TAP Vol 4 Issue 15 by Harborside Press LLC

Off-Label Drug Use

| Game-Changers in Melanoma

| Ibrutinib Controversy: Letters

VOLUME 4, ISSUE 15

110, 111

SEPTEMBER 15, 2013

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

Best of ASCO® Annual Meeting ’13

ASCOPost.com

A Great Privilege to Die Beneath an Open Sky

Platinum Agents in Triple-Negative Breast Cancer: Encouraging New Data By Caroline Helwick

By Chandrakanth Are, MBBS, FRCS, FACS

or the treatment of triple-negative breast cancer, there is renewed interest in investigating the role of platinum chemotherapy, according to Melinda L. Telli, MD, Assistant Professor of Medicine at Stanford University, Palo Alto. At the Best of ASCO meeting in Los Angeles, Dr. Telli reviewed the results of two studies presented at the 2013 ASCO Annual Meeting, and previewed several ongoing studies that are further evaluating the role of these agents.

Old Players in a New Game The family of platinum salts binds directly to DNA, resulting in the formation of DNA-platinum adducts and consequently intra- and interstrand DNA crosslinks that impede cell division. Interest in platinum-based chemotherapy in breast cancer has

been renewed, based on the hypothesis of greater susceptibility of triplenegative and BRCA1/2mutant tumors to DNAdamaging chemotherapy agents. “We have all been intrigued by a small proofof-concept neoadjuvant Melinda L. Telli, MD study from Poland, involving 25 BRCA1 mutation carriers, approximately 80% of whom had triple-negative breast cancer,” Dr. Telli said at the Best of ASCO meeting. In that study, four cycles of treatment with single-agent cisplatin at 75 mg/m2 every 21 days yielded a pathologic complete response rate of 72%.1 “In comparison, we don’t really know the [pathocontinued on page 11

Expert’s Corner

Paging Dr. Google: Practicing Oncology in the Era of Social Media and Telemedicine

t was 1:00 AM, and my beeping pager awakened me. When you’re a surgical oncologist, you know that a page from your chief resident at this hour of the morning usually means someone may need to go to the operating room. And, yes, it was the chief resident about a patient in crisis. Except in this case, it was not an easy decision to make.

Case Notes The patient was a 50-year-old male with known metastatic pancreatic cancer, liver metastasis, and peritoneal carcinomatosis. He was cachectic, weak, and had biliary stents for continued on page 117

Dr. Are is Associate Professor of Surgical Oncology, Vice Chair of Education, and Program Director of the General Surgery Residency Program at University of Nebraska Medical Center, Omaha. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO. Some details have been changed to protect patient privacy.

By Ronald Piana

ver the past few decades, economic and political factors have reshaped oncology, especially in the community setting. To defray risk, we’ve seen a trend toward oncology practices partnering with hospitals or aggregating into larger networks. Moreover,

the Internet and the advent of telemedicine have profoundly changed the way physicians and patients access clinical information and interact. To gain insight into how oncologists are addressing this Brave New World of technology, The ASCO Post spoke with H. Jack West, MD, a medical oncologist and Director Many leading academic centers... of the Thoracic Oncology Program at Swedish Canare now offering remote second cer Institute, Seattle.

opinions and report information or an actual interactive clinical discussion via video. Hopefully, payers will see the value of doing remote clinical work in situations that don’t need interventions.

—H. Jack West, MD

September is Ovarian Cancer Awareness Month

Telemedicine Issues Why haven’t we seen more use of telemedicine in oncology? Telemedicine has two major limitations. First, the reimbursement for telemedicine compared,

MORE IN THIS ISSUE Best of ASCO �� 1, 3, 4, 9, 11 Russell K. Portenoy, MD, on Cancer Pain �� 18 FDA Update �� 28–30 Gynecologic Oncology �� 34, 36, 43, 45 Direct from ASCO �� 68–74 David L. Porter, MD, on Immunotherapy �� 79 Pioneers in Oncology: LaSalle D. Leffall, Jr, MD �� 97 Letters to the Editor: Ibrutinib Controversy �� 110, 111

continued on page 58

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 15, 2013

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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

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

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Joseph S. Bailes, MD Texas Oncology

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

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

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

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

Lynn D. Wilson, MD Yale University School of Medicine

Michael Buckley, Art Director Michael@harborsidepress.com

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

Stanley H. Winokur, MD Singer Island, Florida

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

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

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

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

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

Philip D. Bonomi, MD Rush University Medical Center

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

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

Michael P. Link, MD Stanford University Medical Center

International Editors

Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com

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

Wendy McGullam, Director of Production Wendy@harborsidepress.com

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

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD National Comprehensive Cancer Network

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

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

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

William T. McGivney, PhD Philadelphia, Pennsylvania

Jay S. Cooper, MD Maimonides Medical Center

James L. Mulshine, MD Rush University Medical Center

Jacek Jassem, MD Medical University of Gdansk, Poland

John Cox, DO Texas Oncology

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

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

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

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

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

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

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

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

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

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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.

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Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume

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

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

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 3

Best of ASCO® Thoracic Oncology

VeriStrat Assay Helps Select NSCLC Patients for Second-Line Therapy By Caroline Helwick

eriStrat, a serum-based protein assay, can help select which patients with non–small cell lung cancer (NSCLC) not known to have epidermal growth factor receptor (EGFR) mutations might benefit from an EGFR-targeted agent, according to a study presented at the ASCO Annual Meeting by Vanesa Gregorc, MD, on behalf of Chiara Lazzari, MD,1 and described at the Best of ASCO 2013 meeting in Los Angeles

Heather A. Wakelee, MD

by Heather A. Wakelee, MD, Associate Professor of Medicine, Stanford University, Palo Alto, California. Second-line therapy for advanced NSCLC patients after disease progression on platinum-based regimens typically employs chemotherapy or erlotinib (Tarceva). Improved progression-free survival in patients treated with erlotinib is associated with EGFR-sensitizing mutations, but there is little means of optimizing treatment in patients with wild-type

or unknown EGFR mutation status or squamous histology, she noted. VeriStrat is a commercially available serum-based protein test designed to identify which patients are likely to benefit from an oral EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib (Iressa). The test evaluates pretreatment serum using matrix-assisted laser desorption ionization mass spectrometry to classify a patient as having a “good” or “poor” profile for treatment benefit. In retrospective studies, VeriStrat has demonstrated prognostic and predictive utility. At the Best of ASCO meeting, Dr. Wakelee presented the results of the current PROSE study, which she said is the first completed prospective biomarker-stratified validation study in oncology to test the treatment/ biomarker interaction.

Details of PROSE The study included 285 patients stratified by ECOG performance status, smoking, and blinded pretreatment VeriStrat classification (“good” or “poor”). Patients were randomly assigned to receive erlotinib or chemotherapy at standard doses. The primary endpoint was overall survival, and the primary hypothesis was that there would be a significant interaction between test status and treatment. In the per-protocol primary analysis, 68% of the chemotherapy arm and

Guiding Lung Cancer Therapy ■ The serum-based protein assay VeriStrat may help guide second-line

treatment decisions in patients with non–small cell lung cancer who are EGFR wild-type or of unknown status.

■ Patients classified as VeriStrat “poor” have better overall survival outcomes with chemotherapy rather than erlotinib.

EXPERT POINT OF VIEW

escribing the PROSE study findings at the Best of ASCO meeting, Heather A. Wakelee, MD, Associate Professor of Medicine, Stanford University, Palo Alto, California, concluded, “The results of PROSE indicate that the 30% to 35% of patients classified as VeriStrat ‘poor’ have better survival with chemotherapy than with erlotinib [Tarceva], but they have a worse prognosis than the ‘good’ group. The 65% to 70% classified as VeriStrat good have similar survival with erlotinib or chemotherapy, and better prognosis than the poor group.” “Serum proteomic VeriStrat classification may be clinically useful in guiding treatment decisions in patients with non–small cell lung cancer [NSCLC] who have unknown or wild-type EGFR status in the second-line setting,” she commented. “For those who questioned the utility of erlotinib as a second-line option for EGFR wild-type NSCLC, this may be helpful,” she added, “however, we await the response rate and progression-free survival data to fully evaluate the results of this study.” n

72% of the erlotinib arm were classified as VeriStrat good, while 32% and 28%, respectively, were classified as VeriStrat poor. EGFR and KRAS analysis was performed in about two-thirds of patients.

VeriStrat Profile Predicted Treatment Outcome The trial reached its primary objective of significant interaction between treatment and VeriStrat classification, with an interaction P value of .037. Patients in the VeriStrat poor group performed worse on erlotinib than on chemotherapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.08–2.74) but for the VeriStrat good group, treatment assignment made no significant difference in overall survival (HR = 1.09, 95% CI = 0.79–1.50). Median overall survival by treatment arm was 9.0 months with chemotherapy and 7.7 with erlotinib (a nonsignificant difference). At progression, about half the patients received a third-line regimen.

Differences did emerge, however, according to pretreatment VeriStrat results. Median overall survival was about 11 months for all patients with the VeriStrat good profile, whether they received erlotinib or chemotherapy, but for VeriStrat poor patients, overall survival was doubled with chemotherapy—6.4 months vs 3 months with erlotinib—Dr. Wakelee reported. The results suggested that VeriStrat status is predictive of a differential overall survival benefit for erlotinib vs chemotherapy in the second-line setting, the authors maintained. n

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

Reference 1. Lazzari C, Novello S, Barni S, et al: Randomized proteomic stratified phase III study of second-line erlotinib versus chemotherapy in patients with inoperable non-small cell lung cancer (PROSE). 2013 ASCO Annual Meeting. Abstract LBA8005. Presented June 3, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Russell K. Portenoy, MD, on Cancer Pain see page 18

Kathleen Moore, MD, on Advanced Cervical Cancer see page 36

Visit The ASCO Post online at ASCOPost.com

Lisa A. Carey, MD, on Triple-Negative Breast Cancer see page 54

The ASCO Post | SEPTEMBER 15, 2013

PAGE 4

Best of ASCO® Issues in Oncology

Prescribing of Off-Label Chemotherapy Is Common, and Most Off-Label Drug Use Meets NCCN Compendium Criteria By Charlotte Bath

Disk

S&H

PharmaGraphics

“There was certainly variation between the different sites. For example in colon cancer, the prevalence of off-label use was very low, vs in a disease such as myeloma, the prevalence of off-label use was much higher.” The percentage of patients who received any unproved drug was about 10% for colon cancer and 80% for myeloma. As background, Dr. Krzyzanowska cited a survey of American oncologists from about 5 years ago, which suggested that the majority of American oncologists have discussed and offered off-label therapy to their patients, although a smaller proportion did so on a routine basis. She also referred to a more recent study published in the Journal of Clinical Oncology,2 which found that off-label use of 10 commonly prescribed intravenous chemotherapies amounted to 30%. SIGNOFF

DATE

GNH_HER_Q36341B_JA_D01.indd

JOB#: 36341B CLIENT: Genentech DESC: OS Journal Ad Update PG: Lake, Kathleen/TaranS AD: K Wilkinson PM: N Echandi TRIM: 20.5” x 13.25” BLEED: 22.5” x 15.625” SAFETY: 19” x 12.75” FONTS: Myriad Pro (Bold, Regular, Condensed, Light, Semibold), Helvetica Neue LT Std (45 Light) IMAGES: 36341_B_JA_Chainmail_p1_fn.tif (CMYK; 300 ppi; 100%), Perjeta_US_®_SHS_4C.eps (26.5%) INKS: Cyan, Magenta, Yellow, Black DOC PATH: GNH_HER_Q36341B_JA_D01:Volumes...JA_D01:GNH_HER_Q36341B_JA_D01.indd NOTES: None

ff-label prescribing of drugs remains common in oncology, but about two-thirds of off-label prescribing is consistent with the National Comprehensive Care Network (NCCN) compendium, according to a study1 reviewed at the Best of ASCO® ’13 meeting in Chicago by Monika K. Krzyzanowska, MD, MPH, Princess Margaret Cancer Centre University of Toronto. “The investigators were interested in characterizing appropriate

QC TC AD

FILE NAME: GNH_HER_Q36341B_JA_D01.indd AE: M Sampar PROD: M Haight

Strengths and Limitations

Monika K. Krzyzanowska, MD, MPH

DATE: 7-2-2013 6:06 PM CW: J Wildrick INK Spec: 4C

As strengths of the study, Dr. Krzyzanowska listed the large sample size drug use and, specifically, addressing and insight into temporal trends. The whether oncologists were choosing investigators looked at 10 years of data wisely when it came to drug therapy,” “and interestingly enough, the proporDr. Krzyzanowska explained. tion of off-label use was similar year to year,” she said. Study Details “In terms of limitations, because The investigators used the SEER this was a SEER-Medicare sample, the (Surveillance, Epidemiology and End focus was predominantly on older paResults)-Medicare database to analyze tients and only on intravenous medicause of intravenous chemotherapy drugs tions, so I would argue that it does unamong 42,634 Medicare beneficiaries derestimate off-label use, as I suspect diagnosed with metastatic cancer bethat younger patients may be more Cosmos Communications tween 1998 and 2008. Each drug was likely receive off-label therapy in the 1 Q1to Q2 Y K ja classified according CtoMwhether it had metastatic setting,” Dr. Krzyzanowska 2 25353a 07.9.13 an indication approved by the Food and133 said. “There was also a lack of inforDrug Administration (FDA), based on mation on the motivation for off-label NCCN compendia guidelines, or neiprescribing or the impact in terms of ther of these. “The NCCN compendiboth efficacy and toxicity.” um is recognized as an authoritative refSit Back and Scrutinize erence for insurance coverage for drug The current study adds to the growindications without FDA approval,” the ing literature providing evidence that investigators stated. off-label prescribing in common in Overall results “show about 45% cancer patients, but Dr. Krzyzanowska of patients received at least one unapbelieves that more research needs to be proved drug,” Dr. Krzyzanowska said. AE/AS ED PROD

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Off-Label Prescribing Trends ■ Off-label prescribing of drugs remains common in oncology, but about twothirds of off-label prescribing is consistent with the NCCN compendium.

■ There is wide variation in the use of off-label drugs among cancer sites, with a low prevalence of off-label drug use for colon cancer and high prevalence of off-label use for prostate cancer and myeloma.

The Good, the Bad, and the Ugly

eviewing a study on off-label use of chemotherapy, Monika K. Krzyzanowska, MD, MPH, of Princess Margaret Cancer Centre University of Toronto, reflected on what she called the good, the bad, and the ugly of off-label drug use. “Certainly there are some good aspects about off-label therapy,” she said. Among the good is “early access to medications that have been shown to be efficacious already. It takes a long time to get drug approval, so once the clinical trial is presented or published and the results look promising, if the drug is already on the market, this gives you an opportunity to get access to it early,” she said. Off-label use can also be helpful in treating rare diseases “where it may be your only option.” Off-label use also presents “an opportunity in innovation in the molecular matching between drugs and molecular abnormalities,” Dr. Krzyzanowska said. “I think if we are going to use these drugs in that setting, we really need to be tracking what’s happening so that we learn from all of this.” “In terms of the bad, there has been some work that suggests than when drug therapy that is being tested in a clinical trial is available off-label for another indication, it does have a negative impact on trial accrual,” Dr. Krzyzanowska stated. High costs can also be negative factor. In a study published in the Journal of Clinical Oncology,1 total spending on off-label use of 10 commonly prescribed intravenous drugs totaled $4.5 billion in 2010. “In terms of the ugly part of this equation, we have the issue of harm,” Dr. Krzyzanowska said, because many of the drugs prescribed off-label also have significant side effects. “The second issue is the issue of motivation. Are we prescribing drugs off-label specifically because we think they are going to benefit patients? Or is this a way of avoiding having that difficult conversation that further treatment then would be futile and you really should be looking at supportive care and palliative care?” n

Reference 1. Conti, RM, Bernstein AC, Villiflor VM, et al: Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. J Clin Oncol 31:1134-1139, 2013.

done in this area. “I would really like to see some studies that could show us the benefit side and the toxicity side of offlabel prescribing—so really the clinical outcome,” she said. For now, however, “there is some time to sit back and scrutinize off-label use in practice,” she continued. “I think there are some areas where off-label use has less reason to be done.” As examples, she cited off-label prescribing that is not consistent with the NCCN compendium, as well as off-label prescribing of expensive drugs or “situations where the benefit is likely to be small and risk of toxicity substantial.” Moving forward, Dr. Krzyzanowska suggested increased physician education about appropriate vs inappropriate off-label uses and decision support for physicians. Heightened patient engagement and public awareness are also very

important, she said. Tracking off-label use of drugs and indications would be useful for obtaining more information about particular risk-benefit ratios for specific indications. n

Disclosure: Dr. Krzyzanowska has an uncompensated consultant or advisory role with Bayer/Onyx, has received honoraria from AstraZeneca, Novartis, and Sanofi, and has received research funding from AstraZeneca and Exelixis.

References 1. Hershman DL, Neugut AI, Buono D, et al: Off-label and compendia use of chemotherapy in patients with metastatic cancer. 2013 ASCO Annual Meeting. Abstract 6509. Presented August 9, 2013. 2. Conti, RM, Bernstein AC, Villiflor VM, et al: Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. J Clin Oncol 31:1134-1139, 2013.

