for treatment of patients with advanced solid tumors with a known genomic variant and to provide patient access to these drugs. The primary endpoint is objective tumor response. Data on progressionfree survival, overall survival, duration of treatment, and serious adverse events also will be collected. continued on page 63

ASCOPost.com | FEBRUARY 10, 2015

PAGE 63

Conference on Clinical Cancer Research Friends of Cancer Research continued from page 62

The prospective, nonrandomized clinical trial will enroll patients who are no longer benefiting from standard treatment or for whom no such treatment is available. Patients will be screened for acceptable performance status and organ function, and a tumor

na. It was described by Dane Dickson, MD, Director of Clinical Science. The company is spearheading an off-label program called Molecular Evidence Development Consortium (MED-C), which allows patients access to off-label oncology products while collecting registry data on care and outcomes. Newly diagnosed patients will re-

One of the major challenges to implementing personalized medicine is the lack of information about the risks and benefits of targeted drugs that are used off-label to treat patients whose tumor harbors a genomic abnormality. —Richard L. Schilsky, MD, FACP, FASCO

Response rate is not just a surrogate measure, it is a real-world clinical tool for patient assessment. Significant and prolonged reduction of tumor burden is clinically meaningful and could be used for regulatory approval. —Gideon Blumenthal, MD

genomic test must identify at least one variant that can be targeted with drugs provided by participating pharmaceutical companies. The second pathway is proposed by Palmetto GBA, a subsidiary of BlueCross BlueShield of South Caroli-

ceive standardized molecular testing to identify mutations for which treatments exist in other diseases. They then enter a centrally prescribed treatment pathway, consisting of a number of options for combinations of mutations and disease. Patients with no

Dane Dickson, MD

actionable mutations will receive standard care. These two pathways are similar in some respects and different in others: • TAPUR patients have advanced disease, whereas MED-C’s are newly diagnosed. • TAPUR provides treatment options to patients with any tumor type, whereas MED-C provides infrastructure and methods for advanced molecular testing for only certain disease states. • Both provide FDA-approved drugs and are paid for by pharmaceutical companies. • Both are expected to launch in 2015.

Considerations for Evidence Development The two programs aim to generate data about the reliability and efficacy of targeted agents, but they and others to follow face significant challenges. To begin with, drugs can be selected in one of two ways: to allow any treatment a physician chooses or from a limited list. Either way, use of an off-label drug must be considered medically viable, and it must have an adequate safety profile. A program has to decide how to

design and operate diagnostic testing, which can be left to the discretion of the oncologist and/or site-specific laboratory or can be predefined through a list of qualified tests. Moreover, a program must decide whether it will require next-generation sequencing or other types of molecular testing, and if so, what criteria will be used to determine test inclusion. Rigorous reliability of test results must be ensured. The data collected must include many aspects of treatment and be obtainable without being overly burdensome: basic demographics, histologic diagnosis and genomics, prior therapy and best response, comorbidities, drug regimen, clinical outcomes, and how endpoints are assessed. Payment for off-label use is a critical issue and an important hurdle. Although patients receive drugs at no cost in the two studies, off-label use is not covered for most patients most of the time. Payment for diagnostic testing is also a problem, because there may be no reimbursement when the tests are done in conjunction with use of off-label drugs. Finally, patients’ active engagement with either a trial or “routine” use of off-label drugs is critical. They need to understand the reasons for and conduct of genetic profiling and accept that outof-pocket expenses may be a significant part of (and potentially an impediment to) off-label treatment. n Disclosure: Drs. Pazdur, Armstrong, Rothenberg, Simon, Blumenthal, Schilsky, and Dickson, and Mr. Sommer reported no potential conflicts of interest.

Contact The ASCO Post Advertising

Editorial Correspondence

Rates, reprints, or supplements

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

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

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

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

First-line Treatment for CLL ARZERRA® (ofatumumab) is indicated, in combination with chlorambucil, for previously untreated patients with CLL for whom ﬂudarabine-based therapy is considered inappropriate

An Effective Combination to Extend PFS*

*Assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008). CLL=chronic lymphocytic leukemia; PFS=progression-free survival; AR=adverse reaction; IR=infusion reaction.

Indications

Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in ARZERRA (ofatumumab) is indicated: fulminant hepatitis, hepatic failure and death, has occurred • In combination with chlorambucil, for the treatment of previously in patients treated with ARZERRA. Cases have been reported untreated patients with chronic lymphocytic leukemia (CLL) for in patients who are hepatitis B surface antigen (HBsAg) positive whom fludarabine-based therapy is considered inappropriate and also in patients who are HBsAg negative but are hepatitis B • For the treatment of patients with CLL refractory to core antibody (anti-HBc) positive. Reactivation also has occurred fludarabine and alemtuzumab in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface Important Safety Information for ARZERRA antibody [anti-HBs] positive). WARNING: HEPATITIS B VIRUS REACTIVATION AND HBV reactivation is defined as an abrupt increase in HBV PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously • Hepatitis B Virus (HBV) reactivation can occur in HBsAg negative and anti-HBc positive. Reactivation of HBV patients receiving CD20-directed cytolytic antibodies, replication is often followed by hepatitis, ie, increase in including ARZERRA, in some cases resulting in transaminase levels and, in severe cases, increase in bilirubin fulminant hepatitis, hepatic failure, and death levels, liver failure, and death. [see Warnings and Precautions (5.2)]. • Progressive Multifocal Leukoencephalopathy (PML) Screen all patients for HBV infection by measuring HBsAg and resulting in death can occur in patients receiving anti-HBc before initiating treatment with ARZERRA. For CD20-directed cytolytic antibodies, including ARZERRA patients who show evidence of hepatitis B infection (HBsAg [see Warnings and Precautions (5.4)]. positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing Infusion Reactions hepatitis B regarding monitoring and consideration for HBV ARZERRA can cause serious, including fatal, infusion reactions antiviral therapy. manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, Monitor patients with evidence of current or prior HBV cardiac events (eg, myocardial ischemia/infarction, acute coronary infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment syndrome, arrhythmia, bradycardia), back pain, abdominal pain, with ARZERRA. HBV reactivation has been reported for at least pyrexia, rash, urticaria, angioedema, cytokine release syndrome, 12 months following completion of therapy. and anaphylactoid/anaphylactic reactions. Infusion reactions In patients who develop reactivation of HBV while receiving occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate Administer ARZERRA in an environment where facilities to treatment. Resumption of ARZERRA in patients whose HBV adequately monitor and treat infusion reactions are available. reactivation resolves should be discussed with physicians with Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who Interrupt infusion with ARZERRA for infusion reactions of any develop HBV reactivation. severity. Institute medical management for severe infusion Hepatitis B Virus Infection reactions including angina or other signs and symptoms Fatal infection due to hepatitis B in patients who have not been of myocardial ischemia. If an anaphylactic reaction occurs, previously infected has been observed with ARZERRA. Monitor immediately and permanently discontinue ARZERRA and patients for clinical and laboratory signs of hepatitis. initiate appropriate medical treatment. ®

ARZERRA Plus Chlorambucil Demonstrated a Median PFS of 22.4 Months vs 13.1 Months With Chlorambucil Alone1 Probability of Progression-free Survival

1.0

ARZERRA + chlorambucil (n=221) Chlorambucil (n=226)

0.9 0.8

(HR 0.57 [95% CI: 0.45, 0.72] P<0.001)

0.7

22.4

0.6

13.1

0.4

• 67% incidence of IRs (all grades), including Grade ≥3, serious, or those that led to interruption or discontinuation; majority were Grade 1-2 and decreased after Cycle 1

Months

0.3 0.2 0.1 0.0 0

Number at risk ARZERRA plus 221 192 169 Chlorambucil 173 130 Chlorambucil 226

• 10% incidence of Grade ≥3 IRs; occurred most frequently during Cycle 1 — 6% on Day 1 — 3% on Day 8

Months

0.5

The Most Common ARs (≥10%) Were IRs and Neutropenia1

Time of Progression-free Survival (Months) 148

125

104

ARZERRA in combination with chlorambucil vs chlorambucil alone was studied in a randomized, open-label, parallel-arm, multicenter trial of 447 patients with previously untreated CLL for whom ﬂudarabine-based therapy was considered inappropriate. The population for safety analysis comprised 444 patients.1 HR=hazard ratio; CI=conﬁdence interval.

Important Safety Information for ARZERRA (cont’d) Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

— 56% on Day 1 — 23% on Day 8 • No patients in the chlorambucilalone arm experienced IRs • 3% of IRs led to discontinuation of ARZERRA • 27% incidence of neutropenia with ARZERRA plus chlorambucil vs 18% with chlorambucil alone

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%). In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%). Reference: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GSK; 2014.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

ARZERRA J-Code: J9302 To learn more, please visit www.ARZERRAhcp.com.

The ASCO Post | FEBRUARY 10, 2015

PAGE 66

Announcements

West Cancer Center Announces The University of Tennessee/West Institute for Cancer Research

est Cancer Center has announced the establishment of The University of Tennessee (UT)/West Institute for Cancer Research, a nonprofit public charity fully dedicated to raising funds for adult

cancer research in Memphis. The UT/ West Institute for Cancer Research is soliciting grants from government agencies, foundations, and individuals to be used to broaden cutting-edge research programs

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information, including Boxed Warning, for complete product information. WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA®, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)]. • Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Previously Untreated Chronic Lymphocytic Leukemia ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1) of full prescribing information]. 1.2 Refractory CLL ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.2) of full prescribing information]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately

and to strengthen the ability to provide the best possible cancer treatment. According to Lee Schwartzberg, MD, Director of The UT/West Institute for Cancer Research and Medical

Director of West Cancer Center, “There is great momentum for truly exceptional progress in cancer research. We are engaging top talent to be leaders in the development of new treatments, thera-

discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufﬁcient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. 5.3 Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. 5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. 5.6 Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Infusion Reactions [see Warnings and Precautions (5.1)] • Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)] • Hepatitis B Virus Infection [see Warnings and Precautions (5.3)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.4)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] • Cytopenias [see Warnings and Precautions (5.6)] Previously Untreated CLL: The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 1). Refractory CLL: The most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 3). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The data described in Table 1 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 2 includes relevant hematologic laboratory abnormalities.

(cont’d)

ASCOPost.com | FEBRUARY 10, 2015

PAGE 67

Announcements

pies, and protocols. With the development of The UT/West Institute, our researchers and scientists will now have the much-needed resources to translate discoveries right here in Memphis.” In order to make the biggest impact, funds donated to The UT/West Institute will be primarily focused on research in these four centers of excellence: transla-

Lee Schwartzberg, MD

Table 1. Adverse Reactions With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil ARZERRA Plus Chlorambucil (N = 217)

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Infusion reactionsa

Neutropenia

Asthenia

Headache

Lower respiratory tract infection

Arthralgia

Adverse Reactions

Leukopenia Herpes simplex

Upper abdominal pain

tional drug discovery and development, cancer immunotherapy, women’s cancers, and community outcomes. The UT/West Institute has already received its first major gift of $2.5 million through the Plough Foundation, which will become the much-needed seed money for the translational drug discovery and development center of ex-

and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white. Table 3. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset

Total Population (N = 154) Adverse Reaction Pneumoniaa

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Pyrexia

Cough

Diarrhea

Fatigue

Dyspnea

Rashb

Bronchitis

Nausea

Upper respiratory tract infection

Edema peripheral

Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, ﬂushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex. Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil

Leukopenia

Fludarabine- and Alemtuzumabrefractory (N = 59)

Anemia

ARZERRA Plus Chlorambucil (N = 217)

cellence. Chairman of the Board for the Plough Foundation Diane Rudner said, “Abe Plough, my grandfather and founder of the Plough Foundation, believed that you did the greatest good when you helped the greatest number of people. Today, that very mission is further realized by the Foundation’s commitment to the efforts of The UT/West Institute.” n

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Neutropenia

Lymphopenia

Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data described in Table 3 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA

Back pain

Chills

Nasopharyngitis

Sepsisc

Urticaria

Insomnia

Headache

Herpes zoster

Hyperhidrosis

Hypertension

Hypotension

Muscle spasms

Sinusitis

Tachycardia

Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Includes rash, rash macular, and rash vesicular. c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. a

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the ﬁrst infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the ﬂudarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA. (cont’d)

The ASCO Post | FEBRUARY 10, 2015

PAGE 68

Announcements

Suzanne Topalian, MD, Recognized for Pioneering Work in Immunotherapy Treatment of Melanoma and Other Cancers

he Melanoma Research Alliance has reported that Suzanne Topalian, MD, Chair of the group’s Scientific Advisory Panel, and former Chief Scientific Officer, has been

named one of 10 people in science who mattered in 2014 by the Nature International Weekly Journal of Science. Dr. Topalian was cited for her pioneering work in cancer immuno-

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. 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 ARZERRA with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. 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. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda. 7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

therapy, which has resulted thus far in approval of three new drug therapies for treating melanoma patients, and with possible applications for other cancers.