STRENGTHEN HER DEFENSE XXXXXX

FDA-approved HER2* dimerization inhibitor (HDI) for the first-line treatment of HER2+ metastatic breast cancer (MBC)1,2

Indication

PERJETA速 (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin速 (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNING: Embryo-Fetal Toxicity

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. *HER2 = human epidermal growth factor receptor.

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly improve progression-free survival PERJETA-based regimen extended median progression-free survival (PFS) to 18.5 months (from 12.4 months)1 6.1-Month Improvement in Median IRF-assessed PFS1* Placebo + Herceptin + docetaxel

100

PERJETA + Herceptin + docetaxel

HR=0.62† 95% CI [0.51-0.75] P<0.0001

80 70

18.5

PFS (%)

MONTHS

12.4

MONTHS

30 20 10 0

P+H+D Pl+H+D

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk

• At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

IRF = independent review facility; CI = confidence interval; HR = hazard ratio. *At the time of the final PFS analysis, OS was not mature and first interim OS analysis results did not meet the prespecified stopping boundary for statistical significance.1 † Stratified by prior treatment status and geographic region.1 The CLEOPATRA trial was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of patients with HER2+ locally recurrent, unresectable or metastatic breast cancer (HER2+ status was defined as IHC 3+ or FISH amplification ratio ≥2.0 as determined at a central laboratory) (N=808); patients were randomized in a 1:1 ratio to either PERJETA + Herceptin + docetaxel (n=402) or placebo + Herceptin + docetaxel (n=406).1

Important Safety Information Boxed WARNING: Embryo-Fetal Toxicity

• Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information Left Ventricular Dysfunction

• In the randomized trial, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel

• Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis

• PERJETA has been associated with infusion and hypersensitivity reactions • On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting • In the randomized trial, the overall frequency of hypersensitivity reactions/ anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebotreated group

Significantly prolong overall survival 34% reduction in risk of death with PERJETA1 Second Interim Overall Survival (OS) Results1 Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR=0.66 95% CI [0.52-0.84] P=0.0008‡

OS (%)

MEDIAN NOT YET REACHED

60 50

37.6

20 10 0

P+H+D PI+H+D

402 406

387 383

371 350

342 324

317 285

25 30 MONTHS 230 143 198 128

• More than 50% of patients in the PERJETA + Herceptin + docetaxel arm were alive at the time of the second interim analysis, thereby indicating that the median OS for this arm has not yet been reached1 • At the time of analysis, there were 113 (28.1%) and 154 (37.9%) deaths in the PERJETA + Herceptin + docetaxel arm and the placebo + Herceptin + docetaxel arm, respectively1

MONTHS

• Median follow-up was 30 months (1 year following the first interim analysis) for both the PERJETAbased regimen and the placebo + Herceptin + docetaxel arms (Kaplan-Meier estimate)1-3

84 67

33 22

9 4

0 0

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

Patients at risk

OS = overall survival. ‡ The HR and P-value for the second interim analysis of OS crossed the predefined efficacy stopping boundary (HR≤0.739, P≤0.0138).1

• Consistent PFS and OS benefit demonstrated across several HER2+ MBC patient subgroups1,3 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])1 • The incidence of Grade 3-4 hypersensitivity reactions/anaphylaxis was 2% in the PERJETA-treated group and 2.5% in the placebo-treated group according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) (version 3). Overall, 4 patients in the PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression, defined as 3+ IHC by Dako HercepTest™ or FISH amplification ratio ≥2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC • Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

PER0001010503

Printed in USA.

06/13

Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. April 2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119. 3. Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 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. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

ASCOPost.com | SEPTEMBER 15, 2013

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Best of ASCO® Melanoma

Three ‘Game-Changers’ in the Treatment of Melanoma By Charlotte Bath

here have been three “gamechangers” in the treatment of melanoma, Mark R. Albertini, MD, Associate Professor of Medicine at the

gen-experienced T cells in the periphery and serves to limit the activity of T cells at the time of an inflammatory response, thereby protecting normal tissues from collateral destruction.” There are also distinct differences between anti-PD-1 and anti-PD-L1 blockade, Dr. Albertini pointed out. “They are not identical. They could behave differently because they block different distinct sets of inhibitory interactions.”

Four Studies Mark R. Albertini, MD

University of Wisconsin in Madison, contended at the Best of ASCO Chicago meeting. The first, he explained, was the recognition of different genetic driver mutations—most prominently BRAF mutations—and their pathways, and the development of targeted agents that interfere with these pathways. “The second game-changer involved CTLA-4 blockade,” Dr. Albertini continued, and the CTLA-4 blocking antibody, ipilimumab (Yervoy), which “basically disables the off switch resulting in T cells remaining active,” he said. These two developments have provided “game-changing insights” over the past few years that have completely changed the landscape of melanoma treatment, Dr. Albertini said. “I would like to convince you that game-changer number 3 is the use of the PD-1/ PD-L1 axis for immunomodulation,” he said, backing up that assertion with summaries of four studies presented at the ASCO Annual Meeting that addressed the hypothesis of PD-1/PDL1 as an effective target in melanoma.

Distinct Differences As pointed out in a review by Topalian et al,1 “PD-1 and CTLA-4 play distinct roles in regulating T-cell immunity. CTLA-4 modulates the early phases of activation of naive or memory T cells in response to T-cell receptor stimulation by MHC-peptide complexes displayed by antigen-presenting cells,” Dr. Albertini noted. “In contrast, PD-1 is expressed on anti-

A study using the anti–PD-1 monoclonal antibody lambrolizumab (MK-3475) showed an overall response rate of 38% among patients with advanced melanoma who had or had not received prior treatment with ipilimumab.2 The highest response rate (52%) occurred among patients receiving lambrolizumab at 10 mg/ kg every 2 weeks. While almost 80% of patients experienced some adverse event, the rate of grade 3/4 adverse events was 12.6%, and the treatment was well tolerated, Dr. Albertini said. A study of MPDL3280A, an en-

Albertini explained. “Importantly, you see similar activity both in the patients who are naive to ipilimumab and patients whose disease has been refractory to ipilimumab.” Although about 60% of patients experienced some toxicity, “the majority of adverse events were transient grade 1 or 2 and did not require intervention,” Dr. Albertini reported. Introducing the final abstract,5 concerning the safety and clinical activity of the anti–PD-1 antibody nivolumab in combination with the anti-CTLA-4 antibody ipilimumab in patients with advanced melanoma, Dr. Albertini stated, “I will remind you of the difference in activity that is thought to occur with ipilimumab, with CTLA-4 blockade occurring earlier on, and with PD-1 blockade occurring in the tissue microenvironment—clearly setting up a model for potential combination immunotherapy.” Rapid and deep tumor reductions > 80%, which Dr. Albertini termed “a striking response,” occurred among 13% of patients who received the

[These new findings are] a confirmation of the ability of immunotherapy to produce durable responses in patients with metastatic melanoma. —Mark R. Albertini, MD

gineered PD-L1 antibody, looked at whether tumor expression of PD-L1 would predict which patients would respond.3 The objective response rate among patients with metastatic melanoma was 29% overall, 27% among patients who were PD-L1–positive and 20% among those who were PD-L1– negative. While the response among PD-L1–positive patients was greater, the investigators also saw responses in patients who were negative for PD-L1, Dr. Albertini said. “Importantly, if you include stable disease with responders, you actually see benefit in 58% of patients, 87% of patients who were PD-L1–positive,” he added. A phase I/II trial of the anti–PD-1 antibody nivolumab with peptide vaccine included patients in whom ipilimumab had failed or had not yet been given.4 “Peptide vaccine was included as an immune-monitoring tool,” Dr.

two agents in sequence and among 31% who received the two agents concurrently. “In addition to magnitude of the reduction, what is also impressive is the rapidity of the reduction, these responses occurring quite quickly in contrast to what is more commonly seen with immunotherapeutic approaches,” Dr. Albertini commented. Grade 3/4 related adverse events occurred in 53% receiving concurrent treatment and 18% of patients receiving sequenced treatment. The most common were asymptomatic lab abnormalities, including elevations of lipase. “It is important to note that the related adverse events were managed using standard protocol algorithms that have been well developed from the ipilimumab experience, and no deaths were reported,” Dr. Albertini stated.

Study Strengths and Limitations Grouping these four abstracts together, Dr. Albertini listed the following strengths of this research: ■ The efficacy of the PD-1 pathway blockade is supported by high response rates that appear to be durable,” although more follow-up is needed. ■ PD-1 pathway blockade appears to have acceptable clinical toxicity and adverse events were readily managed using current algorithms. ■ Sequential therapy with anti– PD-1 after ipilimumab can result in clinical benefit. ■ Combination immunotherapy with ipilimumab and nivolumab induced rapid and deep responses that appear better than published monotherapy values. Again grouping the four abstracts together, Dr. Albertini listed the following limitations: We still need to determine the best pathway to inhibit. Should we inhibit PD-1 or PD-L1? ■ We clearly need biomarkers of response to anti-PD-1 therapy. There were many potential biomarkers of response presented. We need to identify those to figure out which patients will go on to have durable responses with these treatments. ■ We need to confirm the high response rate and anticipated durable benefit from combination immunotherapy with ipilimumab and nivolumab. A randomized study will evaluate the combination with the individual components.

Changing the Standard of Care In conclusion, Dr. Albertini said that the anti–PD-1, anti–PD-L1 findings provided “exciting and impressive new data that I predict will change the standard of care for patients with melanoma…. [These new findings are] a confirmation of the ability of immunotherapy to produce durable responses in patients with metastatic melanoma,” he added. “There is high anticipation that PD-1 blockade will result in improved survival for patients with metastatic melanoma,” although further followup is needed. “There is enthusiasm for looking at combination immunocontinued on page 10

The ASCO Post | SEPTEMBER 15, 2013

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Best of ASCO® ‘Game-Changers’ in Melanoma

EMD Serono, Eisai, MedImmune LLC, Merck Serono, Genentech, and Bristol-Myers Squibb.

continued from page 9

References 1. Topalian SL, Drake CG, Pardoll DM, et al: Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24:207-212, 2012. 2. Ribas A, Robert C, Daud A, et al: Clinical efficacy and safety of lambroli-

therapy with PD-1 blockade, specifically combinations with other forms of treatment, including vaccines.” n

Disclosure: Dr. Albertini reported that he has received or is discussing clinical trial research funding support from the following sources:

zumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9009. Presented June 2, 2013. 3. Hamid O, Sosman A, Lawrence DP, et al: Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). 2013 ASCO Annual Meeting. Abstract

9010. Presented June 2, 2013. 4. Weber JS, Kudchadkar RR, Gibney GT, et al: Phase I/II trial of PD-1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab. 2013 ASCO Annual Meeting. Abstract 9011. Presented June 2, 2013. 5. Wolchok JD, Kluger HM, Callahan MK, et al: Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). 2013 ASCO Annual Meeting. Abstract 9012. Presented June 2, 2013.

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

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In Future Issues Watch for coverage of the 2013 Breast Cancer Symposium in future issues of The ASCO Post.

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 11

Best of ASCO® Triple-Negative Breast Cancer continued from page 1

logic complete response] rate for BRCA mutation carriers with triplenegative breast cancer treated with standard anthracycline/taxane chemotherapy, but a retrospective study from MD Anderson showed a 37% [pathologic complete response] rate,” she said. Two additional studies, both from the Dana-Farber Cancer Institute, evaluated neoadjuvant cisplatin at 75 mg/m2 given every 21 days for four cycles. Silver et al reported a response rate of 21% in a study of 28 unselected patients with triple-negative breast cancer,2 whereas the larger 51-patient study by Ryan at el, in which patients also received bevacizumab (Avastin) every 3 weeks for three cycles, found a pathologic complete response rate of 15%.3 “While this is interesting activity, what we have lacked is randomized trial data,” Dr. Telli noted.

of statistical significance in this study. “The interesting finding was the difference in [pathologic complete response] by subtype. Among patients with triple-negative disease, [pathologic complete response] increased by about 20% (58.7% vs 37.9%; P < .05). This impressive result is something we don’t frequently see in triple-negative breast cancer,” Dr. Telli said. “But surprisingly, for HER2-positive patients, there did not appear to be a significant advantage for the addition of carboplatin, with [pathologic complete response] rates lower than what we would have expected (33.1% vs 36.3%, respectively). The main finding is that the advantage seen with carboplatin was driven by patients with triple-negative disease.” Disappointingly, however, the regimen was very toxic. Almost half the patients receiving carboplatin discontinued treatment, mostly due to adverse events. “This chemotherapy

GeparSixto Study The GeparSixto trial, presented at the 2013 ASCO Annual Meeting, provided that data in a randomized phase II study of 595 patients, evaluating the addition of carboplatin to standard neoadjuvant chemotherapy in triple-negative and HER2-positive patient populations.4 Patients received weekly paclitaxel plus weekly nonpegylated liposomal doxorubicin in a dose-intensive regimen over 18 weeks, with or without the addition of carboplatin at AUC 1.5. All HER2-positive patients also received both trastuzumab (Herceptin) and lapatinib (Tykerb), and all triple-negative patients received bevacizumab. The study met its primary endpoint by showing an increase in pathologic complete response with the addition of carboplatin. In the overall population, pathologic complete response was achieved by 46.7% in the carboplatin arm vs 37.2% in the standard arm, with a P value < .2, which met the level

mary endpoint was pathologic complete response, which was achieved by 36% of the overall population but rose to 47% in the BRCA1/2-mutated population and to 56% in triple-negative patients who also had BRCA1/2 mutations. The toxicity profile was more favorable than that of the GeparSixto regimen, she added. As expected, myelosuppression was common (grade 3/4 neutropenia in 49%) and elevations in liver enzymes were seen (grade 3 in 24%). “Some of the important qualityof-life toxicities, however, such as alopecia and neuropathy, were infrequent with this regimen,” Dr. Telli noted.

New Assays “There are exciting new assays coming down the pike to help us identify which patients may respond to platinum agents,” she said. The homologous recombination deficiency assay was developed by Myriad Genetics to detect a genomic homolo-

Careful randomized clinical trial designs that incorporate biomarkers of response are key to moving forward. —Melinda L. Telli, MD

backbone—a dose-intense weekly anthracycline/taxane regimen—is something we don’t use in the United States. The data are exciting, but the regimen is unacceptably toxic,” she commented.

PrECOG 0105 “Our own group presented the results of a platinum-containing regimen that did not include an anthracycline or taxane from a single-arm phase II study in triple-negative and BRCA1/2mutated patients,” Dr. Telli said.5 Eighty patients were treated neoadjuvantly with carboplatin at AUC 2 on days 1 and 8, gemcitabine at 1,000 mg/m2 on days 1 and 8, and iniparib at 5.6 mg/kg on days 1, 4, 8, and 11, every 21 days for six cycles. The pri-

Platinums in Triple-Negative Breast Cancer ■ Interest in evaluating platinum agents in triple-negative breast cancer has been renewed, due to encouraging new data.

■ Neoadjuvant chemotherapy that includes a platinum agent results in high pathologic complete response rates.

■ The homologous recombination deficiency assay might identify which

patients who do not carry a BRCA mutation may have “BRCA-like” breast cancer and respond to platinums.

gous recombination deficiency “footprint” in a tumor caused by defects in the homologous recombination pathway. It has the potential for identifying non–BRCA1/2 mutation carriers with “BRCA-like” cancers who may benefit from DNA repair-targeted strategies. The assay was developed by looking at the association of genomic patterns of loss of heterozygosity and homologous recombination deficiency in ovarian cancer.6 Loss-of-heterozygosity regions of intermediate size were observed more frequently in tumors with defective BRCA1 or BRCA2. Greater genomic instability in the tumor is reflected by an elevated homologous recombination deficiency score, and this is believed to be related to underlying DNA repair defects in that tumor, she explained. “We looked at this assay in the context of the PrECOG 0105 study, and we saw that the mean [homologous recombination deficiency] scores were significantly higher for responders than nonresponders,” she said.7 “But what was really interesting, and where the power of this type of assay lies, is that even if you take out the germline BRCA mutation carriers,

this difference was observed. “Patients with higher scores had much more favorable [pathologic complete response] rates (70%) than those with low homologous recombination deficiency scores (20%),” she reported. “We know the efficacy of platinums in this patient population is influenced by BRCA mutation status, and BRCA mutation carriers achieve higher response rates, but there are certain sporadic triple-negative patients who likely stand to benefit significantly from a platinum-based approach. Tumor measures of genomic instability, such as loss of heterozygosity, may prove to be important biomarkers in these cases,” she said. “Careful randomized clinical trial designs that incorporate biomarkers of response are key to moving forward,” she added. In the near term, trials that are ongoing or in development include: ■ Neoadjuvant anthracycline/cyclophosphamide vs cisplatin in BRCA1/2 mutation carriers ■ CALGB 40603 trial of neoadjuvant weekly paclitaxel plus anthracycline/cyclophosphamide, with or without carboplatin and with or without bevacizumab ■ Hoosier Oncology trial of cisplatin with or without the PARP inhibitor rucaparib as postneoadjuvant therapy in triple-negative and BRCA-positive breast cancer with residual disease after standard neoadjuvant therapy ■ ECOG 5112 trial of neoadjuvant anthracycline/cyclophosphamide followed by paclitaxel vs gemcitabine/carboplatin in triplenegative and BRCA-positive breast cancer, with the primary endpoint being pathologic complete response in patients with high homologous recombination deficiency score (in development) n Disclosure: Dr. Telli has received research support from Sanofi; she has served in a consultant or advisory role (uncompensated) with Sanofi.