13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the ﬁnal dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological signiﬁcance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2, 5.3)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.6)] • Signs of infections including fever and cough [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Monitoring and possible need for treatment if they have a history of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)] • Periodic monitoring for blood counts [see Warnings and Precautions (5.6)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.7)] ARZERRA is a registered trademark of the GSK group of companies. Manufactured by: GLAXO GROUP LIMITED Brentford, Middlesex, TW8 9GS, United Kingdom U.S. License 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved. Revised: 04/2014 ARZ:8BRS ©2014 GSK group of companies. All rights reserved. Printed in USA. AZA522R0 October 2014

Dr. Topalian is Professor of Surgery and Oncology at Johns Hopkins University School of Medicine, and Director, Melanoma Program, Sidney Kimmel Comprehensive Cancer Center, Baltimore. She was the first Chief Science Officer for the Melanoma Research Alliance, a position she held until 2 years ago when she became Head of the organization’s Scientific Advisory Panel.

Suzanne Topalian, MD

From Theory to Breakthrough “All of us at [Melanoma Research Alliance] who work with Dr. Topalian are terrifically excited about her welldeserved recognition, and especially because we know the effort and determination that went into her research that is now yielding a hopeful means of combating and extending the life of patients with melanoma, one of the fastest-growing cancers,” said Wendy Selig, CEO and President of the Melanoma Research Alliance. “That immunotherapy at long last seems to be coming into its own, with possible application for other cancers, especially lung cancer, is a testament to her commitment to a theory that is now widely accepted as a major cancer treatment breakthrough.” Nature wrote that Dr. Topalian as a clinician “always believed that cancer immunotherapy would work—and she was right.”1

About Melanoma Research Alliance Melanoma Research Alliance is a public charity formed in 2007 under the auspices of the Milken Institute, with the generous founding support of Debra and Leon Black. The group has dedicated more than $60 million to research seeking to better prevent, diagnose, and treat melanoma. For more information, please visit www.CureMelanoma.org. n Reference 1. Ledford H: 365 days: Nature’s 10. Nature 516:311-319, 2014.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 69

Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Glioblastoma Compiled by Jo Cavallo

he information contained in this Clinical Trials Resource Guide includes actively recruiting clinical studies for patients with newly diagnosed or recurrent glioblastoma multiforme. The studies include pilot, phase I, I/II, III, and observational trials investigating chemoradiation therapy; MET/ PET scans in predicting response to therapy; standard and new chemotherapies; vaccine therapy; high-dose vitamin C in combination with standard therapy; and molecular profiling to guide treatment. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PILOT

it works when given before and after surgery in treating patients with glioblastoma that has grown or recurred and requires surgery. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Proportion of patients who achieve a drug concentration ≥ 70 nM in contrast-enhancing tumor tissue (time frame: up to 2 years) Principal Investigator: Eudocia Lee, MD, MPH, Dana-Farber Cancer Institute; 866-790-4500 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02133183

Study Type: Phase 0/interventional/single-group assignment Study Title: Pilot Study of METPET (L-[Methyl]-11C Methionine Positron Emission Tomography) to Evaluate for Treatment Response After Chemoradiation Therapy for Newly Diagnosed Glioblastoma Study Sponsor and Collaborators: Massachusetts General Hospital Purpose: To evaluate whether MET-PET scans have value in predicting response to standard chemoradiation therapy in patients with newly diagnosed glioblastoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Effect of 11C methionine PET on progression-free survival (time frame: 2 years) Principal Investigator: Kevin Oh, MD, Massachusetts General Hospital; 617-724-1159, koh2@partners.org. For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01867593

Study Type: Pilot/interventional/ single-group assignment Study Title: A Study to Evaluate Vascular Normalization in Patients With Recurrent Glioblastoma Treated With Bevacizumab Using [11C] Temozolomide PET and Vascular MRI Study Sponsor and Collaborators: Massachusetts General Hospital; National Cancer Institute Purpose: To investigate how the blood vessels in a patient’s tumor change from treatment with bevacizumab and how these changes affect the way the tumor absorbs temozolomide Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To assess temozolomide delivery before and after bevacizumab in glioblastoma (time frame: 2 years) Principal Investigator: Tracy Batchelor, MD, Massachusetts General Hospital; 617-724-8770, tbatchelor@ partners.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01987830.

Study Type: Pilot/interventional/ parallel assignment Study Title: TORC1/2 Inhibitor INK128 Before and After Surgery in Treating Patients With Recurrent Glioblastoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate how much TORC1/2 inhibitor INK128 reaches the brain tumor and how well

Study Type: Pilot/interventional/ single-group assignment Study Title: Pilot Clinical Trial of Allogeneic Tumor Lysate-Pulsed Autologous Dendritic Cell Vaccination in Newly Diagnosed Glioblastoma Study Sponsor and Collaborators: Mayo Clinic; National Cancer Institute Purpose: To test vaccine therapy and temozolomide in patients with newly diagnosed glioblastoma

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Incidence of significant toxicity, defined as grade 3 or higher adverse event that is possibly, probably, or definitely related to treatment measured using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (time frame: up to 84 days) Principal Investigator: Ian Parney, MD, PhD, Mayo Clinic. Contact: Clinical Trials Referral Office; 855-776-0015 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01957956

PHASE I Study Type: Phase I/interventionalsingle-group assignment Study Title: Dendritic Cell Vaccine For Malignant Glioma and Glioblastoma Multiforme in Adult and Pediatric Subjects Study Sponsor and Collaborators: University of Miami Purpose: To test whether dendritic cell vaccine is safe and feasible in patients with high-grade glioma Ages Eligible for Study: 13 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of subjects experiencing adverse events (time frame: 5 years) Principal Investigator: John Goldberg, MD, University of Miami; jgoldberg2@med.miami.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01808820 Study Type: Phase I/interventional/single-group assignment Study Title: Dose-Finding and Safety Study of PVS-RIPO Against Recurrent Glioblastoma Study Sponsor and Collaborators: National Cancer Institute; Brain Tumor Research Charity Grant Purpose: To determine the maximally tolerated dose and dose-limiting toxicity of PVS-RIPO when delivered intracerebrally by convection-enhanced delivery. To estimate progression-free and overall survival in patients with supratentorial resectable, recurrent WHO grade IV malignant glioma

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose (time frame: 28 days post administration of PVS-RIPO) Principal Investigator: Allan Friedman, MD, Duke University Medical Center. Contact: Karen Carter, 919668-2329; Karen.carter@duke.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01491893 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Trial of a Measles Virus Derivative Producing CEA (MV-CEA) in Patients With Recurrent Glioblastoma Multiforme Study Sponsor and Collaborators: Mayo Clinic; National Cancer Institute Purpose: To study the side effects and best dose of viral therapy in treating patients with recurrent glioblastoma multiforme Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Toxicity profile as assessed by National Cancer Institute CTC version 3.0 Principal Investigator: Evanthia Galanis, MD, Mayo Clinic. Contact: Clinical Trials Referral Office, 855-776-0015 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00390299 Study Type: Phase I/interventional/single-group assignment Study Title: A Phase I Study of MLN0128 and Bevacizumab in Patients With Recurrent Glioblastoma and Other Solid Tumors Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of MLN0128 when given in combination with bevacizumab in treating patients with glioblastoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose/recommended phase II dose of MLN0128, continued on page 70

The ASCO Post | FEBRUARY 10, 2015

PAGE 70

Clinical Trials Resource Guide Glioblastoma Trials continued from page 69

determined according to incidence of dose-limiting toxicity as graded using the National Cancer Institute CTCAE version 4.0 (time frame: 28 days) Principal Investigator: Lakshmi Nayak, MD, Dana-Farber Cancer Institute For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02142803 Study Type: Phase I/interventional/nonrandomized/single-group assignment Study Title: A Phase I Trial of HighDose Ascorbate in Glioblastoma Multiforme Study Sponsor and Collaborators: University of Iowa; National Institutes of Health; National Cancer Institute Purpose: To test the safety of adding high-dose ascorbate (vitamin C) to standard radiation and chemotherapy for initial treatment of glioblastoma multiforme Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of grade 3, 4, and 5 adverse events (time frame: weekly during therapy for up to 10 months) Principal Investigator: John M. Buatti, MD, University of Iowa For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01752491 Study Type: Phase I/inter ventional/nonrandomized/parallel assignment Study Title: Phase I Study of AZD1775 (MK-1775) With Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma and Evaluation of Intratumoral Drug Distribution in Patients With Recurrent Glioblastoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To investigate the side effects and best dose of WEE1 inhibitor MK-1775 when given together with radiation therapy and temozolomide in treating patients with newly diagnosed or recurrent glioblastoma multiforme Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose of WEE1 inhibitor MD-1775 with 6 weeks of radia-

tion therapy and temozolomide, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (arm 1); (time frame: up to 6 weeks) Principal Investigator: Brian Alexander, MD, MPH, National Cancer Institute; 617-724-5200 For More Information: Visit Clini-

calTrials.gov and refer to this study by its identifier: NCT01849146.

PHASE I/II Study Type: Phase I/II/interventional/randomized/parallel assignment Study Title: N1174: Phase I/Comparative Randomized Phase II Trial of

TRC105 Plus Bevacizumab vs Bevacizumab in Bevacizumab-Naive Patients With Recurrent Glioblastoma Multiforme Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and the best dose of anti-endoglin monoclonal antibody TRC105 when

ASCOPost.com | FEBRUARY 10, 2015

PAGE 71

Clinical Trials Resource Guide

given together with bevacizumab and to see how well they work in treating patients with glioblastoma multiforme that has recurred Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures:

Maximum tolerated dose of TRC105 combined with bevacizumab based on the incidence of dose-limiting toxicity graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (phase 1); (time frame: 28 days) Principal Investigator: Evanthia Galanis, MD, Alliance for Clinical Tri-

als in Oncology; 507-538-7623 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT014648348

PHASE II Study Type: Phase II/interventional/single-group assignment

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

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

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

Clovis Oncology is leading the fight

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

Study Title: A Pilot Trial Testing the Feasibility of Using Molecular Profiling to Guide an Individualized Treatment Plan in Adults With Recurrent/ Progressive Glioblastoma Study Sponsor and Collaborators: University of California, San Francisco; Translational Genomics Research Institute; Ben & Catherine Ivy Foundation Purpose: To test the feasibility of a specialized tumor board assigning a treatment plan within 35 days of obtaining tumor tissue. The treatment plan will take into consideration each patient’s tumor molecular profile and predictive modeling as well as history and treatment, as well as other medical conditions of the patient. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Feasibility (time frame: 12 months) Principal Investigator: Michael Prados, MD, University of California, San Francisco; 415-353-2652, pradosm@neurosurg.ucsf.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02060890 Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Study of the NovoTTF-100A System, Enhanced by Genomic Analysis to Identify the Genetic Signature of Response in the Treatment of Recurrent Glioblastoma Multiforme Study Sponsor and Collaborators: Washington University School of Medicine Purpose: To determine how well Novocure’s Tumor Treating Electric Fields (NovoTTF) therapy works in treating patients with recurrent glioblastoma multiforme Ages Eligible for Study: 22 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Overall response rate (complete response + partial response + stable disease) (bevacizumab naive; time frame: 6 months) Principal Investigator: David Tran, MD, PhD, Washington State University School of Medicine; 314-362-8967, dtran@dom.wustl.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01954576 n

The ASCO Post | FEBRUARY 10, 2015

PAGE 72

2015

2015 Oncology Meetings February AACR-SNMMI Joint Conference: State-of-the-Art Molecular Imaging in Cancer Biology and Therapy February 11-14 • San Diego, California For more information: www.aacr.org 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congressesmeetings/items/5th-ichno 15th Annual Targeted Therapies of the Treatment of Lung Cancer February 18-21 • Santa Monica, California For more information: www.iaslc.org/events/15th-annualtargeted-therapies-treatment-lungcancer The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/ ASCO Multidisciplinary Cancer Management Course (MCMC) February 21-22 • Naypyidaw, Myanmar For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

5th Annual Texas Adolescent and Young Adult Oncology Conference February 27-28 • Houston, Texas For more information: www.mdanderson.org/educationand-research/education-andtraining/schools-and-programs/ cme-conference-management/ conferences/cme/conferencemanagement-5th-annual-texasadolescent-and-young-adultoncology-conference.html 6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/mbcc/ meetings/32nd-Annual-Miami-BreastCancer-Conference

Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http://moffitt .org/for-physicians-healthcareprofessionals/conferences/ conferences 2015 Multidisciplinary Head and Neck Cancer March 6-7 • Weston, Florida For more information: www.clevelandclinicmeded.com/live/ courses/headandneck/overview.asp Hematology and Medical Oncology Board Review: Contemporary Practice From Memorial SloanKettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

Society of Interventional Radiology February 28-March 5 • Atlanta, Georgia For more information: www.sirmeeting.org

March NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp 13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com

ESMO Symposium on Signalling Pathways in Cancer 2015 March 13-14 • Barcelona, Spain For more information: www.esmo.org/Conferences/ Signalling-Pathways-2015Personalised-Medicine 8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http://www.gotoper.com/ conferences/ipcc/meetings/8thAnnual-Interdisciplinary-ProstateCancer-Congress

25th Annual Interdisciplinary Breast Center Conference March 14-18 • Las Vegas, Nevada For more information: www2.breastcare.org American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp 14th St. Gallen International Breast Cancer Conference March 18-21 • Vienna, Austria For more information: www.oncoconferences.ch State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015 46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

continued on page 78

VOTRIENT is indicated for the treatment of advanced renal cell carcinoma (RCC)1

EFFICACY AGAINST PROGRESSION

VOTRIENT demonstrated an overall median progression-free survival (PFS) of

9.2 months vs 4.2 months with placebo (HR 0.46; 95% CI 0.34-0.62; P<0.001)1*

*Phase 3, randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efﬁcacy and safety of VOTRIENT in ﬁrst-line or cytokine-pretreated patients (N=435) with advanced RCC of clear cell or predominantly clear cell histology. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

Important Safety Information for VOTRIENT WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

Please see additional Important Safety Information for VOTRIENT on subsequent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

EFFICACY LIGHTS THE WAY

®® 1 1 VOTRIENT VOTRIENT (pazopanib) (pazopanib)isisindicated indicatedfor forthe thetreatment treatmentofofpatients patientswith withadvanced advancedrenal renalcell cellcarcinoma carcinoma(RCC). (RCC).

VOTRIENT: Significant PFS improvement in patients with advanced RCC1 Median PFS in patients with advanced RCC receiving VOTRIENT vs placebo1,2

1010

VOTRIENT VOTRIENT Placebo Placebo

11.1 11.1

1212

MONTHS MONTHS

9.2 9.2

MONTHS MONTHS

7.4 7.4

Months Months

8 8 6 6 4 4

MONTHS MONTHS

4.2 4.2

2.8 2.8

MONTHS MONTHS

4.2 4.2

MONTHS MONTHS

2 2 0 0

HRHR 0.46; 0.46; 95% 95% CICI 0.34-0.62 0.34-0.62 (P<0.001) (P<0.001) AllAll patients patients

HRHR 0.40; 0.40; 95% 95% CICI 0.27-0.60 0.27-0.60 (P<0.001) (P<0.001) First-line First-line patients patients

HRHR 0.54; 0.54; 95% 95% CICI 0.35-0.84 0.35-0.84 (P<0.001) (P<0.001) Cytokine-pretreated Cytokine-pretreated patients patients

Randomized, Randomized, double-blind, double-blind, placebo-controlled, placebo-controlled, multicenter multicenter study study to evaluate to evaluate thethe effieffi cacy cacy andand safety safety of VOTRIENT of VOTRIENT in patients in patients (N=435) (N=435) with with advanced advanced RCC. RCC. Patients Patients with with locally locally advanced advanced or metastatic or metastatic RCC RCC of clear of clear cellcell or predominantly or predominantly clear clear cellcell histology histology were were randomized randomized (2:1) (2:1) to receive to receive either either VOTRIENT VOTRIENT 800800 mgmg (n=290) (n=290) once once daily daily or placebo or placebo (n=145). (n=145). TheThe study study included included 1 1 first-line first-line patients patients receiving receiving VOTRIENT VOTRIENT (n=155) (n=155) or placebo or placebo (n=78) (n=78) as well as well as cytokine-pretreated as cytokine-pretreated patients patients receiving receiving VOTRIENT VOTRIENT (n=135) (n=135) or placebo or placebo (n=67). (n=67).

Important Safety Information for VOTRIENT (cont’d) • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thromboembolic Events: Arterial thromboembolic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thromboembolic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events (VTEs) have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, VTEs were reported in 1% of patients treated with VOTRIENT and

in 1% of patients treated with placebo. Monitor for signs and symptoms. • Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred in clinical trials. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension.

• Wound Healing: VOTRIENT may impair wound • Wound Healing: VOTRIENT may impair wound healing. Interruption therapy is recommended healing. Interruption of of therapy is recommended in in patients undergoing surgical procedures; treatment with patients undergoing surgical procedures; treatment with VOTRIENT should stopped least 7 days prior VOTRIENT should bebe stopped at at least 7 days prior to to scheduled surgery. VOTRIENT should discontinued scheduled surgery. VOTRIENT should bebe discontinued in in patients with wound dehiscence. patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported • Hypothyroidism: Hypothyroidism was reported in in (19/290) patients treated with VOTRIENT 7%7% (19/290) of of patients treated with VOTRIENT in in randomized RCC in no patients receiving thethe randomized RCC trialtrial andand in no patients receiving placebo. Monitoring thyroid function tests placebo. Monitoring of of thyroid function tests is is recommended. recommended. • Proteinuria: In the randomized RCC trial, proteinuria • Proteinuria: In the randomized RCC trial, proteinuria reported adverse reaction in 9% (27/290) waswas reported as as anan adverse reaction in 9% (27/290) of of patients receiving VOTRIENT, leading discontinuation patients receiving VOTRIENT, leading to to discontinuation of treatment 2 patients. There were reports of treatment in 2inpatients. There were nono reports of of proteinuria in patients receiving placebo. Monitor urine proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment 24-hour urine protein protein. Interrupt treatment forfor 24-hour urine protein grams discontinue repeat episodes despite ≥3≥3 grams andand discontinue forfor repeat episodes despite dose reductions. dose reductions. • Infection: Serious infections (with without • Infection: Serious infections (with or or without neutropenia), some with fatal outcomes, have been neutropenia), some with fatal outcomes, have been reported. Monitor signs symptoms treat reported. Monitor forfor signs andand symptoms andand treat active infection promptly. Consider interruption active infection promptly. Consider interruption or or discontinuation VOTRIENT. discontinuation of of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated forfor useuse in combination with VOTRIENT is not indicated in combination with other agents. Increased toxicity andand mortality have other agents. Increased toxicity mortality have been observed in clinical trials administering VOTRIENT been observed in clinical trials administering VOTRIENT in combination with lapatinib or or with pemetrexed. in combination with lapatinib with pemetrexed. TheThe fatal toxicities observed included pulmonary fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, andand sudden hemorrhage, gastrointestinal hemorrhage, sudden death. A safe andand effective combination dose hashas notnot death. A safe effective combination dose been established with these regimens. been established with these regimens. • Increased Toxicity in in Developing Organs: TheThe safety • Increased Toxicity Developing Organs: safety andand effectiveness of VOTRIENT in pediatric patients have effectiveness of VOTRIENT in pediatric patients have notnot been established. VOTRIENT is not indicated forfor useuse been established. VOTRIENT is not indicated in pediatric patients. Animal studies have demonstrated in pediatric patients. Animal studies have demonstrated pazopanib cancan severely affect organ growth andand maturation pazopanib severely affect organ growth maturation during early post-natal development, andand resulted in in during early post-natal development, resulted toxicity to the lungs, liver, heart, andand kidney andand in death. toxicity to the lungs, liver, heart, kidney in death. VOTRIENT may potentially cause serious adverse effects VOTRIENT may potentially cause serious adverse effects

1 1 Once-daily Once-dailyoral oraldosing dosing

• The • The recommended recommended starting starting dose dose of of VOTRIENT VOTRIENT is 800 is 800 mgmg once once daily daily without without food food (at(at least least 1 hour 1 hour before before or or 2 hours 2 hours after after a meal). a meal). Daily Daily dose dose should should notnot exceed exceed 800 800 mgmg • Do notnot crush tablets duedue to to thethe potential forfor increased raterate of of absorption, which may • Do crush tablets potential increased absorption, which may affect systemic exposure affect systemic exposure • If•aIfdose is missed, it should notnot bebe taken if itifisit less than 1212 hours until thethe next dose a dose is missed, it should taken is less than hours until next dose • In• advanced RCC, initial dose reduction should bebe 400 mg,mg, andand additional dose In advanced RCC, initial dose reduction should 400 additional dose decrease or or increase should bebe in 200-mg steps based onon individual tolerability decrease increase should in 200-mg steps based individual tolerability • In• the Phase 3 advanced RCC trial, 42% of of patients onon VOTRIENT required a dose In the Phase 3 advanced RCC trial, 42% patients VOTRIENT required a dose interruption; 36% of of patients onon VOTRIENT were dose reduced interruption; 36% patients VOTRIENT were dose reduced • No dose adjustment is required in patients with mild hepatic impairment • No dose adjustment is required in patients with mild hepatic impairment • In• patients with moderate hepatic impairment, alternatives to to VOTRIENT should bebe In patients with moderate hepatic impairment, alternatives VOTRIENT should considered. If VOTRIENT is used in patients with moderate hepatic impairment, thethe considered. If VOTRIENT is used in patients with moderate hepatic impairment, dose should bebe reduced to to 200 mgmg perper dayday dose should reduced 200 • Treatment with VOTRIENT is not recommended in patients with severe hepatic • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment impairment • Monitor serum liver tests before initiation of of treatment andand at at Weeks 3, 3, 5, 5, 7, and 9. 9. • Monitor serum liver tests before initiation treatment Weeks 7, and Thereafter, monitor at at Month 3 and at at Month 4, 4, andand as as clinically indicated. Periodic Thereafter, monitor Month 3 and Month clinically indicated. Periodic monitoring should then continue after Month 4 4 monitoring should then continue after Month • For additional information onon dosing modiﬁ cations based onon drug • For additional information dosing modiﬁ cations based drug interactions, please seesee Sections 2.22.2 and 7 of accompanying Brief interactions, please Sections and 7 of accompanying Brief Summary of of Prescribing Information Summary Prescribing Information

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information for VOTRIENT on adjacent pages. Please see Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

® ® Pazopanib Pazopanib(VOTRIENT (VOTRIENT ) has ) hasa aCategory Category1 1recommendation recommendationasasa afirst-line first-linetherapy therapyininthe theNCCN NCCNClinical ClinicalPractice Practice ® ® Guidelines GuidelinesininOncology Oncology(NCCN (NCCNGuidelines Guidelines) for ) forrelapsed relapsedororStage StageIVIVunresectable unresectableRCC RCCofofpredominant predominantclear clear 3 3 ® ® ® ® cell cellhistology. histology.NCCN NCCNGuidelines Guidelinesalso alsoinclude includetherapies therapiesother otherthan thanpazopanib pazopanib(VOTRIENT (VOTRIENT) as ) asfirst-line first-linetreatment treatmentoptions. options.