References 1. Gronwald J, Byrski T, Huzarski T, et al: Neoadjuvant therapy with cisplatin in BRCA-positive breast cancer patients. 2009 ASCO Annual Meeting. Abstract 502. Presented May 31, 2009. 2. Silver DP, Richardson AL, Eklund AC, et al: Efficacy of neoadjuvant cisplatin in triple negative breast cancer. J Clin Oncol 28:1145-1153, 2010. continued on page 14

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

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

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

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

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

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

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

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

The ASCO Post | SEPTEMBER 15, 2013

PAGE 14

Best of ASCOÂŽ Triple-Negative Breast Cancer continued from page 11

3. Ryan PD, Tung NM, Isakoff SJ, et al: Neoadjuvant cisplatin plus bevacizumab in triple negative breast cancer: Safety and efficacy. 2009 ASCO Annual Meeting. Abstract 551. 4. Von Minckwitz G, Schneeweiss A,

Salat C, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvanat therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2013. 5. Telli ML, Jensen KC, Kurian AW, et al: PrECOG 0105: Final efficacy results from a phase II study of gemcitabine and

carboplatin plus iniparib (BSI201) as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer. 2013 ASCO Annual Meeting. Abstract 1003. Presented June 3, 2013. 6. Abkevich V, Timms KM, Hennessy BT, et al: Patterns of genomic loss of heterozygosity predicts homologous recombination repair defects in epithelial ovarian

cancer. Br J Cancer 107:1776-1782, 2012. 7. Telli ML, Jensen KC, Abkevich V, et al: Homologous recombination deficiency score predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and BRCA1/2 mutation-associated breast cancer. 2012 AACR-CTRC San Antonio Breast Cancer Symposium. Abstract PD09-04. Presented December 13, 2012.

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

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

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

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

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 15

News

High-Tech Imaging Contributes to Overdiagnosis, Overtreatment of Low-Risk Thyroid Cancers By Jo Cavallo

study from the Mayo Clinic Center for the Science of Health Care Delivery finds that advances in imaging technologies, including ultrasound, com-

puted tomography, and magnetic resonance imaging, are fueling an epidemic in the diagnosis and treatment of thyroid cancers that are unlikely to ever cause

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

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

symptoms or death, exposing patients to unnecessary and harmful treatments.1 The new technologies can detect thyroid nodules as small as 2 mm, many of

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

which are papillary thyroid cancers, the most indolent form of thyroid cancer. According to the study, in the United States, the incidence of thyroid cancer has increased from 3.6 cases per 100,000 in 1973 to 11.6 cases per 100,000 in 2009, with small papillary thyroid cancers accounting for 90% of the cases.

Unnecessary Treatment â&#x20AC;&#x153;High-tech imaging technologies such as ultrasound, CT, and MRI can detect very small thyroid nodules many of which are slow-growing papillary thyroid cancers. This is exposing patients to unnecessary and harmful treatments that are inconsistent with their prognosis,â&#x20AC;? said Juan Pablo Brito, MBBS, in a statement. Dr. Brito is an Endocrine Fellow and Health-Care Delivery Scholar at Mayo Clinic and lead author of the study. The researchers said the expanding gap between the incidence of thyroid cancer and stable death rates from papillary thyroid cancer (0.5/100,000 in both 1979 and 2009) suggests that lowrisk cancers are being overdiagnosed and overtreated. Overdiagnosing and overtreating these low-risk cancers, said the researchers, often results in unnecessary thyroidectomies, which are costly, carry a risk of physical complications, such as low calcium levels and nerve injury, and require lifelong thyroid replacement therapy.

Coining a New Term

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

ONCOLOGY

Rather than labeling these small lesions as cancer, Dr. Brito and his colleagues suggest a new term that connotes a favorable prognosis for low-risk thyroid cancers: micropapillary lesions of indolent course (microPLIC). The new term, said the researchers, would make it easier for clinicians to offer patients the choice of active surveillance instead of immediate and often intensive and expensive treatment. n

Disclosure: The study authors reported no potential conflict of interest.

Reference 1. Brito JP, Morris JC, Montori VM: Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumors. BMJ 347:4706, 2013.

The ASCO Post | SEPTEMBER 15, 2013

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Expert’s Corner World Cutaneous Malignancies Congress

What Is the Optimal Treatment of Advanced Melanoma? A Conversation With Mario Sznol, MD By Caroline Helwick

ith exciting targeted and immunotherapeutic agents now part of the arsenal for metastatic melanoma, which drug should move to the head of the line? Mario Sznol, MD, Professor of Medicine at Yale Univer-

Mario Sznol, MD

sity School of Medicine, New Haven, Connecticut, has been involved in key clinical trials of the new agents and was a co-leader of the phase 1 study of the anti–PD-1 monoclonal antibody nivolumab. Dr. Sznol shared his approach to treating advanced melanoma with attendees at the 3rd World Cutaneous Malignancies Congress in San Diego, and he elaborated on the topic in an interview with The ASCO Post.

Key Questions What do you consider the key clinical questions on the minds of clinicians treating metastatic melanoma? There are many. I will list some here: If the patient has a BRAF V600E or V600K mutation, should I start with targeted therapy or immunotherapy, and does tumor volume or rate of progression matter in this setting? ■ If a BRAF inhibitor is indicated, should I use vemurafenib (Zelboraf ) alone, add the MEK inhibitor trametinib (Mekinist) to vemurafenib, or use the combination of dabrafenib (Tafinlar) plus trametinib? And if patients show progression on a BRAF inhibitor, should I add trametinib then? ■ If I start with immunotherapy as a standard of care outside of a clinical trial, should I use high-dose interleukin-2 (Proleukin) or ipilimumab (Yervoy)? ■ What is the future role of the anti– PD-1/PD-L1 antibodies, and how should I incorporate them in treatment?

■ Is there still a role for chemotherapy?

Mutation Testing How would you answer these questions for the oncologist? Let’s start with how you select initial treatment for the patient newly diagnosed with metastatic disease. Although we consider immune therapy first in almost all patients, we will send a tumor sample for mutation testing, and the specifics of this depend on site of origin. If the primary disease was mucosal or acral lentiginous melanoma, we send off a sample for all the mutations (BRAF, NRAS, c-KIT) at once. If the disease originated from a cutaneous primary melanoma, we test for BRAF and NRAS. We add the test for c-KIT in some patients with primary lesions from chronic, sun-damaged skin. For ocular melanoma, we don’t always do genetic testing to determine therapy, although these tumors often have GNAQ or GNA11 mutations and may be somewhat responsive to MEK inhibitors. If the patient does not have a BRAF V600E mutation, we consider that he or she could have other mutations or alterations in BRAF that are not picked up on the conventional test and that could respond to a BRAF or MEK inhibitor, so we may send tissue

Fig. 1: Yale Cancer Center Melanoma Treatment Algorithm. Courtesy of Mario Sznol, MD.

with a targeted agent or immunotherapy in BRAF-mutated patients? The targeted agents are actually lower on our list, but it depends on the individual patient. While some patients can have durable responses to BRAF inhibitors, so far we don’t know if these responses are maintained once you stop the drug, unlike with immunotherapy. If a BRAF inhibitor is indicated, the best recent data indicate it should be used in combination with the MEK inhibitor trametinib. The com-

We believe that having these new drugs will make some of the current treatment algorithms obsolete, and in fact, the field is moving so rapidly that it is hard to predict the optimal algorithm for the next several years. — Mario Sznol, MD

for more sophisticated molecular sequencing. Patients with the unusual mutations or alterations are a vanishingly small population, but that’s what personalized medicine is about. The testing algorithm will soon be changing, though, because multigene testing is becoming more affordable. Hospitals should soon have a panel of perhaps 500 to 1,000 genes.

Treatment Initiation Based on the molecular profile, how do you initiate treatment? Do you start

bined treatment is also better tolerated than a BRAF inhibitor alone, and we have had some success obtaining approval for the combination from insurance companies. Even when we start targeted therapy first, our goal is to reach a level of response where we might stop the targeted therapy and start ipilimumab. We also have the option of going back to targeted therapy if there is no response to the immune therapy. Our preferred approach is to start with a trial of immunotherapy

(Fig. 1). We go through multiple lines of immunotherapy in an effort to induce a long-term remission, which may be a cure in some patients. If possible, we try to offer high-dose interleukin-2, ipilimumab, PD-1 blockade on a trial, or refer for a cell therapy trial, although not necessarily in that order. For ipilimumab, it’s important to understand that some patients slowly build an immune antitumor response over 3 to 6 months, but once they respond they often have durable remissions—they just need time to get there. For patients with very rapid disease progression and for those with poor performance status, ipilimumab is probably not the drug to use first. However, agents such as anti–PD-1, alone or in combination with another agent, could give more rapid tumor responses, and therefore might be appropriate first choices in patients with more rapidly progressive disease or declining performance status.

Next Options What do you do when the patient shows disease progression? If the patient does not respond to immunotherapy and has a BRAF mutation, we move to the targeted agents—right now I prefer the combination of dabrafenib and trametinib. If the combination is not possible, we will offer vemurafenib

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PAGE 17

Expert’s Corner

or dabrafenib alone. If the patient has progression on vemurafenib, and he or she has had a long response to vemurafenib, we consider adding trametinib or changing to dabrafenib plus trametinib. If the patient has a c-KIT mutation, obviously we offer a drug like imatinib (Gleevec). If disease progresses on all these treatments, we consider the patient for a phase I trial. The only role for chemotherapy at our center is in the patient who cannot tolerate, does not respond to, or is not a candidate to receive these newer agents. It is really important to note that we still give priority to clinical trials at every decision point in the treatment process.

Novel Immunotherapeutic Agents How will you use the anti–PD-1/ PD-L1 antibodies? We are very excited about these immunotherapeutic agents, currently nivolumab and lambrolizumab, which block PD-1 but also the antibodies that block PD-L1. About 30% of patients will respond to these agents by objective criteria, and conservatively, about half of this group may achieve very durable responses. The median response duration to nivolumab is 2 years—the longest we have seen in advanced melanoma. Even better responses are observed when we combine nivolumab with ipilimumab. We see overall response rates of 40% to 50%, with about 30% of patients demonstrating at least an 80% tumor regression. This can occur even in patients with very large tumors that are progressing rapidly. The responses happen quickly and are very deep. If you extrapolate from current data, and treatment starts with an anti–PD-1/PD-L1 agent, you can expect that 15% to 20% of your patients will have long, durable responses. With combinations, those durable responses may be achieved in as many as 25% to 30% of patients. In the future, that might, therefore, be your first treatment option in most cases. With anti–PD-1, you can tell your patient that he or she will have a 30% chance of responding, and if a response occurs, there is a 50% chance that it will be durable, with almost no toxicity in most patients; toxicity, however, will be greater when PD-1 blockade is combined with ipilimumab. It’s a no-brainer that we will prob-

ably offer some form of PD-1 blockade first, alone or in combination. Perhaps we may change this view when we see long-term data from the dabrafenib/trametinib or other BRAF/MEK targeted agent combinations. Of course, we need randomized trials of these combinations. I still don’t know with 100% certainty

if nivolumab/ipilimumab is better than nivolumab alone, or better than lambrolizumab alone, or if one anti–PD-1/PD-L1 agent is better than another. But the impression is that for large-bulk, rapidly progressive disease, the combination may be capable of producing impressive responses within a period of weeks in

some patients. We believe that having these new drugs will make some of the current treatment algorithms obsolete, and in fact, the field is moving so rapidly that it is hard to predict the optimal algorithm for the next several years. n Disclosure: Dr. Sznol reported no potential conflicts of interest.

At first glAnce, we sAw Achievement. with focus, we see even more potentiAl. A closer look at targeting CD20 may bring new possibilities into view

cD20: A significAnt tArget The advent of monoclonal antibody therapies has helped transform the treatment of hematologic malignancies.1 CD20 is an important target due to its unique features and presence on a majority of B cells.2 The success of targeting CD20 is due, in part, to the ability to activate cell death through a variety of potential mechanisms.2 In addition, CD20 is a stable antigen that is not typically downregulated or shed upon antibody binding.2

Targeting CD20 is an important strategy for hematologic malignancies, including chronic lymphocytic leukemia (CLL).3 Despite clinical developments, certain patients with hematologic malignancies, including CLL, lack clear or effective treatment options and trade-offs between efficacy and tolerability are often made.3 To meet these needs, we continue to research anti-CD20 antibodies that optimize the potential of this target.

ADvAncements in tArgeting cD20 There is an opportunity to make additional clinical gains with new treatment options for a broader range of patients.3 As a leader in targeted treatments for B-cell malignancies, we remain committed to advancing the science of targeting CD20 in an effort to improve clinical outcomes for patients with hematologic malignancies, including CLL.

To find out more about advancing the science of targeting CD20, visit ResearchBcell.com References: 1. Castillo J, Winer E, Quesenberry P. Newer monoclonal antibodies for hematological malignancies. Exp Hematol. 2008;36(7):755-768. 2. Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95(12):3900-3908. 3. Alduaij W, Illidge TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood. 2011;117(11):2993-3001.

The ASCO Post | SEPTEMBER 15, 2013

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Expert’s Corner Palliative Care

Undertreatment of Cancer Pain Remains a Persistent Problem in Oncology A Conversation With Russell K. Portenoy, MD By Ronald Piana

Russell K. Portenoy, MD

ata indicate that for more than 2 decades, cancer pain has been undertreated in the United States. The paradox of this stubborn clinical problem is that oncology has the ability to manage the great majority of cancer pain. To clarify this issue, The ASCO Post recently spoke with nationally regarded palliative care specialist, Russell K. Portenoy, MD. Dr. Portenoy is Chairman of the Department of Pain Medicine and Palliative Care and Gerald J. Friedman Chair in Pain Medicine and Palliative Care at Beth Israel Medical Center, New York, Chief Medical Officer of MJHS Hospice and Palliative Care, and Professor of Neurology and Anesthesiology, Albert Einstein College of Medicine, Bronx, New York.

Cancer Pain Survey You were one of the authors of a cancer pain survey published in the Journal of Clinical Oncology in 2011. Please explain the intent and results of the survey. My colleague Brenda Breuer, PhD, was lead author on an anonymous survey that we mailed to 2,000 medical oncologists (overall response rate, 32%) who were randomly selected from the AMA’s Physician Masterfile. We formatted the survey to be precise but without being an untoward time burden on busy oncologists. The full 46-item survey took 10 to 11 minutes to complete. Two shortened versions had 25 and 27 items, respectively, and took 6 to 7 minutes to complete. We created two vignettes involving challenging pain circumstances and asked oncologists to specifically recommend a course of action for each. We found that most of the oncologists did not respond correctly. In fact, 60% and 87% gave answers to the

two vignettes, respectively, that were inconsistent with best practice. After publishing the results in JCO,1 letters to the editor commented that the results of our study were very similar to a pain survey of 20 years ago.2 This, of course, is a good metric to tell us that the problem, although identified, persists within the oncology community.

demic medicine. The data also show that when asked how to solve a challenging pain problem, most oncologists get the answers wrong. The documented knowledge deficit and the failure to adhere to best practices is a significant reason that undertreatment of cancer pain is still a problem in the oncology community.

What message do you think the survey gives to the oncology community? Statistical limitations notwithstanding, the results from the vignettes raise a concern that the oncology community needs to further highlight the problem of pain. The community needs to shine a spotlight on the issue and begin to focus on cancer pain management as a best practice that needs periodic updating in terms of educa-

What is the most significant clinical challenge in managing cancer pain? I view the treatment of cancer pain as a continuum of challenges with varying degrees of difficulty. A large majority of our patients with cancer can have their pain adequately controlled with relatively simple techniques that focus on the appropriate choice and use of drugs. It’s important to note that these pain management techniques are within the

Continuum of Challenges

Why shouldn’t a patient whose oncologist is working hard to keep him or her alive expect that same oncologist to evaluate and treat their symptoms of discomfort or pain? That’s one gap in care we need to fill. —Russell K. Portenoy, MD

tion and commitment. The science behind pain medicine has evolved. We need to make sure that medical oncologists are knowledgeable about these advances and that they are using them to manage different challenges in pain.

Why Undertreatment Persists Why is the problem of undertreated pain still a major issue in cancer care? For one, undertreatment is hard to define. To achieve an accurate definition, you first need to know what the best practice is and what the expected response to that best practice should be. Then you need to determine whether best practice was applied and if the response was optimal, based on the literature. So defining undertreatment is more complex than simply using a pain scale. We would expect the vast majority of our patients to have well-controlled pain if simple guidelines for opioid-based therapy were applied in a sophisticated manner. However, data indicate that there is a high prevalence of inappropriate use of opioid therapy among oncologists, both in the community setting and in aca-

purview of all practicing oncologists. However, these fairly easy-to-employ pain strategies—which should be in the armamentarium of every oncologist— are not being evenly applied for the patient populations that need them. Another more challenging category involves pain patients whose treatment requires a specialized set of skills that the general community oncologist probably won’t have—for instance, in the management of neuropathic pain or bone pain. It would be understandable if the community doctor recognized his or her limitations and partnered with a specialist, but we found in our survey that it is a very rare event when an oncologist refers a patient to a cancer pain specialist. Frequent referrals to pain or palliative care specialists were reported by only 14% and 16%, respectively.

‘80/20 Rule’ Do we know why this clinical partnership between the oncology generalist and the pain specialist is not being utilized? It’s another systemic issue with several causes. We have pain special-

ists who are not oncologists but who might have the requisite skills in cancer pain management. For whatever reason, they are not getting referrals. And the palliative care community is getting the patients when end-of-life control is needed instead of bringing us into the clinical care of the patient early on, so that the symptoms related to cancer can be addressed as part of the continuum of care. The undertreatment dilemma could be considered a variation of the 80/20 rule—the principle that for many events, 80% of the effects come from 20% of the causes. In this case, 80% of patients whose pain could be managed with straightforward tactics well within the skill sets of the general oncologist are being undertreated. Then the 20% whose cancer pain needs more advanced techniques are not being referred to specialists. There is no single reason for this culture of undertreated cancer pain. However, our survey suggests that education of oncologists could be part of a strategy to improve the status quo.

Closing Thoughts Any last thoughts on this important issue? We need to think of pain within a model of unmet palliative care needs, including the treatment of other symptoms and other quality-of-life concerns. The palliative care community is very intent on shifting palliative care forward, as a construct that begins upstream in illness. It’s not end-of-life care—it is care that should be initiated at the time of diagnosis. Generalist-level palliative care should be offered to every patient with cancer as a best practice. Why shouldn’t a patient whose oncologist is working hard to keep him or her alive expect that same oncologist to evaluate and treat their symptoms of discomfort or pain? That’s one gap in care we need to fill. n

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

References 1. Breuer B, et al: Medical oncologists’ attitudes and practice in cancer pain management. J Clin Oncol 29:4769-4775, 2011. 2. Von Roenn JH, et al: Physician attitudes and practice in cancer pain management. Ann Intern Med 119:121-126, 1993.

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The ASCO Post | SEPTEMBER 15, 2013

PAGE 26

JCO Spotlight Hematology

No Benefit/Detriment of Donor Change in Second Stem Cell Transplant for Leukemia Relapse By Matthew Stenger

inimal data are available on outcomes of second allogeneic hematopoietic stem cell transplantation from unrelated donors after a first transplant in patients with hematologic relapse of acute leukemia. In a study reported in Journal of Clinical Oncology, Maximilian Christopeit, MD, of University Hospital Halle, Germany, and colleagues in the German Registry for Stem-Cell Transplantation and the Cooperative German Transplant Group evaluated the role of second allogeneic stem cell transplant for relapsed acute leukemia after related or unrelated first transplant and analyzed the effect of donor change on second transplant outcome in both settings.1 They found that the second stem cell transplant produced 2-year overall survival of 25% among all patients and that donor change had neither a beneficial nor detrimental effect on overall survival.

Study Details The study involved 179 consecutive patients receiving a second allogeneic stem cell transplant for acute leukemia relapse after a first allogeneic transplant in Germany between 1998 and 2009. Median age at second transplant was 39 years (range, 16–68 years). Patients had acute myeloid leukemia (n = 132), acute lymphoblastic leukemia (n = 46), or unclassified leukemia (n = 1). Donors at first transplant consisted of 75 matched related donors and 104 unrelated donors. At second transplant, 133 patients (74%) had unrelated donors. After related first transplant, a second transplant was performed from the same matched related donor in 51% of patients, a different matched related donor in 11%, and an unrelated donor in 39%. After unrelated first transplant, 42% received a second transplant from the same unrelated donor and 58% from a different unrelated donor. Patient demographic and clinical characteristics were well balanced among patients receiving a first transplant from a matched related donor vs an unrelated donor, except that patients with unrelated first transplant received less total-body irradiation

(P = .013), .013), more in vivo T-cell depletion (P < .001), and more peripheral blood stem cell grafts (P = .007). At second transplant, patients with a related first transplant had more cyclosporine-based immunosuppression (P = .037) 037) and less in vivo T-cell depletion (P = .02). Overall, 78% of patients received chemotherapy and 21% received donor lymphocyte infusions for initial disease control after relapse. Twentysix percent of patients received second transplant in complete remission.

Outcomes of Second Transplant Independent of donor, 74% of patients achieved complete remission after second transplant, with half of these patients experiencing another relapse. Overall survival and leukemia-free survival rates after second transplant were 31% and 26% at 1 year and 25% and 21% at 2 years. Two-year overall survival was 39% after related second transplant and 19% after unrelated second transplant. Long-term survivors were observed even after two unrelated second transplants. Longer remissions after second transplant than after first transplant were observed in 26% of patients. No

Second Stem Cell Transplant After Leukemia Relapse ■ Second allogeneic stem cell transplant after relapse from a first allogeneic transplant produced 2-year overall survival of 25% among all patients.

■ Use of a new donor in the second transplant did not result in a relevant

overall survival improvement after either related or unrelated first transplant, but related donors in the second transplant produced a better outcome than unrelated donors.

On univariate analysis, donor change (identical vs alternative door) slightly but nonsignificantly improved overall survival from second transplant (HR = 0.76, P = .114). There was no significant effect of donor change on overall survival on multivariate analysis (HR = 0.984, P = .933).

Outcomes by Related/ Unrelated First Transplant Among patients receiving first transplant from a matched related donor, 2-year overall survival and leukemia-free survival rates after second transplant were 37% and 31%, respectively. Donor change was not associated with better outcome (HR = 0.80, P = .449), although among patients receiving second transplant from a different matched related donor (n = 8), estimated 2-year overall survival was 88% (HR = 4.17, P = .048).

Donor change for [a second allogeneic stem cell transplant] is a valid option. However, a clear advantage in terms of overall survival could not be demonstrated. —Maximilian Christopeit, MD, and colleagues

significant differences in overall or leukemia-free survival were observed between patients with acute lymphoblastic leukemia and those with acute myeloid leukemia. Overall survival from second transplant was greater in patients with related vs unrelated first transplant (2-year overall survival 37% vs 16%, hazard ratio [HR] = 1.53, P = .016). Independent of donor at first transplant, overall survival was longer after related vs unrelated second transplant (2-year overall survival 39.5% vs 19%, HR = 1.56, P = .03).

No difference was found between overall survival after second transplant from the same matched related donor and overall survival after second transplant from a new unrelated donor (2year overall survival 34% vs 28%, HR = 1.02, P = .891). On multivariate analysis, donor change was not associated with overall survival (HR = 0.81, P = .512) Among patients receiving first transplant from an unrelated donor, 2-year overall and leukemia-free survival rates after second transplant were 16% and 13%, respectively. On univariate analysis, change of donor

at second transplant was associated with superior overall survival (estimated 2-year overall survival 11% for identical unrelated donors vs 20% for different unrelated donors, HR = 0.63, P = .037). This advantage was limited to patients without acute graftvs-host disease greater than grade 2 and chronic graftvs-host disease. On multivariate analysis, however, change to another unrelated donor was not significantly associated with overall survival (HR = 1.34, P = .245). Multivariate analysis for overall survival from second transplant confirmed the significant effect of established risk factors, including remission duration after first transplant (HR = 2.37, P < .001) .001) and stage at second transplant (HR = 0.53, P = .006). The investigators concluded: “After relapse from allogeneic [first hematopoietic stem cell transplantation, a second transplant] can induce 2-year overall survival in approximately 25% of patients. Unrelated [second transplant] is feasible after related and unrelated [first transplant]. Donor change for [second transplant] is a valid option. However, a clear advantage in terms of overall survival could not be demonstrated.” n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

See Commentary on page 27.

Reference 1. Christopeit M, Kuss O, Finke J, et al: Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change. J Clin Oncol. August 5, 2013 (early release online).

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JCO Spotlight Continued from page 26

Treatment of Relapse of Acute Leukemia Post-Transplant: Still Hope for Patients With Chemosensitive Disease By Richard Champlin, MD

isease recurrence is a devastating event after allogeneic hematopoietic stem cell transplantation as treatment for acute myeloid leukemia (AML). Median time to relapse is approximately 4 months and the majority of relapses occur within 2 years after transplant. The prognosis is usually poor. Overall 5-year survival of all patients relapsing post-transplant for AML or myelodysplastic syndrome (MDS) is about 5%. However, selected patients can respond to further treatment, and a substantial minority can still achieve a durable remission, usually after a second allogeneic transplant or donor lymphocyte infusion.

Relapse Considerations Relapse generally results from residual malignant cells that survive the preparative regimen and are not eliminated by the graft-vs-leukemia effect. In a minority of patients, relapse appears to occur in donor-derived cells. Relapse may occur by immune escape from graft-vs-leukemia effects. This may be due to loss of expression of leukemia related antigens; one case was reported associated with loss of expression of an HLA haplotype by deletion of chromosome 6. Another Dr. Champlin is Chair and Professor of Medicine, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.

mechanism of immune escape is development of tolerance in donor-derived T cells post-transplant. Duration of remission after hematopoietic stem cell transplantation is an important predictor of survival after recurrence; the best results occur in patients with remission duration greater than 6 months. Patients may respond

in patients relapsing post-transplant, and the best results have been achieved when a donor lymphocyte infusion or a second allogeneic transplant is performed to consolidate a chemotherapy-induced response. Results are very dependent on patient selection. Second hematopoietic transplants can induce durable com-

Approximately 20% of patients who respond to further chemotherapy achieve long-term remissions with a second transplant or with intensive chemotherapy followed by a donor lymphocyte infusion, particularly those who had a prolonged disease-free interval after the first transplant. â&#x20AC;&#x201D;Richard Champlin, MD

to salvage chemotherapy, particularly if they had chemosensitive disease before the initial transplant. Reported adverse prognostic factors include receiving the initial transplant while in relapse, having poor cytogenetic and molecular markers, and receiving transplants from alternative donors.

Treatment of Recurrence Chemotherapy alone generally produces only short-term responses

plete remission in a fraction of AML/ MDS patients with relapse posttransplant. Best results have occurred for patients in morphologic complete remission (or minimal disease state) prior to the second transplant; 20% to 30% of patients can achieve longterm survival in this setting. Since much of the benefit of allogeneic hematopoietic transplantation is related to the immune graft-vs-leukemia effect, there has been speculation

that use of a different donor might improve the outcome of a second transplant. This concept was tested in the study by Christopeit et al on behalf of the German Registry for Stem Cell Transplantation, recently published in the Journal of Clinical Oncology. They examined the results of second transplants for patients with relapsed acute leukemia, comparing the results using the same or an alternative donor. They could not demonstrate an advantage for using a different donor for the second transplant. Second transplants from a related donor had a better outcome than those from an unrelated donor.

Conclusion Relapse of AML following an allogeneic hematopoietic transplant is an ominous event with a generally poor prognosis. Selected patients may respond to additional salvage chemotherapy. Approximately 20% of patients who respond to further chemotherapy achieve long-term remissions with a second transplant or with intensive chemotherapy followed by a donor lymphocyte infusion, particularly those who had a prolonged disease-free interval after the first transplant. There is no apparent advantage in selecting a different donor for the second transplant. n Disclosure: Dr. Champlin reported no potential conflicts of interest.

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The ASCO Post | SEPTEMBER 15, 2013

PAGE 28

FDA Update

FDA Approves Mechlorethamine Gel for Cutaneous T-Cell Lymphoma

eptaris Therapeutics, Inc, recently announced that the U.S. Food and Drug Administration (FDA) has granted marketing approval for the orphan drug mechlorethamine gel (Valchlor) for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL) in patients who have received prior skin-directed therapy. This gel is the first and only FDA-approved topical formulation of mechlorethamine, which is commonly known as nitrogen mustard. The gel is applied topically once a day and dries on the skin. Mechlorethamine was approved previously for intravenous treatment of mycosis fungoides, the most common type of CTCL. Topical mechlorethamine preparations are currently recommended for the treatment of early-stage CTCL. Prior to approval of the gel, there were no FDA-approved topical mechlorethamine products; only nonstandardized, pharmacy-compounded petroleum ointment or aqueous-based topical preparations were available. The availability of the FDA-approved mechlorethamine gel will allow physicians to use this FDA-approved version of topical mechlorethamine to treat patients with stage IA and IB mycosis fungoides-type CTCL who have received prior skin-directed therapy. In addition to consistent, controlled manufacturing processes, the gel will be provided with labeling, which includes data and instructions for proper use to help achieve the best possible clinical results.

Patients had received at least one prior skin-directed therapy. Qualifying prior therapies included topical corticosteroids, phototherapy, bexarotene gel (Targretin), and topical nitrogen mustard (mechlorethamine). Patients were

not required to be refractory to or intolerant of prior therapies. In the 13-center study, 260 patients were enrolled in a 1:1 randomization. The vast majority of patients were stage IA and IB. Results of the study

were published earlier this year in JAMA Dermatology. In the study, 60% of patients treated with mechlorethamine gel had a confirmed response at 12 months, defined as reduction of at least 50% in the Com-

Simulated image based on patient with locally advanced BCC at Week 24.

Pivotal Trial The approval of mechlorethamine gel was based on a randomized, observer-blinded, noninferiority pivotal trial comparing the gel to a pharmacy-compounded mechlorethamine preparation in patients with stage IA– IIA mycosis fungoides–type CTCL.

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Boxed Warning And Additional Important Safety Information

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly Embryo-Fetal Death and Severe Birth Defects or through seminal fluid, to participate in the Erivedge • Erivedge capsule can cause fetal harm when pregnancy pharmacovigilance program by contacting administered to a pregnant woman based on its the Genentech Adverse Event Line at (888) 835-2555 mechanism of action Blood Donation • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months risks. Advise female patients of the need after the last dose of Erivedge for contraception during and after treatment and advise male patients of the potential risk Nursing Mothers of Erivedge exposure through semen • Inform female patients of the potential for serious • Advise patients to contact their healthcare provider adverse reactions in nursing infants from Erivedge, immediately if they suspect they 1(or, for males, their ERIV3D0021_F_Transformation_Print_Update_ASCO_r3.indd taking into account the importance of the drug to female partner) may be pregnant the mother

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 29

FDA Update

posite Assessment of Index Lesion Severity (CAILS) score, while 48% of those treated with the compounded control achieved a confirmed response. Complete responses constituted a minority of the CAILS overall response. CAILS responses were seen as early as 1 month, with further responses observed through 11 months of treatment.

No systemic absorption of mechlorethamine was detected with mechlorethamine gel treatment.

‘Good News’ for CTCL Treatment “This is good news for patients and the treatment community,” said Youn H. Kim, MD, Joanne and Peter Haas Jr.

Professor for Cutaneous Lymphoma Research, Professor of Dermatology, and Director, Multidisciplinary Cutaneous Lymphoma Clinic, Stanford University School of Medicine. “We

TRANSFORM THE TREATMENT OF DIFFICULT ADVANCED BASAL CELL CARCINOMA ((aBCC) ERIVEDGE IS A UNIQUE ORAL THERAPY (Not actual size)

• Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, and invasiveness), some patients may not be candidates for surgery or radiation1,2 • Erivedge is an oral treatment option dosed as a 150-mg capsule once daily until disease progression or unacceptable toxicity3 • Erivedge reduced lesions in patients with aBCC1,3 Objective response rates (ORR) by IR from ERIVANCE1,3* laBCC (n=63)

mBCC (n=33)

43% (n=27) (30.5-56.0)

30% (n=10) (15.6-48.2)

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median duration of response (months) (95% CI)

Indication Erivedge® (vismodegib) capsule is a hedgehog pathway inhibitor indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. *Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IR=Independent Review; laBCC=locally advanced BCC; ORR=objective response rate; CI=confidence interval; NE=not estimable; mBCC=metastatic BCC.

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) 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 Brief Summary of Prescribing Information on following page.

See what you can offer your patients with aBCC at www.Erivedge.com References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179. 2. Walling HW, et al. Cancer Metastasis Rev. 2004;23:389-402. 3. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 5/29/13 2:53 PM

now have the confidence of an FDAapproved product backed by evidence from a well-controlled clinical trial that demonstrated clinically meaningful responses in the majority of patients with stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma who have received prior skin-directed therapy,” Dr. Kim said. n

The ASCO Post | SEPTEMBER 15, 2013

PAGE 30

FDA Update

Sorafenib Granted Priority Review for Differentiated Thyroid Cancer

ayer HealthCare and Onyx Pharmaceuticals recently announced that the FDA has granted priority review designation to the supplemental new drug application of sorafenib (Nexavar) tablets for the treatment of locally ad-

vanced or metastatic radioactive iodinerefractory differentiated thyroid cancer.