Important ImportantSafety SafetyInformation Informationfor forVOTRIENT VOTRIENT(cont’d) (cont’d) onon organ organ development development in pediatric in pediatric patients, patients, particularly particularly in in patients patients younger younger than than 2 years 2 years of age. of age. • Pregnancy • Pregnancy Category Category D:D: VOTRIENT VOTRIENT cancan cause cause fetal fetal harm harm when when administered administered to to a pregnant a pregnant woman. woman. Women Women of of childbearing childbearing potential potential should should bebe advised advised of of thethe potential potential hazard hazard to to thethe fetus fetus andand to to avoid avoid becoming becoming pregnant pregnant while while taking taking VOTRIENT. VOTRIENT. • Diarrhea: • Diarrhea: Diarrhea Diarrhea occurred occurred frequently frequently andand was was predominantly predominantly mild mild to to moderate moderate in severity. in severity. Patients Patients should should bebe advised advised how how to to manage manage mild mild diarrhea diarrhea andand to to notify notify their their healthcare healthcare provider provider if moderate if moderate to to severe severe diarrhea diarrhea occurs occurs so so appropriate appropriate management management cancan bebe implemented implemented to to minimize minimize its its impact. impact. • Lipase • Lipase Elevations: Elevations: In aInsingle-arm a single-arm RCC RCC trial, trial, increases increases in lipase in lipase values values were were observed observed forfor 27% 27% (48/181) (48/181) of of patients. patients. In the In the RCC RCC trials trials of of VOTRIENT, VOTRIENT, clinical clinical pancreatitis pancreatitis was was observed observed in <1% in <1% (4/586) (4/586) of of patients. patients. • Pneumothorax: • Pneumothorax: Two Two of of 290 290 patients patients treated treated with with VOTRIENT VOTRIENT andand nono patients patients onon thethe placebo placebo armarm in the in the randomized randomized RCC RCC trialtrial developed developed a pneumothorax. a pneumothorax. • Bradycardia: • Bradycardia: In the In the randomized randomized trialtrial of of VOTRIENT VOTRIENT forfor thethe treatment treatment of of RCC, RCC, bradycardia bradycardia based based onon vital vital signs signs (<60 (<60 beats beats perper minute) minute) was was observed observed in 19% in 19% (52/280) (52/280) of of patients patients treated treated with with VOTRIENT VOTRIENT andand in 11% in 11% (16/144) (16/144) of of patients patients onon thethe placebo placebo arm. arm. • Drug Interactions: Coadministration with strong • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg,(eg, ketoconazole, ritonavir, CYP3A4 Inhibitors ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib andand clarithromycin) increases concentrations of pazopanib

should be avoided, but, if warranted, reduce the dose of VOTRIENT to 400 mg. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. Drugs That Raise Gastric pH: Avoid concomitant use of VOTRIENT with drugs that raise gastric pH (eg, esomeprazole) due to the potential to decrease concentrations of pazopanib. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours.

• Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V3.2014. ©National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed April 30, 2014. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Please Please see see additional additional Important Important Safety Safety Information Information for for VOTRIENT VOTRIENT onon adjacent adjacent pages. pages. Please Please see see Brief Brief Summary Summary ofof Prescribing Prescribing Information, Information, including including Boxed Boxed Warning, Warning, for for VOTRIENT VOTRIENT onon adjacent adjacent pages. pages. www.GSKSource.com www.GSKSource.com ©2014 ©2014 GSKGSK group group of companies. of companies. All All rights rights reserved. reserved. Printed Printed in USA. in USA. 66501R0 66501R0 June June 2014 2014

VOTRIENT.com/HCP/aRCC VOTRIENT.com/HCP/aRCC

EFFICACY LIGHTS THE WAY

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [See Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.4)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients who received placebo on the trial had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood

pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.10)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thromboembolic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thromboembolic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events (VTE) including venous thrombosis and fatal pulmonary embolus (PE) have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Thrombotic Microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan. VOTRIENT is not indicated for use in combination with other agents. Six of the 7 TMA cases occurred within 90 days of the initiation of VOTRIENT. Improvement of TMA was observed after treatment was discontinued. Monitor for signs and symptoms of TMA. Permanently discontinue VOTRIENT in patients developing TMA. Manage as clinically indicated. 5.8 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. 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. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Permanently discontinue VOTRIENT in patients developing RPLS. 5.10 Hypertension: In clinical trials, hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.11 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.12 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.13 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.14 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.15 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.16 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days

old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.17 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thromboembolic events, thrombotic microangiopathy, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.10, 5.14-5.15)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, doubleblind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3Grade 4 Gradesa Grade 3Grade 4 % % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Additional adverse reactions from other clinical trials in RCC patients treated with VOTRIENT are listed below: Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle spasms.

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290)

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

Placebo (N=145)

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

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53 41

10 7 <1

2 <1 0

22 19 33

1 <1 1

0 0 0

B:14.25”

T:13”

S:12.5”

Sodium decreased 31 4 1 24 4 0 Magnesium 26 <1 1 14 0 0 decreased Glucose decreased 17 0 <1 3 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. Bradycardia: In the randomized trial of VOTRIENT for the treatment of RCC, bradycardia based on vital signs (<60 beats per minute) was observed in 19% (52/280) of patients treated with VOTRIENT and in 11% (16/144) of patients on the placebo arm. Bradycardia was reported as an adverse reaction in 2% (7/290) of patients treated with VOTRIENT compared to <1% (1/145) of patients treated with placebo. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: Pancreatitis 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Consider an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 [see Clinical Pharmacology (12.3) of full prescribing information]. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Dosage and Administration (2.2)]. Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Drugs That Inhibit Transporters: In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered. 7.3 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.4 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. 7.5 Drugs That Raise Gastric pH: In a drug interaction trial in patients with solid tumors, concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), decreased the exposure of pazopanib by approximately 40% (AUC and Cmax). Therefore, concomitant use of VOTRIENT with drugs that raise gastric pH should be avoided. If such drugs are needed, short-acting antacids should be considered in place of PPIs and

H2 receptor antagonists. Separate antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Clinical Pharmacology (12.3) of full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.17)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the postweaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.16)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively, of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is

highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • 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). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of the GSK group of companies.

GlaxoSmithKline Research Triangle Park, NC 27709

The ASCO Post | FEBRUARY 10, 2015

PAGE 78

2015

2015 Oncology Meetings continued from page 72

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919 International Society of Geriatric Oncology (SIOG) USA Forum April 11 • Tampa, Florida For more information: www.siog.org HPV-Induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx ASCO/C-KIN Joint Session at Cancer & the Kidney International Network’s First Annual Conference (C-KIN 2015) April 14-15 • Brussels, Belgium For more information: www.c-kin.org/conference2015/ ASCO Multidisciplinary Cancer Management Course (MCMC) April 15 • Vina Del Mar, Chile For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org ONS 40th Annual Congress April 23-26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015 3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum

May The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html IMPAKT 2015 Breast Cancer Conference May 7-9 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2015-Breast-Cancer 13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) May 11-13 • Mainz, Germany For more information: www.meeting.cimt.eu American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org

ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form

June

July

International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

2015 Clinical Update: 21st Century Prevention of HPVAssociated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer

NRG Oncology Meeting July 10-13 • Chicago, Illinois For more information: www.gog.org

Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com/conferences/ibc/ meetings/14th-Annual-InternationalCongress-on-the-Future-of-BreastCancer The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2 Anticancer Drug Action and Resistance: From Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015 CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: http://www.apos-society.org/ professionals/meetings-ed/ annualconference.aspx 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

ASCOPost.com | FEBRUARY 10, 2015

PAGE 79

Patient’s Corner

Cancer Has Given Me More Than It Has Taken Away

Side effects from therapy for throat cancer have left me nearly deaf and unable to eat the foods I love. But I’m happy just to be alive. By Doug Bradley, as told to Jo Cavallo

n the fall of 2010, I developed a sore throat and tonsillitis while on a hike in North Carolina. Although it was not uncommon for me to have sore throats accompanied by some swelling on my tonsils, this time much of the inflammation and swelling were centered on just my left tonsil. After 7 days of antibiotics failed to resolve the problem, I became alarmed and sought the advice of a physician colleague, who prescribed 20 more days of antibiotics, which cured the sore throat but not the persistent swelling in my left tonsil. After another examination of my throat, he recommended I see an ear, nose, and throat specialist for a second opinion. By this time, the lymph nodes on the left side of my neck were also swollen. Although I was an emergency room nurse at the time and didn’t have much experience taking care of patients with cancer, during the examination I asked the specialist if I might have throat cancer and he assured me that I didn’t. “Cancer presents differently. There is pain and bleeding, neither of which you have,” said the doctor, as he scheduled me for a tonsillectomy. Still concerned, while I awaited the surgery, I searched online for information on tonsil cancer and found a message posted by a survivor who had had the exact same symptoms I was having, and I became worried. A biopsy of the

inflamed tonsil and surrounding lymph nodes confirmed my worst fears: I had stage IV human papillomavirus–related throat cancer.

Lasting Effects I met first with a radiation oncologist, who prescribed 33 rounds of radiation therapy, and then a medical oncologist, who prescribed three rounds of cisplatin. The treatment was aggressive and grueling. The cisplatin exacerbated the minor tinnitus I had suffered

such excessive salivation excretions, I had to carry a cup around to use as a spittoon, and my mouth and throat were so swollen, I needed a feeding tube for 7 months for nutrition. Even now, swallowing food and drink can be difficult, and I have to be careful about my diet. The damage to my salivary glands causes my mouth to get so dry that I start slurring my words after speaking for a short while. Many people think that once treatment is over and you are cancer-free, your life gets back to normal, but the ef-

I have no regrets about my cancer diagnosis and its aftermath. The experience has made me determined to have a productive and meaningful life and to help other survivors do the same. —Doug Bradley

from for several years and caused hearing loss, but I was afraid my oncologist would stop the therapy if he knew about the side effects I was experiencing, so I kept silent. Today, my hearing loss is so severe, I use hearing aids. The long-lasting side effects from all the radiation to my head and neck are even worse. During the radiation therapy, I had

fects from cancer can be lifelong. Still, I don’t care about any physical loss I’ve experienced from cancer; I’m grateful just to be alive.

Cost of Survivorship Furthermore, cancer has given me more than it has taken away. I was overweight when I was diagnosed, but

Patient Guides Available Through ASCO University Bookstore • ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare. • ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship. Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

now I exercise regularly and maintain a healthy weight. In that respect, I’m in the best physical shape of my life. Cancer has also made me a more compassionate nurse and person. I have launched a support group for survivors of head and neck cancer at our local hospital and offer counseling to online support groups as well. It is shocking for me to hear from so many survivors about the lack of information they received from their medical team about the potential side effects of their treatment and how distressed they are by the physical and even mental limitations they now face. I was very lucky to have the doctors I had, especially my radiation oncologist, who painstakingly explained every detail of what I could expect from treatment and never sugarcoated what I was likely to go through during and after therapy was over. Survivors need to know the truth about the lifealtering and permanent effects they will likely have to contend with as a result of their cancer—the cost of survivorship. I have no regrets about my cancer diagnosis and its aftermath. The experience has made me determined to have a productive and meaningful life and to help other survivors do the same. n Doug Bradley lives in Fayetteville, Georgia.