DECISION Trial The regulatory submission is based on data from the phase III DECISION

trial,1 an international, multicenter, placebo-controlled investigation of sorafenib in patients with locally advanced or metastatic radioactive iodine–refractory thyroid cancer. The DECISION trial included

a total of 417 patients with locally advanced or metastatic, radioactive iodine–refractory, differentiated thyroid cancer (papillary, follicular, Hürthle cell, and poorly differentiated) who had received no prior chemotherapy, tyrosine kinase inhib-

Safety:7" Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term

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

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

All aBCC1 Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2013 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832301

itors, monoclonal antibodies that target vascular endothelial growth factor (VEGF) or VEGF receptor, or other targeted agents for thyroid cancer. Patients were randomly assigned to receive 400 mg of oral sorafenib twice daily (207 patients) or matching placebo (210 patients).

Key Data

Safety:10"

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)]

In the DECISION trial, sorafenib significantly extended progressionfree survival, the primary endpoint of the study, compared to placebo (hazard ratio = 0.587, 95% confidence interval = 0.454–0.758, P < .0001), which represents a 41% reduction in the risk of disease progression or death for patients who received sorafenib compared to placebo-treated patients. The median progression-free survival was 10.8 months in patients treated with sorafenib, compared to 5.8 months in patients receiving placebo.

Safety and Tolerability The safety and tolerability profile of sorafenib for patients in the trial was generally consistent with the known profile of sorafenib. The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue, weight loss, and hypertension. Results from the trial were presented at ASCO’s Annual Meeting in June 2013. n Reference 1. Brose MS, Nutting C, Jarzab B, et al: Sorafenib in locally advanced or metastatic patients with radioactive iondinerefractory differentiated thyroid cancer: The phase III DECISION trial. 2013 ASCO Annual Meeting. Abstract 4. Presented June 4, 2013.

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 31

Journal Spotlight Breast Cancer

Cohort Analysis: Adjuvant Tamoxifen Reduces Risk of Contralateral Breast Cancer in BRCA1/2 Mutation Carriers By Matthew Stenger

n a study reported in Journal of Clinical Oncology, Kelly-Anne Phillips, MBBS, MD, of the University of Melbourne, and colleagues analyzed the association of adjuvant

Kelly-Anne Phillips, MBBS, MD

tamoxifen use and risk of contralateral breast cancer among women carrying BRCA1 and BRCA2 mutations in the International BRCA1 and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry.1 Use of tamoxifen was associated with reduced risk of contralateral disease, with the benefit appearing to be independent of estrogen receptor (ER) status of first breast cancer.

Study Details The study used pooled observational cohort data, self-reported at enrollment and at follow-up. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral breast cancer since 1970 who had no other invasive cancer and no tamoxifen use before first breast cancer and did not develop contralateral breast cancer within 6 months after

first breast cancer diagnosis. Two primary analyses were performed. One combined retrospective (ie, time before cohort entry) and prospective (ie, time after cohort entry) follow-up, with follow-up starting at the date of diagnosis of first breast cancer. The second analysis included only data beginning from the time of cohort entry (left truncation of analysis time). The retrospective/prospective analysis included 1,583 BRCA1 and 881 BRCA2 mutation carriers, of whom 383 (24%) and 454 (52%), respectively, took tamoxifen after first breast cancer diagnosis. Prospective follow-up data (since date of cohort

This study provides observational evidence that, for BRCA1 and BRCA2 mutation carriers, tamoxifen use for first breast cancer might reduce the risk of contralateral breast cancer. —Kelly-Anne Phillips, MBBS, MD, and colleagues

entry) were available for 1,083 women (44%), comprising 657 BRCA1 and 426 BRCA2 mutation carriers, of whom 176 (27%) and 235 (55%), respectively, took tamoxifen after first breast cancer diagnosis. Overall, the median time since diagnosis of first breast cancer was 6.6 years, and the median time since cohort entry was 3.2 years. ER status of the first breast cancer was known for 44%; the first breast cancer was ER-negative for 76% of BRCA1 mutation carriers and ERpositive for 77% of BRCA2 mutation

Tamoxifen and Contralateral Breast Cancer Risk ■ The overall analysis indicated that tamoxifen use was associated with a 62% reduction in risk for contralateral breast cancer among BRCA1 carriers and a 67% reduction in BRCA2 carriers.

■ In analysis left-truncating at recruitment to the cohort, the 42% and 52% risk reductions associated with tamoxifen use did not reach significance.

■ The benefit of tamoxifen did not appear to be affected by ER status of first breast cancer.

carriers; 67% of those with an ER-positive first breast cancer used tamoxifen (60% and 71% for BRCA1 and BRCA2 mutation carriers, respectively) compared with 17% of those with an ERnegative first breast cancer (15% and 25%, respectively). A total of 37% of BRCA1mutation carriers and 33% of BRCA2 mutation carriers underwent bilateral oopherectomy, usually after their first breast cancer. Tamoxifen users tended to be older at diagnosis of first breast cancer (P < .001), which was more likely to be ER-positive (P < .001) .001) and have lobular histology (P = .01). Tamoxifen users were also more likely to have received

chemotherapy (P = .001) and to have had bilateral oopherectomy (P < .001).

Reduced Risk With Tamoxifen In the combined retrospective/prospective analysis, there were 520 contralateral breast cancers over 20,104 person-years of observation, including disease in 24% of BRCA1 and 17% of BRCA2 mutation carriers. In the prospective-only analysis, there were 100 contralateral breast cancers over 4,392 person-years of follow-up. In the combined analysis, after adjustment for age at diagnosis, year of diagnosis, bilateral oophorectomy, and country, hazard ratios (HRs) for contralateral breast cancer for women taking tamoxifen were 0.38 (95% confidence interval [CI] = 0.27–0.55, P < .001) for BRCA1 mutation carriers and 0.33 (95% CI = 0.22–0.50, P < .001) for BRCA2 mutation carriers. In the prospective analysis, after adjustment for age at diagnosis and country, respective hazard ratios were 0.58

(95% CI = 0.29–1.13, P = .1) and 0.48 (95% CI = 0.22–1.05, P = .07). There were no significant differences in the hazard ratios between BRCA1 and BRCA2 mutation carriers using the combined data (P = .7 .7 for heterogeneity), prospective data only (P = .9 for heterogeneity), or retrospective data only (P = .7 for heterogeneity).

Effect of ER Status In the combined analysis, hazard ratios for contralateral breast cancer for tamoxifen users were 0.33 (95% CI = 0.13–0.79) for ER-negative status and 0.59 (95% CI = 0.23–1.52) for ERpositive status among BRCA1 carriers and 0.44 (95% CI = 0.14–1.35) and 0.30 (0.15–0.62), respectively, among BRCA2 carriers. However, analysis adjusting for or stratifying on ER status of the first breast cancer showed that the observed associations were not accounted for by this tumor characteristic. Hazard ratios for tamoxifen use did not significantly differ by ER status (P = .3 for heterogeneity for both BRCA1 and BRCA2 mutation carriers), although the overall numbers of ER-positive breast cancers in BRCA1 mutation carriers and ER-negative breast cancers in BRCA2 mutation carriers were small. The investigators concluded, “This study provides observational evidence that, for BRCA1 and BRCA2 mutation carriers, tamoxifen use for first breast cancer might reduce the risk of contralateral breast cancer. Further follow-up of these cohorts will provide increased statistical power for prospective analyses and thus a more definitive answer to this important question in the future.” n

Disclosure: Dr. Phillips and colleagues reported no potential conflicts of interest. See Commentary on page 32.

Reference 1. Phillips K-A, Milne RL, Rookus MA, et al: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. August 5, 2013 (early release online).

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | SEPTEMBER 15, 2013

PAGE 32

Journal Spotlight Continued from page 31

Tamoxifen in Women With BRCA1 and BRCA2 Mutations: Another Option? By Rowan T. Chlebowski, MD, PhD

n analyses of pooled information from cohorts of women with BRCA1 and BRCA2 mutations who have had a prior breast cancer diagnosis, Phillips and colleagues examined the association between tamoxifen use compared to nonuse on contralateral breast cancer risk.1 Tamoxifen use was associated with lower contralateral breast cancer risk for both BRCA1 and BRCA2 mutation carriers, with a suggested influence on both estrogen receptor (ER)-positive and -negative disease. Although the numbers of contralateral breast cancer events, especially among tamoxifen users, are limited, the report nonetheless provides the strongest evidence yet that tamoxifen may reduce breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

for several factors generally associated with contralateral breast cancer risk--tamoxifen users were older and more commonly had an initial ER-positive cancer, received chemotherapy, and had bilateral salpingooophorectomy. The potential for confounding is

Study Limitations

perhaps greatest in the population in which the initial breast cancer was ER-positive. In that setting, the decision against adjuvant tamoxifen use could be associated with potential confounding factors. As women with BRCA mutations who have climacteric symptoms may be current menopausal hormone therapy users,3 they should be aware of the mixed chemoprevention tamoxifen trial findings4 that has led the recent ASCO guideline update to find insufficient evidence to support a primary breast cancer risk-reduction

The analyses truncated at cohort recruitment are important, as they address the issue of guarantee-time bias.2 They yield suggestive, but not statistically significant, associations for tamoxifen use and breast cancer risk. The authors recognize the limitations of their nonrandomized design, as adjustments were needed Dr. Chlebowski is Chief, Division of Medical Oncology and Hematology, HarborUCLA Medical Center, Los Angeles.

role of tamoxifen in menopausal hormone therapy users.5

Clinical Considerations As the authors outline, it is unlikely that a full-scale randomized clinical trial of tamoxifen in a BRCA mutation carrier population can success-

Discussion of these results in the clinic requires careful attention to potential adverse effects of tamoxifen use in the context of other available options to reduce breast cancer risk. â&#x20AC;&#x201D; Rowan T. Chlebowski, MD, PhD

fully go forward. In addition to further follow-up of women in current cohorts, information from emerging, large electronic datasets may further inform this question in the future. While the current study provides some evidence that tamoxifen is associated with reduced contralateral breast cancer risk in women with BRCA1 and BRCA2 mutations, given the nature of the available study population, questions remain. Therefore, discussion of these results in the clinic requires careful attention to poten-

tial adverse effects of tamoxifen use in the context of other available options to reduce breast cancer risk. n

Disclosure: Dr. Chlebowski has served in a consultant or advisory role for AstraZeneca, Novartis, and Pfizer. He has received honoraria from Novartis and AstraZeneca and research funding from Amgen.

References 1. Phillips KA, Milne RL, Rookus MA, et al: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. August 5, 2013 (early release online). 2. Giobbie-Hurder A, Gelber RD, Regan MM: Challenges of guaranteetime bias. J Clin Oncol 31:2963-2969, 2013. 3. Finch A, Evans G, Narod SA: BRCA carriers, prophylactic salpingooophorectomy and menopause: Clinical management considerations and recommendations. Womens Health (Lond Engl) 8:543-555, 2012. 4. Visvanathan K, Chlebowski RT, Hurley P, et al: American Society of Clinical Oncology Clinical Practice Guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 27:3235-3258, 2009. 5. Visvanathan K, Hurley P, Bantug E, et al: Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 31:2942-2962, 2013.

More on Breast, Cervical, and Ovarian Cancers in This Issue

Kathleen Moore, MD, on Survival in Advanced Cervical Cancer see page 36

Weiva Sieh, MD, PhD, and Krishnansu S. Tewari, MD, on Prognostic Markers in Ovarian Cancer see pages 43 and 45

David Cameron, MD, and Lisa A. Carey, MD, on Triple-Negative Breast Cancer see pages 53 and 54

Visit The ASCO Post online at ASCOPost.com

Treating Advanced Medullary Thyroid Cancer (MTC) Is a Difﬁcult Journey

Move Forward With CAPRELSA The First FDA-Approved Medication for Advanced MTC CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

Important Safety Information, Including Boxed WARNING, for CAPRELSA WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH • CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA • Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration • Monitor electrolytes periodically • Avoid drugs known to prolong the QT interval • Only prescribers and pharmacies certiﬁed with the restricted distribution program are able to prescribe and dispense CAPRELSA • Do not use in patients with congenital long QT syndrome • CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA • Do not start CAPRELSA treatment in patients whose QTcF interval (corrected QT interval, Fridericia) is greater than 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction • Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose • Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT assessments as described above • Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions • Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation To prescribe CAPRELSA, you must enroll in the CAPRELSA REMS Certiﬁcation Enrollment Program and complete the prescriber training program. Please see following pages for more information on the CAPRELSA REMS Program. Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

www.caprelsa.com/hcp

In the treatment of advanced MTC... CAPRELSA Showed a Relative Reduction in Risk of Progression vs Placebo in the ZETA Study1 • CAPRELSA was studied in an international, randomized, double-blind, placebo-controlled, phase 3 trial to determine efﬁcacy and safety in adult patients with unresectable locally advanced or metastatic MTC1,2

HR=0.35 (95% CI: 0.24, 0.53) P<.00011

Progression-free survival (PFS)

1.0

Median PFS* not reached (95% CI: 22.6 months, non estimable)

0.75

0.50

16.4 months median PFS (95% CI: 8.3, 19.7)

0.25

CAPRELSA 300 mg

Placebo

59/231

41/100

Events/Patients

0.0 0

Months Number at Risk CAPRELSA 300 mg

231

173

145

118

Placebo

100

• At the time of the primary analysis of PFS, 15% of patients had died and there was no signiﬁcant difference in overall survival between the 2 treatment groups1

Additional Important Safety Information for CAPRELSA • Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed • Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event

• Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage • Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA

Additional Important Safety Information for CAPRELSA • Diarrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose • Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSAtreated patients. Obtain TSH at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly • Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA • Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS • Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval

• Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis • CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy have not been established • CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid pregnancy and be advised that they must use effective contraception during CAPRELSA treatment and for at least 4 months following the last dose of CAPRELSA • The most commonly reported adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5% are diarrhea/colitis (57%), rash (53%), acneiform dermatitis (35%), hypertension (33%), nausea (33%), headache (26%), upper respiratory tract infections (23%), decreased appetite (21%), and abdominal pain (21%) • CAPRELSA REMS Program: Because of the risks of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com

Affordable Access May Be Available With CAPRELSA Patient Access Services (CPAS) For more information, contact the CPAS Program at 1-800-367-4999, or visit www.caprelsa.com/hcp

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages. *PFS is deﬁned as time from the date of randomization until the date of objective disease progression based on Response Evaluation Criteria in Solid Tumors (RECIST) assessment or death (by any cause in the absence of progression), provided death was within 3 months from the last evaluable RECIST assessment.2 Centralized, independent blinded review of the imaging data was used in the assessment of PFS.1 References: 1. CAPRELSA [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2013. 2. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.

www.caprelsa.com/hcp

CAPRELSA® (vandetanib) Tablets BRIEF SUMMARY. Before prescribing, please see full Prescribing Information. WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certiﬁed with the restricted distribution program are able to prescribe and dispense CAPRELSA [see Warnings and Precautions].

INDICATIONS AND USAGE CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.

DOSAGE AND ADMINISTRATION The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can also be administered through nasogastric or gastrostomy tubes. Dosage Adjustment For adverse reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities. Interrupt CAPRELSA for the following: • Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns to less than 450 ms. • CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1. For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade 1 severity, if continued treatment is warranted. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately [see Warnings and Precautions]. For patients with renal impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Warnings and Precautions and Use in Speciﬁc Populations]. For patients with hepatic impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment [see Use in Speciﬁc Populations].

CONTRAINDICATIONS Do not use in patients with congenital long QT syndrome [see Boxed Warning].

WARNINGS AND PRECAUTIONS QT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.4) in full Prescribing Information]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor QT interval frequently. Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to prolong the QT interval [see Warnings and Precautions and Drug Interactions]. If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently. Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration]. Skin Reactions and Stevens-Johnson Syndrome Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients treated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions [see Dosage and Administration]. Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation. Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms. Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed. Ischemic Cerebrovascular Events Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event. Hemorrhage Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage.

Heart Failure Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA. Diarrhea Diarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration [see Warnings and Precautions]. Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration]. Hypothyroidism In the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 - 4 weeks and 8 - 12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly. Hypertension Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA [see Dosage and Administration]. Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS. Drug Interactions Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) [see Drug Interactions]. Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and Administration and Use in Speciﬁc Populations]. Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration]. Embryofetal Toxicity Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day and had adverse effects on female fertility, embryofetal development, and postnatal development of pups. 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. Women of childbearing potential should avoid pregnancy. Advise women of childbearing potential that they must use effective contraception during CAPRELSA treatment and for at least four months following the last dose of CAPRELSA [see Use in Speciﬁc Populations]. CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense CAPRELSA. To learn about the specific REMS requirements and to enroll in the CAPRELSA REMS Program, call 1-800-236-9933 or visit www.caprelsarems.com.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: • QT Prolongation and Torsades de Pointes [see Boxed Warning, Warnings and Precautions] • Skin Reactions and Stevens-Johnson Syndrome [see Warnings and Precautions] • Interstitial Lung Disease [see Warnings and Precautions] • Ischemic Cerebrovascular Events [see Warnings and Precautions] • Hemorrhage [see Warnings and Precautions] • Heart Failure [see Warnings and Precautions] • Diarrhea [see Warnings and Precautions] • Hypothyroidism [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] • Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions] • Drug Interactions [see Warnings and Precautions] • Renal Impairment [see Warnings and Precautions] • Hepatic Impairment [see Warnings and Precautions] • Embryofetal Toxicity [see Warnings and Precautions] Clinical Studies 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. Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%).

CAPRELSA® (vandetanib) Tablets Table 1 – Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥5% (All Grades)1] System Organ Class Preferred Term

CAPRELSA 300 mg N=231

Placebo N=99

All Grades (%)

Grade 3-4 (%)

All Grades (%)

Grade 3-4 (%)

Diarrhea/Colitis

Nausea

Gastrointestinal Disorders

Abdominal Pain2

Vomiting

Dyspepsia

Dry Mouth

Skin and Cutaneous Disorders Rash3

Dermatitis Acneiform/Acne

Dry Skin

Photosensitivity Reaction

Pruritus

Nail abnormalities4

Alopecia

N/A

Headache

Dysgeusia

Decreased Appetite

Hypocalcemia

Vascular Disorders Hypertension/Hypertensive Crisis/Accelerated Hypertension Nervous System Disorders

General disorders Fatigue5 Infections Upper Respiratory Tract Infections6 Metabolic and Nutritional Disorders

Investigations ECG QT Prolonged7 Eye Disorders Corneal Abnormalities8

Blurred Vision

Renal Disorders Proteinuria Psychiatric Disorders Depression Endocrine Disorders Hypothyroidism Musculoskeletal Disorders Muscle Spasms 1 2 3 4 5 6 7 8

CTCAE version 3 was used to grade adverse events. Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort. Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema. Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection. Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group. Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and tracheitis. 69% had QT prolongation >450ms and 7% had QT prolongation >500ms by ECG using Fridericia correction. Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits, acquired corneal dystrophy.

Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). Blurred vision was more common in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination, including slit lamp examination, in patients who report visual changes. Class effects CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibition of VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSA treated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% in patients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study. Table 2 – Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1] Laboratory Abnormalities

CAPRELSA 300 mg N = 231 All Grades Grade 3-4 (%) (%)

DRUG INTERACTIONS CYP3A4 Inducers Drugs that are CYP3A4 inducers can decrease vandetanib plasma concentrations. Avoid concomitant use of known strong CYP3A4 inducers during CAPRELSA therapy. Avoid the use of St. John’s Wort because it can decrease vandetanib exposure unpredictably. CYP3A4 Inhibitors In healthy subjects, no clinically significant interaction was shown between CAPRELSA and the potent CYP3A4 inhibitor, itraconazole. Drugs that Prolong the QT Interval Avoid the administration of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. Risk Summary Based on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to those expected at the recommended human dose of 300 mg/day. If CAPRELSA 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. Animal data When vandetanib was administered to female rats prior to mating and through the first week of pregnancy at a dose of 25 mg/kg/day (approximately equal to the human exposure at the recommended dose based on Cmax), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos. During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times the human exposure at the recommended dose by Cmax) treatment with vandetanib resulted in increases in late embryofetal death and decreases in fetal birth weight. A no effect level for malformations was not identified in this study. Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times, the Cmax in patients with cancer at the recommended dose) resulted in dose dependent increases in both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicating delayed fetal development. In a rat pre- and post-natal development study, at doses producing mild maternal toxicity (1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development. Nursing Mothers In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug. 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 CAPRELSA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established. Geriatric Use The MTC study of CAPRELSA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently compared to younger patients. Renal Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 6), moderate (n = 8), and severe (n = 6) renal impairment and normal (n = 10) renal function. Subjects with mild renal impairment had comparable mean AUC and clearance values to those with normal renal function. In subjects with moderate and severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively, compared to patients with normal renal function. Reduce the starting dose to 200 mg in patients with moderate and severe renal impairment [see Dosage and Administration and Warnings and Precautions]. Hepatic Impairment The pharmacokinetics of CAPRELSA were evaluated after a single dose of 800 mg in subjects with mild (n = 8), moderate (n = 7), and severe (n = 6) hepatic impairment and normal hepatic function (n = 5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration and Warnings and Precautions]. Females and Males of Reproductive Potential Contraception Females of reproductive potential should avoid pregnancy. Use effective contraception during treatment and up to 4 months after the last dose of CAPRELSA. Infertility There are no data on the effect of CAPRELSA on human fertility. Results from animal studies indicate that vandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1) in full Prescribing Information].

OVERDOSAGE

Placebo N = 99 All Grades Grade 3-4 (%) (%)

In the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day half-life, adverse reactions may not resolve quickly.

Chemistries Hypocalcemia

ALT Increased

Hypoglycemia

Creatinine Increased

Hypomagnesemia

10 9

<1 0

5 3

2 0

Hematologic Neutropenia Thrombocytopenia 1

CTCAE version 3 was used to grade laboratory abnormalities.

No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study.

The ASCO Post | SEPTEMBER 15, 2013

PAGE 34

Journal Spotlight Gynecologic Oncology

What Para-Aortic Nodal Involvement Predicts About Survival in PET-CT–Negative Locally Advanced Cervical Cancer By Matthew Stenger

n a study reported in Journal of Clinical Oncology, Sebastien Gouy, MD, of Institut Gustave Roussy and colleagues evaluated survival outcomes in patients with locally advanced cervical cancer and negative positron-emission tomography/computed tomography (PET-CT) imaging results who underwent laparoscopic para-aortic staging surgery before chemoradiotherapy.1 They found that event-free survival was similar in patients with no nodal involvement and in those with nodal metastasis ≤ 5 mm but significantly poorer in those with nodal involvement > 5 mm. Results for overall survival were similar.

Study Details The prospective study was performed in three French comprehensive cancer centers. Overall, it included 237 patients treated from 2004 to 2011 for locally advanced cervical cancer who had PET-CT-negative imaging of the para-aortic area and underwent laparoscopic para-aortic lymphadenectomy. Radiation fields were extended to the para-aortic area

when para-aortic nodes were found to be involved. Chemoradiotherapy modalities were homogeneous across the three institutions. Patients with a poor-prognosis histologic subtype or

tive PET-CT results—including 16 (6.8%) with a para-aortic nodal metastasis measuring > 5 mm and 13 (5.5%) with a nodal metastasis measuring ≤ 5 mm. Among patients with

We obtained the same survival rate for patients with para-aortic nodal metastasis ≤ 5 mm and patients without para-aortic lymph node involvement, suggesting that this strategy is highly efficient in such patients. —Sebastien Gouy, MD, and colleagues

peritoneal carcinosis were excluded from the study. Clinical International Federation of Gynecology and Obstetrics stages were IB2 in 79 patients (33%), IIA in 10 (5%), IIB in 121 (50%), III in 22 (10%), and IVA in 5 (2%). Histologic subtype was squamous carcinoma in 129 (84%), and the remainder had adenocarcinoma/adenosquamous lesions. The vast majority of patients had conformational radiation therapy (95%), cisplatin-based concurrent chemotherapy (99.6%), and uterovaginal brachytherapy (97%). In total, 29 patients (12.2%) had nodal involvement—ie, false-nega-

Para-Aortic Nodal Involvement in Cervical Cancer ■ In patients with locally advanced cervical cancer and PET-CT-negative

imaging of the para-aortic area who underwent laparoscopic para-aortic lymphadenectomy, 12% had para-aortic nodal involvement.

■ Three-year event-free survival was similar in those with no involved nodes

and those with nodal metastasis ≤ 5 mm and significantly better than those with nodal metastases > 5 mm.

■ Survival of patients with para-aortic nodal involvement > 5 mm remained poor, despite the absence of extrapelvic disease on PET-CT imaging.

para-aortic metastasis ≤ 5 mm, 10 had a single metastatic node and 3 had two positive nodes. Among patients with metastasis > 55 mm, 3 had a single metastatic node.

Survival Outcomes In the entire population, overall survival was 88% at 3 years, 86% at 4 years, and 78% at 5 years, and eventfree survival was 71%, 66%, and 62%, respectively. Event-free survival rates at 3 years in patients without para-aortic nodal involvement, with metastasis measuring ≤ 55 mm, and with metastasis measuring > 5 mm were 74%, 69%, and 17%, respectively (P � .001). � .001). .001). Respective 3-year overall survival rates were 89%, 100%, and 40% (P = .04). Analysis by number of involved nodes showed 3-year event-free survival rates of 74%, 81%, and 16% for those with 0 involved nodes, 1 involved node, and ≥ 2 involved nodes, respectively (P � .001).

Prognostic Factors Overall, factors that were prognostic for event-free survival were in-

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volved para-aortic nodes vs nodes free of disease (HR = 2.6, P = .003), pN1 > 5 mm vs pN0 (HR = 5.8, P � .001), pN1 > 5 mm vs pN0/pN1 ≤ 5 mm (HR = 5.8, P � .001), pN1 ≥ 2 nodes vs pN0 (HR = 4.4, P � .001). There was a borderline significant effect for delay between PET-CT and chemotherapy ≥ 45 days vs � 45 days (HR = 1.9, P = .06). Factors that were not prognostic for event-free survival were histologic subtype, stage, pelvic uptake on PET, duration of chemotherapy, delay between surgery and chemotherapy, and delay between PET-CT and chemotherapy ≥ 30 vs � 30 days. The investigators concluded: “To our knowledge, this is the largest series of patients reported undergoing such a strategy. We obtained the same survival rate for patients with paraaortic nodal metastasis ≤ 5 mm and patients without para-aortic lymph node involvement, suggesting that this strategy is highly efficient in such patients. Conversely, the survival of patients with para-aortic nodal involvement > 5 mm remained poor, despite the absence of extrapelvic disease on PET-CT imaging in this subgroup.” n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org. See commentary on page 36

Reference 1. Gouy S, Morice P, Narducci F, et al: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol. July 15, 2013 (early release online).

Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

To learn more about this study, please visit www.ClinicalTrials.gov.

The ASCO Post | SEPTEMBER 15, 2013

PAGE 36

Journal Spotlight Gynecologic Oncology Continued from page 34

Pretreatment Lymph Node Dissection May Improve Survival in Advanced Cervical Cancer, But for Too Few? By Kathleen Moore, MD

omen with cervical cancer metastasized to para-aortic lymph nodes have historically had a poor prognosis, with 3-year overall survival rates of 25% to 40%.1-3 This has been attributed to the presence of occult systemic disease at the time of presentation and a high rate of distant recurrences following therapy. The practice of pretreatment paraaortic lymph node dissection among patients with locally advanced cervical cancer, as in the study reported by Gouy et al, remains a controversial practice. The potential benefit is supportable by three assumptions: (1) that pretreatment imaging assessment of lymph node involvement is limited, (2) that treatment will be modified based on the findings of the lymph node dissection, and (3) that these modifications will result in improved survival.

nodes remains problematic. It should be noted that the work by Gouy and colleagues provides useful estimates for false-negative rates for PET-CT in both pelvic PET-CT–positive and PET-CT–negative populations, which is, in and of itself, an important contribution to the literature.

Treatment Modification That knowledge of positive paraaortic lymph nodes changes management is clear—especially when microscopically positive para-aortic lymph nodes are found and subsequently treated. In the Gouy et al study, 12% of the population received extended-field radiation therapy following identification of involved lymph nodes. Perhaps more impor-

While pretreatment lymph node dissection does appear to improve survival for patients with PET-negative para-aortic lymph node metastases ≤ 5 mm, this group … is a small subset of the entire locally advanced cervical cancer population.

Imaging of Para-aortic Lymph Nodes Imaging for para-aortic lymph nodes with either standard computed tomography (CT) or magnetic resonance imaging (MRI) is indeed limited, with sensitivities of 55.5% and 57.5%, respectively.4 Positron-emission tomography (PET) or PET-CT does appear to have increased sensitivity. A review of patients who underwent PET followed by histologic evaluation of the para-aortic lymph nodes found an overall sensitivity of 78%, but the false-negative rate for detecting para-aortic lymph node metastases was 12%. This increased to 22% for patients with PET uptake in the pelvis.4 Gouy and colleagues report a false-negative rate for PET-CT that is consistent with the published literature at 12% (29/237 patients), with slightly less than half of these being micrometastases ≤ 5 mm (13/29) and the rest > 5 mm.5 Even though the sensitivity of PET appears superior to CT and MRI, detection of para-aortic lymph Dr. Moore is Mai Eager Anderson Chair of Cancer Clinical Trials, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City.

series that report improved survival for patients after debulking of grossly involved nodes.6-11 The Gouy et al study found that for patients identified as having para-aortic lymph node metastases ≤ 5 mm and who were subsequently treated with extended-field radiation therapy, survival was no different than for those with negative para-aortic lymph nodes. Whether this is due to identification and treatment of the micrometastases vs the actual removal is difficult to discern from the data, but in a patient population in which treatment decisions based on PET alone would have resulted in pelvic irradiation alone, these 13 patients would have been undertreated and at risk for at least para-aortic lymph

—Kathleen Moore, MD

tant, 208 patients were not at risk for overtreatment with extended-field radiation therapy based on definitive knowledge of their para-aortic lymph nodes.5 This is again consistent with the literature, which indicates that in a para-aortic lymph node PET-negative population, approximately 78% of patients with locally advanced cervical cancer would have been overtreated with extended-field radiation therapy were it not for histologic confirmation of negative para-aortic lymph nodes.4

Survival Benefit That the removal of positive paraaortic lymph nodes in and of itself improves survival is yet unproven. The benefit of lymph node dissection has been demonstrated in retrospective

node failure if not distant failure. Unfortunately, for patients with para-aortic lymph nodes > 5 mm, 5 mm, mm, survival remained poor, with only 17% event-free at 3 years vs 69% and 74% for patients with para-aortic lymph nodes ≤ 55 mm and negative para-aortic lymph nodes, respectively.5

Moving Forward Studies in locally advanced cervical cancer have primarily focused on the addition of either cytotoxic12-15 or biologic16,17 agents to concurrent cisplatin and radiation. These efforts have not demonstrated large gains in outcome and have added toxicity, prompting different strategies for improving outcomes in patients with high-risk locally advanced cervical cancer. Gynecologic Oncology Group

(GOG) 9926 (NCT01295502) is an ongoing phase I trial for patients with positive para-aortic lymph nodes receiving extended-field radiation therapy and concurrent cisplatin followed by adjuvant paclitaxel and carboplatin. GOG 9929 (NCT01711515) follows extended-field radiation therapy and concurrent cisplatin with ipilimumab (Yervoy). With the recent National Cancer Institute press release reporting improved overall survival for patients with advanced/recurrent cervical cancer treated with bevacizumab (Avastin) on GOG 240, further exploration of bevacizumab as an adjuvant therapy to follow chemoradiation therapy may be a consideration in this high-risk group of patients, as well.18,19 Patients with PET-positive paraaortic lymph nodes would qualify for our most aggressive therapies without undergoing a pretreatment lymph node dissection, since the sensitivity of a positive PET approximates 73%, making histologic confirmation unnecessary. Patients who have no uptake in the pelvic lymph nodes on PET have a false-negative rate for positive para-aortic lymph nodes of 9%, so the possible risks of the pretreatment lymph node dissection (delay to start of chemoradiotherapy) may outweigh any benefits. The group of patients with PETpositive uptake in the pelvic nodes and negative uptake in the para-aortic lymph nodes has a false-negative rate of 24% according to the Gouy et al study, which is consistent with estimates from the literature.5 This is the group of patients for whom pretreatment lymph node dissection makes the most sense, especially if, as Gouy et al report, approximately half of these patients have metastases ≤ 5 mm and can be shifted into paraaortic lymph node–negative survival curves with identification and appropriate treatment.

Potential Complications While pretreatment lymph node dissection does appear to improve survival for patients with PET-negative para-aortic lymph node metastases ≤ 5 mm, this group represents

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 37

Journal Spotlight

approximately 5% of the para-aortic lymph node PET-negative locally advanced cervical cancer population and is a small subset of the entire locally advanced cervical cancer population. The potential complications of pretreatment lymph node dissection cannot be overstated. Gouy et al report a median time of 14 days between PET and lymph node dissection and 35 days between PET and start of chemoradiotherapy. Only two patients in their series experienced additional delay due to postoperative morbidity, but the literature reports rates of complications between 1% and 19% following lymph node dissection, varying according to the surgical approach used.4 This raises the possibility of additional delays prior to the initiation of curative therapy with widespread adoption of this practice. Given the reality that most patients are not cared for at centralized treatment centers, the likelihood of complications and delays may be higher than that predicted by Gouy and colleagues, and the improvement for this minority of patients will be difficult to justify given the risk to those with little expected benefit from the procedure.