The ASCO Post Wants to Hear From You

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

The ASCO Post | FEBRUARY 10, 2015

PAGE 80

Announcements

Elizabeth M. Jaffee, MD, Named Deputy Director of Johns Hopkins Kimmel Cancer Center

lizabeth M. Jaffee, MD, a pioneer in the field of vaccine therapy for pancreatic cancer and leader in immunology research, has been appointed Deputy Director of the Johns Hopkins Kimmel Cancer Center. Dr. Jaffee, the Dana and Albert “Cubby” Broccoli Professor of Oncology at the Johns Hopkins University School of Medicine, has been a faculty member there since 1992.

sitions at Johns Hopkins and elsewhere. She earned the Vice Dean’s Award for the Advancement of Women Faculty at Johns Hopkins and holds six vaccine patents. She is Associate Director for

Translational Research and Co-Director of the Immunology Program in the Kimmel Cancer Center, Deputy Director of the Clinical and Translational Research Institute for the Johns Hopkins Univer-

sity School of Medicine, and a member of both the National Cancer Institute’s National Cancer Advisory Board and the American Association for Cancer Research’s Board of Directors. n

Elizabeth M. Jaffee, MD

As Deputy Director, Dr. Jaffee will help guide a senior leadership team responsible for developing and overseeing strategic planning, clinical research, new facilities planning and support for basic scientific discovery. She succeeds Stephen B. Baylin, MD, the Virginia and D.K. Ludwig Professor for Cancer Research, who is stepping down as deputy after a decade in the post and will return to his full-time research role and Director of the Division of Cancer Biology at the Kimmel Center.

Advances in Immunology In announcing Dr. Jaffee’s appointment, Kimmel Center Director William G. Nelson, MD, PhD, said the focus was on selecting an accomplished physician-scientist with patient-care experience and dedication to mentoring young investigators. “Her long-standing research on the development of vaccines to treat pancreatic cancer has led to significant advances in the field of immunology and personalized cancer medicine, and she has done all of this while also taking on numerous responsibilities in leadership.” Dr. Nelson’s announcement also paid tribute to Dr. Baylin, noting that “Dr. Baylin is a distinguished scientist who has been a transformative figure in the field of epigenetics.” He added, “his leadership has guided us through many challenges and new opportunities, and I am delighted he will continue his outstanding career at the Kimmel Center.” Dr. Jaffee codirects the Skip Viragh Center for Pancreatic Cancer, and serves in several science leadership po-

ASCOPost.com | FEBRUARY 10, 2015

PAGE 81

Announcements

Loretta Doan, PhD, Named Vice President of Policy and Global Affairs at AACC

he American Association of Clinical Chemistry (AACC) has announced that Loretta L. Doan, PhD, has assumed the position of Vice President of Policy and Global Affairs. Prior to joining AACC, Dr. Doan served as Director of Science

Policy at the Endocrine Society, an organization representing more than 18,000 scientists and clinicians. At the Endocrine Society, she led a diverse portfolio of science policy initiatives that advanced the field of endocrinology, including a program

focused on the standardization of hormone assays. In her role at AACC, Dr. Doan will primarily be responsible for leading AACC’s science policy and advocacy efforts, which in 2014 involved issues ranging from funding for newborn

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

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

Learn more at TargetMAPK.com.

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

screening to the U.S. Food and Drug Administration’s proposal to regulate laboratory-developed tests. Dr. Doan will also work to build the association’s global presence and enhance the visibility of the field of laboratory medicine and its practitioners.

Loretta L. Doan, PhD

“Dr. Doan has a unique skill set that combines strong scientific credentials with extensive experience in public policy and communicating scientific content and concepts to a range of audiences,” said AACC CEO Janet B. Kreizman. “With her proven ability to design and advance public policy initiatives, we are confident that she will be a strong asset in AACC’s effort to promote greater public understanding of laboratory tests, and to ensure that laboratory medicine professionals are heard when health and science policy issues are being addressed.”

Essential Contribution “It is a privilege to have been selected as AACC’s Vice President of Policy and Global Affairs,” said Dr. Doan. “I look forward to working with AACC staff and members, both in the United States and internationally, to build awareness of the essential contribution of laboratory medicine professionals to improving patient outcomes through effective laboratory testing, diagnosis, and treatment.” Dr. Doan joined the Endocrine Society in 2006 to serve as the organization’s Manager of Science Policy, and launched the society’s first science policy program before being appointed Associate Director of Science Policy in 2008 and Director of Science Policy in 2011. Prior to the Endocrine Society, Dr. Doan completed a 2-year postdoctoral fellowship in the Experimental Immunology Branch of the National Cancer Institute at the National Institutes of Health. Dr. Doan earned her PhD in biochemistry and molecular biology from the University of Louisville, Kentucky.n

The ASCO Post | FEBRUARY 10, 2015

PAGE 82

In the News Treatment Side Effects

‘Chemobrain’ Study Aims to Correlate Structural Changes Within the Brain and Psychomotor Function By Charlotte Bath

“T

he novelty of our approach is that we are going to be using multiple modalities” to study the effects of chemotherapy and hormonal therapy on the brain, looking for structural changes within the brain and how these changes might affect psychomotor function, particularly upper-extremity movements that require fast responses and two-limb coordination,” explained Didier Allexandre, PhD, a research scientist at the Kessler Foundation, based in West Orange, New Jersey, and a coinvestigator of the study. “The uniqueness of this research is that we are doing a longitudinal study, assessing changes in the quality of neural fibers in the brain—these fibers connect and conduct signals between neurons located in different regions and between brain and muscle, and are collectively referred to as white matter—following the therapies,” Guang Yue, PhD, noted. Dr. Yue is Director of Human Performance and Engineering Research at the Kessler Foundation, Professor at Rutgers New Jersey Medical School, and the study’s principal investigator.

Guang Yue, PhD

“If chemotherapy drugs damage the white matter, signal conduction will be slowed and communication between brain regions (eg, left vs right sides) will be compromised. Consequently, the movement response will be slowed due to prolonged traveling time of the motor command from the brain to move the hand, and ability to coordinate movements of the two arms will be impaired because of deterioration in communication between two sides of the brain,” Dr. Yue continued. “We will be looking for objective changes in brain white matter on neuroimaging, electroencephalographic (EEG) parameters, and transcranial magnetic stimulation–evoked muscle responses, and we’ll be correlating those alterations with psychomotor performance using the arms in women being treated for breast

cancer, summed up study co-investigator Serena Wong, MD. Dr. Wong is a medical oncologist at Rutgers Cancer Institute of New Jersey and Assistant Professor of Medicine at Rutgers Robert Wood Johnson Medical School, New Brunswick. The study is funded by the National Institutes of Health, with support from the Kessler Foundation, a nonprofit organization involved in research to improve cognition, mobility, and outcomes for people with neurologic disabilities. The three investigators described their “chemobrain” translational study in a conference call with The ASCO Post.

Concentrating on Hand Movements The condition commonly known as chemobrain is usually associated with problems in concentrating, remembering, and multitasking, but it also can make it more difficult to do tasks requiring rapid, precise, and coordinated hand movements. “Earlier studies have varied widely in their conclusions of how common chemobrain is, from as little as 5% of patients up to as many as 60%,” according to an article about the current study in the Newark Star-Ledger.1 Dr. Wong estimated that from her own experience, cognitive changes seem to affect about one-third of breast cancer patients during and immediately after treatment. Because of the capability to obtain precise performance measures and explain changes in performance by the white matter structural and neurophysiologic adaptations, “we decided to concentrate more on the psychomotor and less on the classic chemobrain effects such as impaired memory, cognition, and problem-solving,” Dr. Allexandre said. Some tests being used in the study “are more heavily related to cognition, and some are more heavily related to motor,” Dr. Allexandre noted, but all tests “have a motor component.” They would include timed tests during assigned tasks, such as moving pegs on a board. “We are looking at brain structure. We are looking at the health of the connection within the brain,” by using structural magnetic resonance imaging, Dr. Allexandre said. “We are going to look as well at the actual motor, or psychomotor function, using performance tests, for example, how fast patients react to stimuli by pressing a button.” Transcranial mag-

netic stimulation will “assess the health of the nervous system from the brain to the hand,” Dr. Allexandre explained, and EEGs will “measure brain function while performing motor tasks.”

Tests Designed for Specific Purposes “The designs of the tests all have very specific purposes,” Dr. Yue elaborated. “For example, we are going to measure brain white matter structure, the fibers

what confusing because it is multifactorial. There are many potential factors that can contribute to a patient’s cognitive dysfunction, such as anxiety or depression, which are, of course, common in cancer patients, as well as sleep disturbances, fatigue, or medication side effects,” Dr. Wong explained. “But a lot of women being treated for breast cancer are given hormonal therapy. We know that when women go through menopause, and the estro-

The novelty of our approach is that we are using multiple modalities to study the effects of chemotherapy and hormonal therapy on the brain, looking for structural changes and how they might affect motor function, particularly hand movements. —Didier Allexandre, PhD

connecting neurons from one to another or from one region to another region. Previous studies have shown that cancer survivors treated by chemotherapy have damage in the brain white matter. But these studies all compare cancer patients with healthy controls.” The current study, however, will follow patients after they finish chemotherapy and compare quality of the brain fibers then to the baseline measurements. “If the fibers are damaged, we would assume the conduction velocity or the quality of the conduction would be affected,” Dr. Yue said. “Then what we will do is stimulate a motor area of the brain and measure how fast the muscles will respond. If the fiber quality is affected, the signal will travel more slowly from the brain to the muscle,” he said, and the patient will not be able to react as quickly on motor tasks.” The ability of patients to coordinate movements between their two arms will also be measured. “The hypothesis is that if fibers connecting the two sides of the brain are damaged, then the patient’s ability to cooridinate movements of the two arms will be impaired.”

Teasing Apart the Role of Hormonal Therapies “The phenomenon of cognitive dysfunction in breast cancer can be some-

gen levels drop, regardless of whether or not they have a cancer diagnosis, we often hear complaints about cognitive changes. We don’t know to what extent hormone therapy contributes to cognitive decline in those who report this ‘chemobrain,’ and so we want to really tease that apart,” Dr. Wong continued. “We want to know how much of it is due to chemotherapy and how much of it is due to hormones, and that is why we have the three arms of the study: (1) chemotherapy plus or minus hormonal therapy; (2) hormonal therapy alone; and (3) the healthy control arm.” “We are looking mainly at chemotherapy and comparing it with the other two groups,” Dr. Allexandre elaborated. “We want to perform baseline tests before chemotherapy and then 1 month and again 6 months after treatment so that we can observe the short-term and permanent to mid-term effects of the therapy. It is well known that some of the symptoms recede relatively quickly after treatment.” “Most people generally recover within a year, although some patients even a few years out report they are never quite back to baseline functioning,” Dr. Wong noted. “There have been a few studies looking at women who had been treated several years prior for breast cancer. They were imag-

ASCOPost.com | FEBRUARY 10, 2015

PAGE 83

In the News

Patients May Voice Concerns About Chemotherapy Effects on the Brain Even If They Have Never Heard of ‘Chemobrain’

he concept of “chemobrain” is underrecognized, noted Serena Wong, MD, co-investigator of a clinical trial examining the effects of chemotherapy and hormonal therapy on the brain. Dr. Wong is a medical oncologist at Rutgers Cancer Institute of New Jersey and Assistant Professor of Medicine at Rutgers Robert Wood Johnson Medical School, New B runswick. Many patients report symptoms associated with the condition commonly known as “chemobrain,” but “don’t know that is a phenomenon, a syndrome that has been named,” Dr. Wong said. “Patients will say, ‘I’ve been having trouble with short-term memory, word finding.’ And I will tell them, ‘Yes, this is a phenomenon called chemobrain.’ Then they are sort of relieved, because they think, ‘Oh, I thought it was just me. I’m so tired all the time.’ They chalk it up to having been through a lot of stress over the previous year, with the diagnosis, or to factors such as anemia, fatigue, and anxiety. Maybe that is a big component. It is hard to tease apart. But we have to think: What is our therapy doing?”

ing studies, and they showed that there were still some structural changes that could be seen on imaging. Whether or not those translated into real-life cognitive deficits that the patients complained about was not always clear, but at least some of the studies seemed to suggest that this was in fact the case,” she added.