Toward Standardization of Imaging Efforts are underway to validate better pretreatment imaging assessment of lymph nodes via two large trials evaluating PET and MRI using ultrasmall iron oxide particles

(GOG0233/ACRIN 6671 and ACRIN 6682). In addition, as mentioned in the Gouy et al article, two randomized phase III trials of the effect of pretreatment lymph node dissection on survival in locally advanced cervical cancer are ongoing. The results of these studies are anxiously awaited and will inform standardization of imaging vs lymph node dissection in this population. n

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

References 1. Berman ML, Keys H, Creasman W, et al: Survival and patterns of recurrence in cervical cancer metastatic to periaortic lymph nodes (a Gynecologic Oncology Group study). Gynecol Oncol 19:8-16, 1984. 2. Varia MA, Bundy BN, Deppe G, et al: Cervical carcinoma metastatic to paraaortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherpay: A Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys 42:1015-1023, 1998. 3. GrigsbyÂ PW, Heydon K, Mutch DG, et al: Long-term follow-up of RTOG 92-10: Cervical cancer with positive para-aortic lymph nodes. Int J Radiat Oncol Biol Phys 51:982-987, 2001. 4. Gouy S, Morice P, Narducci F, et al: Nodal-staging surgery for locally advanced cervical cancer in the era of PET. Lancet Oncol 13:e212-e220, 2012. 5. Gouy, S, Morice P, Narducci F, et al: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy

before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 31:3026-3033, 2013. 6. Cosin JA, Fowler JM, Chen MD, et al: Pretreatment surgical staging of patients with cervical carcinoma: The case for lymph node debulking. Cancer 82:2241-2248, 1998. 7. Goff BA, Muntz HG, Paley PFJ, et al: Impact of surgical staging in women with locally advanced cervical cancer. Gynecol Oncol 74:436-442, 1999. 8. Hacker NF, Wain GV, Nicklin JL: Resection of bulky positive lymph nodes in patients with cervical carcinoma. Int J Gynecol Cancer 5:250-256, 1995. 9. Kim PY, Monk BJ, Chabra S, et al: Cervical cancer with para-aortic metastases: Significance of residual para-aortic disease after surgical staging. Gynecol Oncol 69:243-247, 1998. 10. Wharton JT, Jones III HW, Day TG Jr, et al: Pre-irradiation celiotomy and extended field irradiation for invasive carcinoma of the cervix. Obstet Gynecol 49:333-338, 1977. 11. Fletcher GH: Lucy Wortham James Lecture: Subclinical disease. Cancer 53:1274-1284, 1984. 12. Walker JL, Morrison A, DiSilvestro P, et al: A phase I/II study of extended field radiation therapy with concomitant paclitaxel and cisplatin chemotherapy in patients with cervical carcinoma metastatic to para-aortic lymph nodes: A Gynecologic Oncology Group study. Gynecol Oncol 112:78-84, 2009. 13. Rose PG, DeGeest K, McMeekin DS, et al: A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol

107:274-279, 2007. 14. Rose PG, Sill MW, McMeekin DS, et al: A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol 125:158-162, 2012. 15. DiSilvestro P, Walker J, Morrision A, et al: Radiation therapy with concomitant paclitaxel and cisplatin chemotherapy in patients with cervical carcinoma limited to the pelvis: A phase I/II study of the Gynecologic Oncology Group. Gynecol Oncol 103:1038-1042, 2006. 16. Schefter TE, Winter K, Kwon JS, et al: A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma: Preliminary results of RTOG 0417. Int J Radiat Oncol Biol Phys 83:1179-1184, 2012. 17. Moore KN, Sill M, Miller DS, et al: A phase I trial of tailored radiation therapy with concomitant cetuximab and cisplatin in the treatment of patients with cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol 127:456461, 2012. 18. NCI Press Release: Bevacizumab significantly improves survival for patients with recurrent and metastatic cervical cancer. Posted 02/07/2013. Available at www.cancer.gov. Accessed August 21, 2013. 19. Paclitaxel and cisplatin or topotecan with or without bevacizumab in treating patients with stage IVB, recurrent or persistent cervical cancer (NCT00803062). Available at http://clinicaltrials.gov/ct2/ show/NCT00803062. Accessed August 21, 2013.

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The ASCO Post iPad App FREE from iTunes today!

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The ASCO Post | SEPTEMBER 15, 2013

PAGE 40

Announcements

Couple Pledges $10 Million Gift to MD Andersonâ&#x20AC;&#x2122;s Head and Neck Cancer Center

he University of Texas MD Anderson Cancer Center in Houston, Texas, recently announced that Charles and Daneen Stiefel, of Ra-

leigh, North Carolina, have pledged $10 million to the Head and Neck Cancer Center at MD Anderson. In honor of their generosity, the institution will

name the Charles and Daneen Stiefel Center for Head and Neck Cancer. Charles Stiefel, former chair and CEO of Stiefel Laboratories, is a member of

the MD Anderson Cancer Center Board of Visitors and is active on a key committee that advises the institution on clinical business issues. Devoted to supporting

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Announcements

a number of health-related initiatives, the Stiefels are members of the Anderson Assembly, which recognizes donors of $1 million or more to the institution. The couple established the Charles and Daneen Stiefel Chair in Cancer Research in 2009 with a $1 million gift in gratitude for the care Charles Stiefel received as an MD Anderson patient.

Cancer Survivor

Charles and Daneen Stiefel

Mr. Stiefel sought care at MD Anderson Cancer Center after being diagnosed in 2006 in Miami with squamous cell carcinoma at the base of his tongue. During what he thought was his final checkup, an ultrasound revealed a new malignant tumor on his thyroid gland. That cancer was eliminated through

surgery, and today he is cancer-free. Mr. Stiefel credits his care team, Merrill S. Kies, MD, Professor of Thoracic/Head and Neck Medical Oncology, David I. Rosenthal, MD, Professor of Radiation Oncology; and Randal S. Weber, MD, Chair of Head and Neck Surgery, with saving his life. n

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The ASCO Post | SEPTEMBER 15, 2013

PAGE 42

Awards

Breast Cancer Researchers Awarded Komen for the Cure Grants

usan G. Komen for the Cure recently announced it has awarded grant funding of more than $1.4 million to five researchers at Indiana University School of Medicine and a oneof-a-kind tissue bank. The grants will

be part of the $42 million Komen will award in 2013 for cancer research.

Grants Focus on Biology/ Recurrence of Breast Cancer The 2013 research grants to Indi-

ana University School of Medicine faculty and researchers at the Indiana University Melvin and Bren Simon Cancer Center will focus on breast cancer biology and recurrence. The grants include:

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■ $225,000 to Komen Scholar Sunil Badve, MD, Professor of Pathology and laboratory medicine, to develop genetic tests that can more accurately predict the likelihood of recurrence and long-term prognosis for people with estrogen receptor positive tumors. ■ $225,000 to Komen Scholar Theresa Guise, MD, Jerry W. and Peggy S. Throgmartin Professor of Oncology and Professor of Medicine, to focus on identifying the mechanisms causing breast cancer-associated muscle dysfunction and how they relate to decreases in muscle mass, commonly labeled as “wasting.” ■ $175,000 to Komen Scholar Kathy Miller, MD, Ballve Lantero Scholar in Oncology and Associate Professor of Medicine, for a clinical trial to investigate novel therapies that could prevent recurrence of triple-negative breast cancer after a woman’s initial treatment for the disease. ■ $225,000 to Komen Scholar Harikrishna Nakshatri, PhD, Marian J. Morrison Professor of Breast Cancer Research and Professor of Surgery and Biochemistry, to study a class of proteins knows as “dependence receptors” in estrogen-positive tumors that, when paired with specific partner proteins, aid in the proliferation of cancer cells. ■ $62,500 to Komen Scholar Bryan Schneider, MD, Associate Professor of Medicine and of Medical and Molecular Genetics, for continuing work to identify genetic markers that will help doctors identify patients who will have adverse reactions to taxane therapies for breast cancer. ■ $500,000 to the Susan G. Komen Tissue Bank at the IU Simon Cancer Center to fund the collection of normal breast tissue from women in Kenya to help understand the underlying biology and genetic issues that lead to more aggressive forms of breast cancer, and higher mortality rates from breast cancer, in women of African descent. n

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PAGE 43

Journal Spotlight Gynecologic Oncology

Progesterone and Estrogen Receptor Expression Are Prognostic Markers for Endometrioid and High-Grade Serous Ovarian Cancer By Matthew Stenger

ew markers of ovarian cancer prognosis have been established, perhaps because potential subtype associations are missed in studies including patients with all histopathologic subtypes. In a study reported in The Lancet Oncology, Weiva Sieh, MD, PhD, Assistant Professor of Health Research and Policy at Stanford University, and colleagues assessed the prognostic ef-

Weiva Sieh, MD, PhD

fect of progesterone receptor (PR) and estrogen receptor (ER) status among nearly 3,000 women with invasive epithelial ovarian cancer.1 They found that tumor ER and PR are prognostic markers for endometrioid and highgrade serous ovarian cancers.

Study Details In the study, 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data from women who had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumor grade and stage had to be available. PR and ER status was assessed by central immunohistochemistry analysis done by blinded pathologists. PR and ER staining was defined as negative (� 1% tumor cell nuclei), weak (1% to � 50%), or strong (≥ 50%). A total of 2,933 women with invasive epithelial ovarian cancer were included in the analysis, consisting of 1,742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma.

PR and ER Expression PR and ER expression differed among ovarian cancer subtypes. The proportion of tumors that stained positive (weak or strong) for PR was highest for endometrioid carcinoma (67%) and low-grade serous carcinoma (58%), intermediate for high-grade serous carcinoma (31%), and lowest for mucinous carcinoma (17%) and clear-cell carcinoma (8%). More tumors stained positive for ER than for PR in all subtypes, with the proportion of ER-positive tumors being highest for low-grade serous carcinoma (87%) and high-grade serous carcinoma (81%) and lowest for mucinous carcinoma (21%) and clearcell carcinoma (20%). For ER-positive tumors, coexpression of PR was most likely for endometrioid carcinoma (82%) and least likely for high-grade serous carcinoma (34%) and clear-cell carcinoma (32%). The proportion of tumors that were ER- or PR-positive or both was highest for low-grade serous carcinoma (91%), high-grade serous carcinoma (84%), and endometrioid (82%) tumors and lowest for mucinous carcinoma (23%) and clear-cell carcinoma (21%).

Associations With Survival Both PR expression (log-rank P � .0001) and ER expression (logrank P � .0001) were associated with improved disease-specific survival in

Biomarkers in Ovarian Cancer ■ Progesterone receptor (PR) expression was associated with improved

disease-specific survival in endometrioid and high-grade serous carcinoma and estrogen receptor (ER) expression was associated with improved disease-specific survival in endometrioid carcinoma.

■ Positive PR or ER expression was associated with significantly improved

disease-specific survival in endometrioid carcinoma independent of study site, age, stage, and grade.

associated with worse survival in clearcell carcinoma, but the association was not significant after adjustment for other clinical covariates. In analysis adjusting for site, age, stage, and grade, strong (hazard ratio [HR] = 0.71, P = .0061) but not weak PR expression was associated with significantly improved high-grade serous carcinoma survival, with similar associations observed after adjustment for residual disease in the subset of patients for whom such data were available. Strong PR expression was associated with improved low-grade serous carcinoma survival (HR = 0.39, P = .019), but the association was no longer significant after adjustment for residual disease. Both weak (HR = 0.61, P = .047) and strong (HR = 0.38, P = .0005) .0005) expression of PR and weak (HR = 0.40, P = .0041) and strong (HR = 0.41, P = .0001) .0001) expression of ER were associated with improved endometrioid carcinoma survival, with similar asso-

Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormonereceptor status predicts response to endocrine treatment, and whether it could guide personalized treatment for ovarian cancer. —Weiva Sieh, MD, PhD, and colleagues

endometrioid carcinoma. PR expression (log-rank P = .0006) but not ER expression was associated with improved disease-specific survival in high-grade serous carcinoma. There were no significant survival differences for low-grade serous or mucinous carcinomas; ER expression seemed to be

ciations observed after adjustment for residual disease. Overall, positive hormone receptor expression (weak or strong PR or ER expression or both) was associated with improved endometrioid carcinoma survival (HR = 0.33, P � .0001). The best prognostic model for endometrioid carcinoma

(identified by a comparison of model likelihoods) combined women with hormone receptor–positive tumors (PR or ER or both) into the low-risk group. A summarized by the authors, “We have shown that patients with endometrioid carcinoma who have hormone-receptor-positive tumors are less likely to die from their disease than are those with hormone-receptor-negative tumors. Furthermore, we established that patients with [high-grade serous carcinoma] whose tumors stain strongly positive for PR have improved survival compared with those whose tumors stain negative or weakly positive for PR.” They further noted that the magnitude of these effects is similar to the protective effect of germline BRCA mutations on ovarian cancer survival and that the effects were stronger than the observed associations of grade and extent of residual disease with survival in endometrioid carcinoma. The authors concluded, “PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormonereceptor status predicts response to endocrine treatment, and whether it could guide personalized treatment for ovarian cancer.” n Disclosure: For full disclosures of the

study authors, visit www.thelancet.com.

See Commentary on page 45.

Reference 1. Sieh W, Köbel M, Longacre TA, et al: Hormone-receptor expression and ovarian cancer survival: An Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol 14:853-862, 2013.

In the research of advanced cancers

What if the PD-1 checkpoint pathway played an important role in tumor growth? The programmed death 1 (PD-1) checkpoint pathway plays a key role in modulating the immune system. However, some tumors exploit this pathway to evade the bodyâ&#x20AC;&#x2122;s protective immune response to cancer1-5 In a normal state, the immune system recognizes tumors and can mount an active antitumor response6,7 Antigen-presenting cell

Step 1:

Tumor releases antigen8 T cells

Through tumor-immune surveillance, activated T cells can eradicate tumor cells from the body 6,7

Step 2:

Antigen-presenting cells activate T cells that proliferate, migrate to, and attack the tumor8

Tumor

One way that tumors can evade normal immune attack is by exploiting the PD-1 immune checkpoint pathway via the PD-1 receptor1,2,5

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway. This inhibits activated T cells and suppresses T-cell attack1,2,4,5

PD-1 receptor

By exploiting the PD-1 checkpoint pathway, cancer cells evade the immune response and continue to proliferate1,2,6,8 PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2. References: 1. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptopic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 2. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 3. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 4. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 5. Dong H, Strome SE, Salomao DR, et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 6. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 7. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 8. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.bmsimmunooncology.com. ÂŠ2013 Bristol-Myers Squibb Company. All rights reserved. ONCUS13UB01112-02-01 06/13 Printed in USA.

ASCOPost.com | SEPTEMBER 15, 2013

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Perspective Continued from page 43

Timely Findings From the Ovarian Tumor Tissue Analysis Consortium By Krishnansu S. Tewari, MD

n the Ovarian Tumor Tissue Analysis Consortium Study recently published by Sieh et al,1 tissue microarrays from 2,933 cases of epithelial ovarian carcinoma demonstrated that progesterone receptor (PR) expression and estrogen receptor (ER) expression were associated with significantly improved disease-specific survival in endometrioid adenocarcinoma of the ovary (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21–0.51, P � .0001). � .0001). .0001). In addition, strong PR expression was independently associated with improved disease-specific survival in high-grade serous adenocarcinoma of the ovary (HR = 0.71, 95% CI = 0.55–0.91, P = .0080). The Consortium Study findings are noteworthy because they provide a molecular validation paradigm of episodic clinical activity attributed to the weak estrogen tamoxifen in some patients with ovarian carcinoma. That activity was sufficient to position tamoxifen in a randomized phase III trial against thalidomide (Thalomid) for biochemical-recurrent disease.2 In that study, the antiangiogenic properties of thalidomide did not outperform tamoxifen.

Growing Body of Literature More important, the report from the Ovarian Tumor Tissue Analysis Dr. Tewari is Director of Research, Division of Gynecologic Oncology, University of California, Irvine.

Consortium is timely and joins the ranks of a growing body of literature attesting to both the prognostic value of the steroid hormone receptors in distinct histologic subtypes of ovarian carcinoma and the therapeutic potential of targeting these receptors. In 2013, Zhao et al performed a meta-analysis that included 35 studies.3 In overall survival analy-

trioid and high-grade serous ovarian carcinomas. Argenta et al have also just reported the results of a phase II study using the ER antagonist fulvestrant (Faslodex) in patients with recurrent disease.5 Clinical benefit via stable disease, partial response, or complete response was experienced by half of the study group and ER-a expression

Prospective validation is required for any molecular phenomena indicating that prognostic steroid hormone biomarkers can serve as pathway targets that might affect survival outcomes. — Krishnansu S. Tewari, MD

ses, the pooled hazard ratio for elevated PR levels reached 0.88 (95% CI = 0.82–0.95), indicating that increased PR expression could be associated with improved survival. Earlier this year, using a novel cell culture assay, Diep et al demonstrated a molecular link between PR expression and induction of Forkheadbox transcription factor–dependent cellular senescence.4 Taking into consideration the Consortium Study findings, it appears that clinical priming of this pathway using PR agonists may provide a useful strategy to induce irreversible cell-cycle arrest in endome-

was also associated with clinical benefit. Like the Consortium Study findings, these confirm that ovarian cancer includes a subset of tumors with sensitivity to estrogen pathway blockade.

Closing Thoughts Prospective validation is required for any molecular phenomena indicating that prognostic steroid hormone biomarkers can serve as pathway targets that might affect survival outcomes. One important avenue that should be explored is whether the frequency of ER and PR in endometrioid ovarian carci-

nomas segregates the risk of lymph node metastases and distant spread just as cellular and tumor grade does in endometrioid adenocarcinoma of the uterus.6 n Disclosure: Dr. Tewari reported no potential conflicts of interest.