Actively Recruiting “This study will enable investigators to better understand the relationship between cancer treatments and brain function. Our goal is to find ways to minimize or even prevent the effects of ‘chemobrain,’ thus helping to improve the patient’s quality of life,” Dr. Wong added in a statement announcing the study.2 “We are actively recruiting,” Dr.

If patients aren’t familiar with chemobrain, should physicians proactively bring up the topic with women receiving or about to receive chemotherapy for breast cancer? “I think they should,” Dr. Wong said. “Sometimes physicians focus on the tangibles—the nausea, the vomiting, the diarrhea, fevers—and it can be easy to forget to mention something like chemobrain. But I do think it is something oncologists should counsel their patients on,” Dr. Wong advised. “However, the fear of possibly developing cognitive difficulties, which are usually relatively modest and tend to improve with time, should not deter someone from accepting potentially life-saving therapy.”

confounding factors. “Certainly, if someone is particularly depressed or anxious, we would recommend that they receive treatment for that,” Dr. Wong advised. “If patients are having sleep distur-

medications can also be a bit sedating. “Regular exercise is certainly something that I think is quite helpful. And sometimes, there are medications, such as modafinil, which is used in shift workers to help increase attention and mem-

Sometimes physicians focus on the tangibles—nausea, vomiting, diarrhea, fevers—and it can be easy to forget to mention chemobrain. But it is something oncologists should counsel their patients on. —Serena Wong, MD

Being Proactive The goal of the study is to find ways to minimize or even prevent the effects of chemobrain. While awaiting those results, “There are certain things that we recommend to patients right now, which could potentially help them,” Dr. Wong told The ASCO Post. “Being proactive is a good approach.” Depression and anxiety can be Wong said. “We would like to get 20 patients in each arm of the study.” Postmenopausal women between the ages of 50 and 70 years old who have had or are scheduled to have breast cancer surgery are eligible for the study if they are receiving or scheduled to receive chemotherapy and/or hormonal therapy. For the chemotherapy arm, “we are only including women who have received an anthracycline or a taxane—two of the most common chemotherapeutic agents given in early-stage breast cancer,” Dr. Wong noted. “It was our goal to be able to recruit patients just before they start their treatment,” Dr. Allexandre said. “But it has been extremely difficult to approach these patients at a time when it is extremely stressful” and ask them to con-

bances, we recommend that they see a sleep specialist, or we could prescribe sleep aids. However, the caveat with sleep aids is that they are also sedative, and so we have to use them with caution and make sure that we use the lowest effective dose,” she added. “Sedation in itself can contribute to some cognitive dysfunction,” she noted, and some antinausea sider yet another issue—chemobrain— that they may not even foresee. “So now we are trying to find a compromise. We are still looking for people before they start treatment—that would be the ideal—but we will also enroll patients who have already started chemotherapy,” Dr. Allexandre said. “If they’ve had one or two cycles of chemotherapy, we could potentially enroll them,” Dr. Wong said. That would still allow the investigators to observe the immediate effects of therapy and then the longitudinal effects 4 to 6 months after the end of chemotherapy. Eligible patients must also be righthanded. This criterion was included to eliminate handedness as a confounding factor if a certain area of the brain is highlighted more during specific tests.

ory. “I don’t prescribe that personally that often,” Dr. Wong said, “but there are some early data suggesting that it could be helpful in this situation. Referral to a neuropsychologist can be very helpful as well if a patient is having particularly troublesome or persistent symptoms.” n Disclosure: Dr. Wong reported no potential conflicts of interest.

For the control group, investigators are seeking healthy postmenopausal women who have no evidence of breast cancer and who meet the other criteria. Physicians interested in finding out more about the study or referring patients should contact Dr. Allexandre at 973-324-3525. n Disclosure: Drs. Allexandre, Yue, and Wong reported no potential conflicts of interest.

References 1. O’Brien K: How you can help Rutgers unlock the mysteries of ‘chemo brain.’ Newark Star-Ledger, January 3, 2015. 2. Rutgers Cancer Institute of New Jersey aids in clinical trial examining effects of ‘chemo brain’ in breast cancer patients. Rutgers Cancer Institute press release, January 5, 2015.

twitter.com/ascopost

The ASCO Post | FEBRUARY 10, 2015

PAGE 84

Lab Notes

Ongoing Molecular Research in the Science of Oncology NOVEL STRATEGIES ‘Bipolar’ Androgen Therapy in Castration-Resistant Prostate Cancer Resistance to castrating therapy and androgen deprivation therapy in prostate cancer is due in part to adaptive upregulation of androgen receptor levels by castration-resistant prostate cancer cells in the setting of prolonged exposure to a low-testosterone environment. In a study reported in Science Translational Medicine, Schweizer and colleagues investigated whether such androgen receptor overexpression might be exploited in castrationresistant prostate cancer by alternating between exposure to supraphysiologic testosterone levels, to promote castration-resistant prostate cancer cell death, and near-castrate testosterone levels, an approach termed ‘bipolar’ androgen therapy. In a pilot study, 16 asymptomatic patients with a low/moderate metastatic burden received testosterone cypionate (400 mg intramuscularly, day 1 of 28-day cycle) and etoposide (100 mg, days 1–14). Patients with declining prostate-specific antigen levels after 3 cycles continued on intermittent testosterone monotherapy, with castrating therapy being continued to suppress endogenous testosterone. Bipolar androgen therapy was well tolerated and resulted in prostate-specific

antigen response in half of the patients and radiographic response in half. All patients eventually had prostatespecific antigen progression, but four remained on treatment for at least 1 year. Each of 10 evaluable patients had prostate-specific antigen reduction in response to androgen-ablative therapies after bipolar androgen therapy, suggesting that this approach may restore sensitivity to androgen-deprivation therapy. The investigators concluded: “[Bipolar androgen therapy] shows promise as treatment for [castration-resistant prostate cancer] and should be further evaluated in larger trials.” Schweizer MT, et al. Sci Transl Med 7:269ra2, 2015.

PEDF Improves Lung Cancer Response to Radiation via Vasculature Normalization In a study reported in Cancer Gene Therapy, Xu and colleagues found that the addition of pigment epitheliumderived factor (PEDF) to radiation improved tumor response in a mouse model of lung cancer. Lewis lung cancer allografts in nude mice were treated with radiation, PEDF, and PEDF plus radiation. Significant inhibition of tumor growth was found when radiation was administered during a vascular normalization window between days 3 and 7 after the start of PEDF. PEDF treatment re-

sulted in a significant reduction in the thickness of the basement membrane and a significant increase in pericyte coverage. The tumor hypoxic fraction decreased between days 3 and 7 after PEDF treatment, suggesting improved intratumoral oxygenation. The investigators concluded: “Taken together, our results show that PEDF improved the effects of radiation therapy on [Lewis lung cancer] allografts by inducing a vascular normalization window from the 3rd to the 7th day after PEDF treatment. Our findings provide a basis for treating lung cancer with the combination of PEDF and radiation.” Xu Z, et al: Cancer Gene Ther. January 16, 2015 (early release online).

POTENTIAL THERAPEUTIC TARGETS LAMC2 Increases the Metastatic Potential of Lung Adenocarcinoma Mechanisms of lung cancer metastasis remain largely undefined. In a study reported in Cell Death & Differentiation that used genome-wide transcriptional analysis in a metastasis model, Moon and colleagues found that the epithelial basement membrane protein laminin γ2 (LAMC2) was significantly upregulated in lung adenocarcinoma metastatic cells. Elevated LAMC2 was associated with increased traction force, migration, and invasion of lung adenocarcinoma cells and induction of epithelial-mesenchymal transition. LAMC2 knockdown resulted in decreased traction force, migration, and invasion and reduced epithelial-mesenchymal transition reduction in vitro and reduced metastasis in a mouse model. The migration and invasion mediated by epithelial-mesenchymal transition were integrin β1- and ZEB1-dependent. High LAMC2 levels were significantly associated with expression of the mesenchymal marker vimentin and were significantly associated with a higher risk of tumor recurrence or death in lung cancer patients. The investigators concluded: “We suggest that LAMC2 promotes metastasis in lung adenocarcinoma via epithelial-mesenchymal transition and may be a potential therapeutic target.” Moon YW, et al. Cell Death Differ. January 16, 2015 (early release online).

Zoledronic Acid Inhibits Angiogenesis in Ovarian Cancer Patients The bisphosphonate zoledronic acid has been reported to produce antitumor effects, although the mechanisms of such effects remain unclear. In a study reported in Clinical Cancer Research, Gonzalez-Villasana and colleagues found evidence that zoledronic acid inhibited ovarian cancer angiogenesis by inhibiting Rac1 activation. In in vitro studies, zoledronic acid inhibited ovarian cancer cell invasion with HeyA8-MDR and OVCAR-5 cell lines, reduced production of proangiogenic cytokines, inactivated Rac1, and decreased the levels of Pak1/p38/matrix metalloproteinase 2. In mouse models, zoledronic acid treatment reduced tumor growth, angiogenesis, and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. The antitumor effects were increased in both mouse models when zoledronic acid was combined with nab-paclitaxel (Abraxane). The investigators concluded: “[Zoledronic acid] has robust antitumor and antiangiogenic activity and merits further clinical development as [ovarian cancer] treatment.” Gonzalez-Villasana V, et al: Clin Cancer Res. January 16, 2015 (early release online).

IMMUNOTHERAPY Therapeutic DNA Vaccination Against Colorectal Cancer via MYB Targeting The oncoprotein and transcription factor MYB is overexpressed in colorectal cancer and critical to proliferation and tumor cell survival. In a study reported in Clinical & Translational Immunology, Cross and colleagues developed a DNA vaccine to generate an MYB-specific immune response on the hypothesis that MYB peptides are aberrantly presented on the surface of colorectal cancer cells. The fusion vaccine consisted of a fulllength MYB cDNA joined to two CD4 epitopes from tetanus toxoid, with multiple inactivating mutations being inserted into the oncogene sequence. Vaccination was tested against tumors initiated by the MYB-expressing cancer cell lines CT26 in BALB/c mice and MC38 in C57BL/6 mice. Low-dose cyclophosphamide was used to overcome T-regulatory cell immune suppression and anti–PD-1 (pro-

ASCOPost.com | FEBRUARY 10, 2015

PAGE 85

Lab Notes

grammed cell death protein 1) antibodies were used to block T-cell exhaustion. No antitumor effect was observed in either mouse model with cyclophosphamide alone; anti–PD-1 antibody produced a slight delay in tumor growth in MC38-bearing mice and a greater delay in CT26-bearing mice. Therapeutic vaccination resulted in a protective effect

when the MC38 tumor burden was low and was found to induce tumor-specific cell killing and increased protection when MC38 and CT26 tumor burdens were higher and when the vaccine was used in combination with an anti–PD-1 antibody or cyclophosphamide. Cross RS, et al: Clin Transl Immunol 4:e30, 2015.

Adding CD47 to Artificial Antigen-Presenting Cells May Stimulate T-Cell Responses and Improve Functionality Artificial antigen-presenting cells have been shown to stimulate antigenspecific T-cell responses, but their effect in vivo may be compromised by rapid macrophage clearance. In a study

reported in Clinical Cancer Research, Bruns and colleagues added CD47 to classic two-signal artificial antigen-presenting cells to produce a three-signal “don’t eat me” artificial antigen-presenting cell that might better avoid macrophage uptake and clearance. Control artificial antigen-presenting cells and the CD47-positive antigenpresenting cells were analyzed in vitro in human primary T-cell and macrophage co-cultures and compared in vivo in a NOD/SCID T-cell proliferation model and a B16-SIY melanoma model. In culture with human macrophages, CD47-positive antigen-presenting cells exhibited CD47 concentration-dependent inhibition of phagocytosis with no reduction in their ability to generate and expand antigen-specific T cells; the T cells generated by these antigenpresenting cells had killing abilities and polyfunctionality equivalent to those of control antigen-presenting cell–generated T cells. In in vivo studies, CD47positive antigen-presenting cells exhibited increased stimulatory capacity and tumor inhibition compared with control antigen-presenting cells. The investigators concluded: “Our data for the first time show that [artificial] antigen-presenting cells functionalized with CD47 maintain their stimulatory capacity in vitro and demonstrate enhanced in vivo efficiency. Thus, this next generation [artificial] APCCD47+ has a unique potential to enhance the application of the [artificial] antigenpresenting cell technology for future immunotherapy approaches.” n Bruns H, et al: Clin Cancer Res. January 15, 2015 (early release online). Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Now Available: ASCO’s Clinical Cancer Advances 2015 Report Clinical Cancer Advances is ASCO’s annual review of the major achievements in clinical cancer research and care, documenting progress against cancer and highlighting emerging trends in the field. For the first time, as part of the 2015 report, ASCO has named the “Advance of the Year,” an area of clinical cancer research that stands out from all the rest. The report has also been enhanced with new features in honor of the publication’s 10th anniversary, including a review of the past 10 years of clinical cancer research achievements and a forecast for the coming decade. To learn more and find out which area of progress is ASCO’s “Advance of the Year,” read the full report on CancerProgress.Net/CCA.

The ASCO Post

Like us on

Facebook facebook.com/TheASCOPost

The ASCO Post | FEBRUARY 10, 2015

PAGE 86

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Mammographically Dense Breasts Highly Prevalent Among American Women A study on the prevalence of mammographically dense breasts in the United States “estimated that approximately 43% of women aged 40 to 74 years have heterogeneously or extremely dense breasts, corresponding to approximately 27.6 million U.S. women,” researchers reported in the Journal of the National Cancer Institute. Data from 1,518,599 mammograms conducted from 2007 through 2010 at mammography facilities in the Breast Cancer Surveillance Consortium (BCSC) were used to determine mammographic breast density distribution by age and body mass index, and these breast density distributions applied to age-specific and body mass index-specific counts of the female population taken from the 2010 U.S. Census and the National Health and Nutrition Examination Survey to estimate the number of American women with dense breasts. The combined proportion of mammograms rated as heterogeneously or extremely dense was inversely associated with body mass index and age. Among women with a normal body mass index (18.5–24.9 kg/m2), 58.9% had heterogeneously or extremely dense breasts, compared with 25% of women with body mass index characterized as obese (> 30 kg/m2). The proportion of women with mammograms rated as either heterogeneous or extremely dense decreased from 56.6% for women aged 40 to 44 to 28.4% for women aged 85 or older. “In light of the ongoing controversies regarding mammography screening for women before age 50, it is notable that nearly 45% of women aged 40 to 74 years with dense breasts are younger than age 50 years,” the authors noted. “Policymakers should consider the large prevalence of women with dense breasts when debating breast density notification legislation,” advised Brian L. Sprague, PhD, of the Office of Health Promotion Research at the University of Vermont in Burlington and colleagues. “Health-care providers need to carefully consider strategies to ensure that women who are notified have opportunities to discuss available evidence, evaluate breast cancer risk, and pursue supple-

mental screening options if deemed appropriate.” Sprague BL, et al: J Natl Cancer Inst 106(10):dju255, 2014.

MELANOMA Adding Sargramostim to Ipilimumab Improved Overall Survival Among Patients With Unresectable Stage III or IV Melanoma Patients with unresectable stage III or IV melanoma treated with ipilimumab (Yervoy) plus sargramostim (Leukine) had longer overall survival and less toxicity than did those treated with ipilimumab alone, according to a phase II randomized clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG). There was no difference, however, in progression-free survival. “These findings require confirmation in larger studies with longer follow-up,” F. Stephen Hodi, MD, of Dana-Farber Cancer Center in Boston, and colleagues reported in JAMA. Ipilimumab is a fully human immunoglobulin G1 molecule that blocks cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and has been shown to prolong survival in patients with metastatic melanoma. Sargramostin is a granulocyte-macrophage colony-stimulating factor (GM-CSF). “One key unanswered question,” the authors noted in the introduction of their report, “is whether the systemic administration of GMCSF enhances CTLA-4 blockade.” Study participants had unresectable stage III or IV melanoma, at least one prior therapy, no central nervous system metastases, and an ECOG performance status of 0 or 1. Of the total of 245 patients, 123 were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle, and 122 were randomized to receive ipilimumab alone. “Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle,” the investigators noted. The median age was 61 years in the group receiving ipilimumab plus sargramostim and 64 years in the group receiving ipilimumab alone. Almost all patients were white, and about two-thirds were men.

The median follow-up was 13.3 months (range, 0.03–19.9). The median overall survival was 17.5 months among patients receiving ipilimumab plus sargramostim vs 12.7 months for patients receiving ipilimumab alone. “The overall survival was significantly improved with the addition of sargramostim to ipilimumab, with a stratified log-rank one-sided P value of .01,” the investigators stated. Rates for 1-year survival were 68.9% with combined therapy vs 52.9% with ipilimumab alone. The median progression-free survival was 3.1 months in both groups. Safety analysis was performed on 120 patients in the combinedtherapy group and 118 in the ipilimumab-alone group. “Toxicity was significantly lower in the ipilimumab-plus-sargramostim group than in the ipilimumab-only group (P = .04),” the investigators noted. Grade 3 to 5 adverse events occurred in 44.9% of patients on combined therapy and 58.3% of those on monotherapy. “Most notable,” according to the authors were differences in gastrointestinal toxicities (16.1% in patients treated with ipilimumab plus sargramostim vs 26.7% ipilimumab alone) and pulmonary toxicities (0% vs 7.5%). “The improved toxicity profile must be considered as contributing to the improved survival, even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded,” the researchers wrote. Hodi FS, et al: JAMA 312:17441753, 2014.

ESOPHAGEAL ADENOCARCINOMA High Genetic Propensity to Obesity Raises Risk of Esophageal Adenocarcinoma “People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with a low genetic propensity,” according to analyses of data from the Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study. “These analyses provide the strongest evidence to date that obesity is independently associated” with Barrett’s esophagus and esophageal adenocarcinoma and “is not due to confounding or bias inherent in conventional epidemiologic analyses,” Aaron P. Thrift,

PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues concluded in the Journal of the National Cancer Institute. The analysis included data for 999 patients with esophageal adenocarcinoma, 2,061 patients with Barrett’s esophagus, and 2,169 population controls. Compared with control patients, patients with esophageal adenocarcinoma were older and more likely to be male, to have ever smoked, to have had symptoms of gastroesophageal reflux (the primary risk factor for esophageal adenocarcinoma and Barrett’s esophagus), and to have used acid-suppressant medications, whereas patients with Barrett’s esophagus were more likely to have ever had gastroesophageal reflux symptoms and to have used acid-suppressant medications. “We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of body mass index on the risk of esophageal adenocarcinoma and Barrett’s esophagus,” the investigators stated. The Mendelian approach, they explained, “uses instrumental variables (eg, genetic variations that proxy for directly measured environmental factors) to make causal inferences about the relationship between a risk factor and an outcome; results from this method are considered to be analogous to the outcomes of a randomized trial.” For this trial, investigators used “a genetic risk score, derived from 29 genetic variants shown to be associated with body mass index, as an instrument for lifetime body mass index. A higher score indicates propensity to obesity.” The genetic risk score was not found to be associated with potential confounders, including smoking and gastroesophageal reflux symptoms. In the instrumental variable analyses, esophageal adenocarcinoma risk increased by 16%, and Barrett’s esophagus risk increased by 12% per 1 kg/ m2 increase in body mass index. “Body mass index was statistically significantly associated with esophageal adenocarcinoma and Barrett’s esophagus in conventional epidemiologic analyses,” the authors noted. n Thrift AP, et al: J Natl Cancer Inst 106(11):dju252, 2014. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | FEBRUARY 10, 2015

PAGE 87

Expert’s Corner Rare Cancers

Unraveling the Mysteries of Epithelioid Hemangioendothelioma A Conversation With Brian P. Rubin, MD, PhD By Jo Cavallo

Genetic Translocation Specific to the Disease How is your characterization of the epithelioid hemangioendothelioma gene

fusion changing patient care? In epithelioid hemangioendothelioma, a genetic translocation involving chromosomes 1 and 3 results in the fusion

of a gene known as WWTR1 (or TAZ) to a gene known as CAMTA1 in almost all epithelioid hemangioendothelioma continued on page 88

A CE/CME Conference for Advanced Practitioners in Oncology Brian P. Rubin, MD, PhD

pithelioid hemangioendothelioma is a rare and devastating vascular sarcoma that affects between 100 and 200 people, mostly young adults, each year in the United States. The cancer may arise as a solitary lesion but more commonly presents with metastatic involvement, usually in the liver and lungs. When confined to soft tissue, mortality from epithelioid hemangioendothelioma is between 13% and 18% but increases dramatically to 40% and 65% when it is found in the lungs and livers, respectively. Although localized epithelioid hemangioendothelioma can be surgically resected, currently there is no effective therapy for systemic disease. And because the cancer is so rare, public funding for research is scarce, making the development of targeted therapies difficult. However, in 2011, Brian P. Rubin, MD, PhD, and his colleagues reported that a gene fusion was found in over 90% of the epithelioid hemangioendothelioma tumors they examined.1 This characterization is changing the understanding of the molecular pathways in epithelioid hemangioendothelioma and is leading to potential therapies for this cancer. The ASCO Post talked with Dr. Rubin, Professor and Vice-Chair of Pathology; Director, Soft Tissue Pathology; and Director, Bone and Soft Tissue Pathology Fellowship Program at Robert J. Tomsich Pathology & Laboratory Medicine Institute and Department of Medicine Genetics at the Cleveland Clinic and Lerner Research Institute, about how characterizing the gene fusion in epithelioid hemangioendothelioma is changing patient care; the prospect of more effective therapies for patients with this tumor type; and why research in this rare cancer is difficult to pursue.

Save the Date November 5-8, 2015 JW Marriott Phoenix Desert Ridge

For conference exhibitor or sponsorship opportunities, contact David Horowitz at 631-935-7658 or email at david@harborsidepress.com Learn more at jadprolive.com

The ASCO Post | FEBRUARY 10, 2015

PAGE 88

Expert’s Corner Unraveling the Mysteries continued from page 87

tumors, and that told me that all cases of epithelioid hemangioendothelioma are oncogene “addicted” to this gene fusion. We developed a fluorescence in situ hybridization (FISH)–based bioassay for the diagnosis of epithelioid hemangioendothelioma and found the gene fusion in 90% to 95% of the tumor tissues we examined—and not in other tumors—so we know that this translocation is absolutely specific to this disease. The immediate result of developing a FISH-based assay for WWTR1CAMTA1 fusion is it is a wonderful diagnostic test and allows pathologists

have had before to study epithelioid hemangioendothelioma.

MEK Inhibitor Under Study As a result of the epithelioid hemangioendothelioma cell line you developed, are you testing new therapies for this type of tumor? Yes. We have been studying a MEK inhibitor, trametinib (Mekinist), which is having great efficacy in our cell-based model. The drug is already approved by the U.S. Food and Drug Administration for melanoma, so we are also using it off-label on a couple of patients. It is a tough drug to take, with severe rash being one of the side effects, but one patient has been on the drug for 6 months

For rare cancers, it is important for scientists to go directly to patients, patient groups, and private foundations for research funding. —Brian P. Rubin, MD, PhD

to confirm a diagnosis of epithelioid hemangioendothelioma, which can be confused with carcinoma and other epithelioid vascular neoplasms. The second result of our finding is it has allowed us to create cell-based biologic models of epithelioid hemangioendothelioma, which we can use to devise therapeutic strategies to treat these cancers, which are essentially untreatable. One of the reasons so little research is being done in epithelioid hemangioendothelioma is because these cell lines do not exist and cell lines are very difficult to develop, especially in these rare cancers, where you might only have one or two chances a year to obtain a fresh tumor for culture. Discovering the gene fusion gave us a tool to move forward with manufacturing an epithelioid hemangioendothelioma mouse cell line by expressing the WWTR1-CAMTA1 gene fusion in the mouse cell line. So even though the cell line isn’t an epithelioid hemangioendothelioma biologic model, it is closer than anything we

and is showing a great response. With a lot of rare cancers, it is tough to do clinical trials, so a lot of drugs are used off-label in an experimental fashion, because there is no therapy for these patients.

Unclear Natural History Is epithelioid hemangioendothelioma largely a fatal disease? It is an interesting disease. With this cancer, essentially half of patients will present with widespread metastasis, including literally hundreds of tumor nodules, but some of these patients have stable disease. They can live for decades with a disease that looks like it should kill them. In fact, many patients are told, “You are going to die in 6 months.” I think this disease is different from other cancers in that some patients can have widespread metastasis but not die because even though there is widespread metastasis, in some of these patients it is not an aggressive cancer. And that’s because the first genetic event that caused the cancer to develop is es-

sentially a very prometastatic gene. It is the genetic changes that happen later in epithelioid hemangioendothelioma that cause it to become aggressive. We don’t know the natural history of the disease completely, so although some patients survive for a really long time, other patients will progress rapidly and die within months. And currently, you cannot tell which patients will maintain stable disease and which ones will develop aggressive epithelioid hemangioendothelioma? That’s right, and it is a major research question for me right now.

Effective Therapies ‘Around the Corner’ How hopeful are you that there will be new effective therapies for epithelioid hemangioendothelioma? I think we are going to have new therapies for epithelioid hemangioendothelioma, and they will be very effective. This cancer is addicted to the WWTR1-CAMTA1 fusion protein, which is a transcription factor. There is no doubt in my mind that this mutation is the cancer target, so we can target that protein either directly or indirectly, for example, by hitting it with a MEK inhibitor, because we believe that most of the activities of the transcription factor run through the MAPK pathway. But ideally, we want to develop a therapy that attacks the transcription factor directly, and one of the problems with that is researchers haven’t developed techniques to do that yet. If we can figure out a way to target either the WWTR1-CAMTA1 protein or something highly related to that translocation, we may not be able to cure these patients, but we will be able to control their disease, even in aggressive cases. I think what we could soon achieve with epithelioid hemangioendothelioma is disease stabilization in patients who have very rapidly developing disease, and cures for the cancer are going to be around the corner.

Research Funding Challenges With your discovery of the translocation, will funding for this rare cancer be easier to obtain? The National Institutes of Health (NIH) said it would probably fund my research if I could produce epithelioid hemangioendothelioma cell-line models, but as I explained earlier, growing and making cancer cell lines in these rare cancers when you do not have fresh tumor for culture are not trivial. The bottom line is that if the NIH is going to make having a biologic cell-line model that is relevant to the cancer you are studying a prerequisite for funding, rare cancers are never going to be funded at high levels, and that is the current state with epithelioid hemangioendothelioma. What I have found is that patients and their families are willing to support this work, because they realize it is not being funded on a national level. Grassroots fundraising has become very important to my laboratory, and we have raised $150,000 from patients in the past year, which is on the level of funding from an NIH Research Project Grant Program (RO1). So for rare cancers, it is important for scientists to go directly to patients, patient groups, and private foundations for research funding. I link to epithelioid hemangioendothelioma patients on their Facebook page, and many e-mail me with questions about their disease, and I am happy to help them. Despite the difficulties of research funding, I like the personal aspect of working on a rare cancer, where I know so many of the patients directly. They are invested in what I am doing, and I am invested in helping them improve and prolong their lives. n

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

Reference 1. Tanas MR, Sboner A, Oliveira AM, et al: Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci Transl Med 3:98ra82, 2011.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | FEBRUARY 10, 2015

PAGE 89

Letters to the Editor

Growing Support Group for Epithelioid Hemangioendothelioma Spins the ‘Wheel of Hope’

wo years ago, my son was diagnosed with the rare vascular sarcoma epithelioid hemangioendothelioma, on which there is incredibly little reseach and knowledge (see page 87 for more on this rare cancer). PubMed revealed a “characteristic” description: unpredictable behavior, no correlation with cytology, and no standard treatment. Visits to the best sarcoma specialists only confirmed the total lack of understanding of epithelioid hemangioendothelioma. While searching for data, I came across the support group HEARD—a collection of more then 250 epithelioid hemangioendothelioma stories gathered by its founder Cynthia Pollak during her struggle to save her son (heardsupport.org). Cynthia realized that information is the key to treatment. She showed me the way. I found a few patients with epithelioid hemangioendothelioma on rare cancer chats, and we started talking about the creation of an online epithelioid hemangioendothelioma hub. I remember bursting into a wild jig when 20 patients joined our Facebook group; it seemed to be so many! At the time of this letter, we now have more then 500 members and are growing every day. Besides fundraising, sharing experiences, and directing patients to the right specialists, our group is collecting information on anything that can help clinicians and researchers overturn the “black hole” status of this cancer. And our efforts are paying off. Just recently, after a few patients reported good responses to mTOR inhibitors, we

launched a thorough “investigation”; we found all reported responders on the Internet and among our members and identified clinicians using mTOR inhibitors on epithelioid hemangioen-

dothelioma and reached out to them. We organized a phone conference—attended by leading sarcoma specialists treating epithelioid hemangioendothelioma—and presented the data. As

2015

a result, there is now consideration of a clinical trial. The wheel of hope has started to spin! n —Jane Gutkovich Queens, New York

Annual Conference ADVANCING THE STANDARD OF CANCER CARE TM

March 12 – 14, 2015 The Diplomat • Hollywood, Florida

Plenary

Sessions*

Early Bir DEADLI d NE! Mon day, y 2, 201

Februar

• Principles of Immunotherapy (Part I)

The ASCO Post Wants to Hear From You

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

• Immunotherapy for Melanoma, Kidney, and Prostate Cancers (Part II) • Making NCCN Guidelines Relevant Around the Globe: The Challenge of Resource Stratification

Plus, customize your learning with Track Sessions! See agenda for more details.

Join NCCN as we celebrate 20 years of improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives.

* Subject to change.

Visit NCCN.org/AC2015 to register

or to view more information for this educational program. JNCCN-N-0202-0115

The ASCO Post | FEBRUARY 10, 2015

PAGE 90

Perspective

continued from page 1

the Salinas Valley and the “disappeared” children of Argentina in the 1970s. Does your proposal that all young women be offered screening for BRCA1 and BRCA2 mutations tap into that place? These projects are all related to the same worldview. Most recently, I was delighted when the Supreme Court ruled that genes are natural products. We have a right to own our own genomes. By offering screening for BRCA1 and BRCA2 to all women at about age 30, it will be possible to prevent breast or ovarian cancer in those with cancer-predisposing mutations because they will know who they are. It is a way to empower women to be able to control their own futures.

school, I would have the perspective of both a scientist and a physician, and that is so valuable. By having dual knowledge, you understand how things work from scientific and clinical perspectives. I look at the young surgeons in our group who come into the laboratory each morning having just cared for their patients. They have insights that I completely miss because of their clinical experience. At the University of Washington, I’m an Associate Director of our Medical Scientist Training Program (MSTP). Our director is Marshall Horwitz, MD, PhD, who studies genetics of hematopoietic malignancies; two other senior faculty members are associate directors as well.

As a young mother, how did you manage to balance family and work? I can’t claim to have balanced it. I was sleep-deprived for years. I just kept going. It gets easier. As a young woman in a field previously dominated by men, was your work questioned more than that of your male colleagues? Were you trusted less? I don’t really know, because I have only one side of the experience and don’t think it’s worth trying to guess. It’s more important to focus on a current

By offering screening for BRCA1 and BRCA2 to all women at about age 30, it will be possible to prevent breast or ovarian cancer in those with cancerpredisposing mutations because they will know who they are. It is a way to empower women to be able to control their own futures.

Medical Scientists You worked for 40 years on research that eventually led to the discovery of the BRCA1 locus. If you were starting this mission today, you could potentially make this discovery in a matter of months, not decades. How would this have changed your experience as a young researcher? That’s a very good question! We are the consequence of our historic period in science, as in everything else, and my early work was spent with linkage analysis, physical mapping, positional cloning, and manual sequencing. I learned a tremendous amount by having to do this work base pair by base pair for about 1 million base pairs. It was an incredible education in genetics, molecular and cell biology, and medicine. But I am glad that new investigators don’t have to do the same. If I were starting out today, I would try to do one thing differently. I would try to go to both medical school and graduate school. As it was, I studied math, then evolutionary biology and genetics, and loved it. But if I had gone to medical school as well as to graduate

dren and to think about children while playing with science. The more one does both, the better one becomes at both.

—Mary-Claire King, PhD

pretend to have—enough faith in yourself to get past the disappointments of experiments that fail. It’s easy to think one is a failure, because in science, most experiments do fail. We have to expect that. We have to learn to be comfortable with uncertainty. A particular challenge for physicians/scientists is to be able to act in the face of uncertainty in their clinical role while painstakingly pursuing conclusive evidence in their scientist role. It’s difficult cognitively and philosophically.

Grateful Cancer Survivors I noticed a group of breast cancer survivors flocking to you after your presentation. Your work means so much to them. What do they say to you? We recently received flowers at the laboratory with a note that read: “From three sisters who lost our grandmother and our aunt but will not lose our mother and not be lost ourselves.” But the other side of this coin is that whenever I learn of a woman with BRCA-positive breast or ovarian cancer, I ask, “Why? This didn’t need to happen.” And that is at the heart of my proposal for offering BRCA testing on a population scale.

Future Hopes All of us find it a terrific privilege to work with MSTP students—they are the very best of their generation.

Family/Work Balance What other advice would you give young people learning to live in the world of scientific research? Do work that you enjoy. I think it’s only possible to succeed with work that one lives and breathes. If you love your projects, it’s easy to think about them all the time, and other aspects of life also will fall into place. It’s possible to think about science while playing with chil-

meeting like the 2014 ASCO Annual Meeting, with the attendance and the speakers probably close to half women. Things are changing profoundly in our professions, but the biggest challenge remains how to have enough time in the day to care for children while at the same time having a demanding career.

Being Comfortable With Uncertainty How does one gain confidence in one’s work, when there is so much competition in the research field? Perhaps the key is to have—or to

Winter 2015 Send your high-resolution digital photo with caption to editor@ASCOPost.com to be considered for publication in a future issue.

So, when your career ends (some 50 years from now!), what do you hope has been accomplished from your work? I hope that genomic testing for inherited cancers will be fully integrated into routine medical care, that we will have seamless referral of women with mutations for medical and surgical follow-up, and that this occurs in a healthcare system that serves all of us—so a woman need not be lucky enough to have a job with benefits to receive the care she deserves. n Disclosure: Dr. King reported no potential conflicts of interest.

Photo: Cold Spring Harbor, NY • Courtesy of ThinkStock

Mary-Claire King, PhD

New Interactive Video-Based Program Explains Clinical Trials to Patients

PRE-ACT

PREPARATORY EDUCATION ABOUT CLINICAL TRIALS

Help Patients Make More Informed Decisions About Clinical Trial Participation Personalized Experience

Tailored video-based educational program specific to each patient

Clinically Tested

Tested with more than 1,200 patients in a phase III randomized clinical trial

Free Program

Video library containing over 20 videos is available to all users free

BE SURE TO TELL YOUR PATIENTS ABOUT THIS PROGRAM

www.cancer.net/PREACT

Bristol-Myers Squibb. Research that leads the way in Immuno-Oncology.

What if you could help the body’s own immune system combat cancer? Bristol-Myers Squibb is researching ways to make this possible. At Bristol-Myers Squibb, we’re committed to Immuno-Oncology (I-O), a rapidly evolving field that enlists the immune system in the fight against cancer. As we learn more about how cancer evades the immune system, the growing potential of Immuno-Oncology continues to drive our research efforts. To find out more about Immuno-Oncology and our leading-edge research, visit ImmunoOncologyHCP.com

ONCUS14UB02260-09-01 12/14