References 1. Sieh W, Köbel M, Longacre TA, et al: Hormone-receptor expression and ovarian cancer survival: An Ovarian Tumor Tissue Analysis Consortium study. Lancet Oncol 14:853-862, 2013. 2. Hurteau JA, Brady MF, Darcy KM, et al: Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrentonly epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group study. Gynecol Oncol 119:444-450, 2010. 3. Zhao D, Zhang F, Zhang W, et al: Prognostic role of hormone receptors in ovarian cancer: A systematic review and meta-analysis. Int J Gynecol Cancer 23:25-33, 2013. 4. Diep CH, Charles NJ, Gilks CB, et al: Progesterone receptors induce FOXo1-dependent senescence in ovarian cancer cells. Cell Cycle 12:14331449, 2013. 5. Argenta PA, Um I, Kay C, et al: Predicting response to the anti-estrogen fulvestrant in recurrent ovarian cancer. Gynecol Oncol. Jul 30, 2013 (early release online). 6. Monk BJ: Personal communication to K.S. Tewari. August 20, 2013.

September Is National Ovarian Cancer Awareness Month A Statement by Kathleen Sebelius

uring September, we observe National Ovarian Cancer Awareness Month to recognize those who have died and recommit ourselves to helping the women who are fighting for their health. Every year, more than 20,000 women in the United States are diagnosed with ovarian cancer, which is the fifth leading cause of can-

cer death for women and accounts for more than 14,000 deaths a year. The Administration advances scientific research to improve prevention, diagnosis and treatment. When ovarian cancer is found in its early stages, treatment is most effective, but there is currently no proven method to screen for ovarian cancer in women. The Affordable Care Act is making health care more accessible and

providing important protections for women. Insurers must cover at no out-of-pocket cost an annual wellwoman visit, which is a good time for women to discuss their concerns about ovarian cancer with their health care provider. The law also guarantees coverage for genetic counseling and testing for certain women at high risk for ovarian cancer. Also, in 2014, the health law makes it illegal to deny coverage or charge

more if a woman has ovarian cancer or other pre-existing condition. Information for the public about the risks and symptoms of ovarian and other gynecologic cancers is available from the Centers for Disease Control and Prevention at http:// w w w.c d c . go v / c a n c e r / o v a r i a n / index.htm n Kathleen Sebelius is Secretary of the Department of Health and Human Services.

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Lab Notes

Ongoing Molecular Research in the Science of Oncology IMMUNOTHERAPY Cytokine-Induced Killer Cells Effective Against Autologous Metastatic Melanoma Including Cells With Stemness Features

In a study reported in Clinical Cancer Research, Gammaitoni and colleagues investigated the tumor-killing activity of cytokine-induced killer cells against autologous metastatic melanoma and putative cancer stem cells. The investigators developed a pre-

clinical autologous model using same patient-generated cytokine-induced killer cells and tumor targets to capture the unique biology of each patient/tumor pairing. A putative melanoma stem cell subset was visualized and immunophenotypically defined

in primary tumor cell cultures using a novel gene-transfer strategy exploiting the ability of such cells to activate the promoter of stemness gene Oct4. Cytokine-induced killer cells from 10 patients with metastatic melanoma

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Lab Notes

Ongoing Molecular Research continued from page 49

were expanded, and primary tumor cell cultures established and characterized from the same patients were used as autologous targets. The patient-derived cytokine-induced killer cells efficiently killed autologous metastatic melanoma cells, with up to 71% specific killing.

In in vivo testing, the cells produced delayed tumor growth, increased necrotic areas, and lymphocyte infiltration at tumor sites in autologous metastatic melanoma. The metastatic melanoma cultures featured an average of 11.5% putative melanoma stem cells, as assessed by Oct4 promoter activity and expression of stemness markers (Oct4,

ABCG2, ALDH, and MITF), with expression being confirmed on melanoma stem cell target molecules recognized by the cytokine-induced killer cells. Cytokine-induced killer cell killing activity against melanoma stem cells was up to 71%. The investigators concluded, â&#x20AC;&#x153;For the first time, the intense killing ac-

tivity of cytokine-induced killer cells against autologous metastatic melanoma, including [melanoma stem cells], has been shown. These findings move clinical investigation of a new immunotherapy for metastatic melanoma, including [melanoma stem cells], closer.â&#x20AC;? Gammaitoni L, et al: Clin Cancer Res 19:4347-4358, 2013.

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Lab Notes

DRUG RESISTANCE Resistance to Anti-VEGF Drugs in Glioblastoma Is Linked to Mesenchymal Transition Antiangiogenic therapy reduces tumor vascular permeability and delays tumor progression but may ultimately

promote an aggressive treatment-resistant phenotype. In a study reported in Clinical Cancer Research, Piao and colleagues attempted to identify factors responsible for glioblastoma resistance to antiangiogenic therapy. Glioma stem cell NSC11 and U87 cell lines with acquired resistance to bevacizumab (Avastin) were developed

from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance. Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance

to anti-VEGF therapy were resistant to bevacizumab and did not have prolonged survival compared with untreated controls. Gene-expression profiling showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation in anti-VEGF therapyâ&#x20AC;&#x201C;resistant cell lines

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Lab Notes

Ongoing Molecular Research continued from page 51

compared with untreated controls. Bevacizumab-treated tumors showed a highly significant correlation with published mesenchymal gene signatures on gene-set enrichment analysis. Mice with resistant tumors showed significantly greater infiltration of myeloid cells in

NSC11 and U87 resistant tumors. The investigators concluded, “Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.” Piao Y, et al: Clin Cancer Res 19:4392-4403, 2013.

OUTCOME PREDICTORS Prognostic Significance of MTOR Pathway Component Expression in Neuroendocrine Tumors The MTOR serine/threonine kinase pathway is implicated in regula-

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tion of neuroendocrine tumor growth. In a study reported in Journal of Clinical Oncology, Qian and colleagues investigated the potential prognostic significance of MTOR pathway component expression in patients with neuroendocrine tumors. Immunohistochemical expression of MTOR and phospho (p)–MTOR, its downstream targets RPS6KB1, RPS6, and EIF4EBP1, and its upstream regulators was examined in a cohort of 195 archived neuroendocrine tumors. The association of expression levels with clinical outcomes was evaluated with adjustment for other prognostic variables. Anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets were observed. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with a high MKI67 (Ki-67) labeling index. No clinical correlations with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA were observed. However, high expression levels of MTOR or its activated downstream targets p-RPS6KB1, pRPS6, and p-EIF4EBP1 were associated with adverse clinical outcomes. In particular, in a multivariate analysis among patients with primary tissue tumor available, p-RPS6KB1 expression (hazard ratio [HR] = 3.13, P = .002) and p-RPS6 expression (HR = 2.62, P = .019) were associated with significantly shorter overall survival. Among patients with small intestinal neuroendocrine tumors, MTOR expression (HR = 5.15, P = .01) was associated with significantly shorter disease-free survival. In patients with metastatic disease, expression levels of MTOR (HR = 2.94, P = .011), p-RPS6KB1 (HR = 3.28, P = .015), p-RPS6 (HR = 2.69, P = .043), and p-EIF4EBP1 (HR = 3.15, P = .009) were associated with significantly shorter overall survival. The investigators concluded, “[W]e found expression of MTOR and its downstream effectors to be associated with adverse clinical outcomes in a large cohort of patients with neuroendocrine tumors. Confirmatory studies, as well as studies evaluating the potential predictive value of these markers in patients receiving everolimus [Afinitor] or other MTOR inhibitors, are warranted.” n Qian ZR, et al: J Clin Oncol. August 26, 2013 (early release online). Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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Journal Spotlight Breast Cancer

No Invasive Disease–Free Survival Benefit for Bevacizumab Added to Adjuvant Chemotherapy in Triple-Negative Breast Cancer By Matthew Stenger

n a study (BEATRICE trial) reported in Lancet Oncology, David Cameron, MD, Professor of Oncology and Director of Cancer Services, NHS Lothian at the University of Edinburgh, and colleagues evaluated the strategy of adding the antiangiogenic agent bevacizumab (Avastin) to adjuvant chemotherapy in women with triple-negative breast cancer.1 The study showed that the addition of bevacizumab did not improve invasive disease–free survival (an endpoint specifically excluding all in situ cancer events). An exploratory biomarker analysis suggested benefit of bevacizumab in patients with high pretreatment vascular endothelial growth factor receptor 2 (VEGFR-2) levels.

(63% and 64%). Similar proportions of patients received anthracycline and taxane therapy (59% and 58%), nontaxane anthracycline-containing therapy (36% and 37%), nonanthracycline taxane-containing therapy (5% of both), and radiation therapy (74% and 73%).

Invasive Disease–Free Survival Chemotherapy was completed as planned in 92% of the chemotherapy group and 93% of the bevacizumab group, and bevacizumab was com-

On the basis of our findings, bevacizumab cannot be recommended as adjuvant therapy for breast cancer in the overall population of patients treated in BEATRICE. Nevertheless, biomarker results suggest that within this population, there might be subsets of patients in whom bevacizumab has an effect.

Study Details In this open-label phase III trial, 2,591 patients with triple-negative operable primary invasive breast cancer from 360 sites in 37 countries were randomly assigned to receive a minimum of four cycles of adjuvant chemotherapy alone (n = 1,290) or with bevacizumab at an equivalent of 5 mg/kg every week for 1 year (n = 1,301). The primary endpoint was invasive disease–free survival. The chemotherapy and bevacizumab groups were well balanced for age (median, 50 years in both), premenopausal status (52% in both), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 93% and 92%), ethnicity (white in 75% and 72%), tumor size (T1 in 35% and 37%, T2 in 59% and 58%), positive axillary nodes (1–3 in 25% of both, ≥ 4 in 12% of both), ductal or invasive histology (92% and 93%), grade 3 tumor (69% and 70%), and breast-conserving surgery

—David Cameron, MD, and colleagues

pleted as planned in 68%. After median follow-up of 32.0 months in the bevacizumab group and 31.5 months in the chemotherapy group, there was no difference between the bevacizumab group and the chemotherapy group in invasive disease–free survival, with invasive disease–free survival events occurring in 14% of the bevacizumab group vs 16% of the chemotherapy group (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.72–1.07, P = .18); 3-year invasive disease–free survival was

Phase III BEATRICE Trial ■ The addition of bevacizumab to adjuvant chemotherapy did not

improve invasive disease–free survival in women with triple-negative breast cancer.

■ An exploratory analysis suggested benefit of bevacizumab in patients with high baseline levels of VEGFR-2.

83.7% with bevacizumab and 82.7% with chemotherapy alone. Subgroup analyses according to stratification factors and other clinically important characteristics showed no evidence of differences in invasive disease–free survival between treatment groups. After 200 deaths, there was no difference in overall survival (HR = 0.84, P = .23). Hazard ratios for the other secondary endpoints of breast cancer–free interval (HR = 0.89, P = .28) and distant disease-free survival (HR = 0.90, P = .33) also favored bevaci-

zumab but were not significant. Sites of recurrence were similar in the two treatment groups, with the most common being distant recurrence (11% in the bevacizumab group and 11% in the chemotherapy group). The most common sites of distant recurrence were lung (28% and 27%), liver (20% and 15%), and bone (17% and 20%). Distant central nervous system or meningeal recurrence accounted for 7% of recurrences in the bevacizumab group and 12% in the chemotherapy group.

Biomarker Analysis Exploratory biomarker assessment in approximately 45% of patients suggested that patients with high pretreatment plasma VEGFR-2 levels might benefit from the addition of bevacizumab. The hazard ratios for invasive disease–free survival

for bevacizumab vs chemotherapy were 0.61 among patients with levels above the median value and 1.24 for those with levels below median (P = .0291 for interaction).

Toxicity Grade 3 or higher adverse events occurred in 72% of patients in the bevacizumab group and 57% of the chemotherapy group. There was a high incidence of grade 3 or higher hematologic adverse events in both groups. The bevacizumab group had an increased frequency of grade 3 or worse hypertension (12% vs 1%), severe cardiac events occurring at any point during the 18-month safety-reporting period (1% vs � 0.5%), and treatment discontinuation (bevacizumab, chemotherapy, or both, 20% vs 2%). There was no increase in fatal adverse events with bevacizumab (4 vs 3). The authors noted that further follow-up is needed to assess the potential effect of bevacizumab on overall survival. The overall survival analysis is prespecified to occur after 340 deaths or median follow-up of 5 years, whichever occurs first. The authors concluded: “On the basis of our findings, bevacizumab cannot be recommended as adjuvant therapy for breast cancer in the overall population of patients treated in BEATRICE. Nevertheless, biomarker results suggest that within this population, there might be subsets of patients in whom bevacizumab has an effect. Identification of those patients who stand to benefit most from bevacizumab, in both the metastatic and adjuvant settings, is a priority.”n

Disclosure: The study was funded by F Hoffmann-La Roche.

See commentary on page 54

Reference 1. Cameron D, Brown J, Dent R, et al: Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): Primary results of a randomised, phase 3 trial. Lancet Oncol. August 6, 2013 (early release online).

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Journal Spotlight Continued from page 53

The BEATRICE Study: Where Does Targeting Breast Cancer Vasculature Stand in 2013? By Lisa A. Carey, MD

ntiangiogenic strategies using the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) gained traction in breast cancer with the publication of the Eastern Cooperative Oncology Group (ECOG) 2100 trial in 2007. That study demonstrated a progression-free survival advantage in stage IV disease with the addition of bevacizumab to taxane chemotherapy. Enthusiasm waned with the more modest, although still significant, progression-free survival improvements seen in subsequent studies, such as AVADO and RIBBON-1 and -2. More discouraging was the pooled analysis of overall survival in the first-line studies that found no evidence of a survival advantage to adding bevacizumab to a variety of chemotherapy backbones in unselected breast cancer.1 Based on this trajectory, bevacizumab gained provisional approval by the U.S. Food and Drug Administration for metastatic breast cancer in 2008, but that approval was revoked in 2011 in a controversial decision.

with high expression of VEGF and related signatures. Clinical data have been more uncertain. While the RIBBON-2 study suggested an effect of bevacizumab in pretreated metastatic triple-negative breast cancer in subset analysis, there was no suggestion of an overall survival advantage in the first-line studies. Neoadjuvant studies have also had mixed results. The triple-negative breast cancer subset appeared to

which is short although not unreasonable, given the early relapse pattern of triple-negative breast cancer—no evidence of an effect of bevacizumab on the primary endpoint of invasive disease–free survival (ie, specifically excluding in situ cancer events) was seen, with a nonsignificant hazard ratio of 0.88 (95% confidence interval = 0.72–1.07) and no real evidence of a differential effect in identifiable clinical subgroups. No significant differ-

While the BEATRICE study was disappointing in that it failed to give the “home run” of a well-tolerated targeted therapy that could augment adjuvant therapy in triple-negative breast cancer, the effort to identify predictive biomarkers beyond tumorbased markers provides some hope for the future. —Lisa A. Carey, MD

Triple-Negative Breast Cancer Given that our increasing understanding of breast cancer heterogeneity means that we should no longer perform studies in unselected breast cancer, it was reasonable to ask whether any identifiable subset might benefit from bevacizumab. Triple-negative breast cancer lacks expression of any of the targetable proteins in breast cancer—namely, the estrogen (ER), progesterone (PR), and HER2 receptors. This type of breast cancer was an appealing candidate because it is sorely in need of nonchemotherapy options for treatment and carries a poor prognosis, and because preclinical models and tumor-based studies suggest that triple-negative breast cancer is one the most hypoxic breast cancer subtypes, Dr. Carey is Richardson and Marilyn Jacobs Preyer Distinguished Professor of Breast Cancer Research at UNC Lineberger Comprehensive Cancer Center, and Division Chief, Hematology/Oncology, Physician-in-Chief, North Carolina Cancer Hospital, University of North Carolina at Chapel Hill.

derive particular benefit in terms of pathologic complete response rate from the addition of bevacizumab to anthracycline/taxane–based chemotherapy in GeparQuinto,2 whereas the opposite was true in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial.3 Results of Cancer and Leukemia Group B (CALGB) 40603, which randomly assigned patients with newly diagnosed triple-negative breast cancer to chemotherapy with or without bevacizumab and included mandatory tumor biopsies and germline DNA, have not yet been reported.

BEATRICE Findings The large (> 2,500 participants) randomized phase III BEATRICE study examined whether bevacizumab could improve relapse rates when administered for 1 year in addition to standard adjuvant chemotherapy in early-stage triple-negative breast cancer. At an event-driven analysis at 31 months’ median follow-up—

ence was seen in the secondary endpoints of disease-free interval, distant metastasis, or survival, although data for these may be immature. The bevacizumab arm had the expected increased rate of significant hypertension (≥ grade 3 in 12% vs 1% with chemotherapy alone), more proteinuria, and a small but significant increase in cardiac dysfunction (symptomatic dysfunction in 1% vs � 0.5%). A far greater proportion of patients discontinued treatment early in the bevacizumab arm (20%) than in the chemotherapy-alone arm (1%), a difference that might have contributed to an erosion of effect if one existed. Sadly, fewer than 50% of enrolled patients agreed to participate in the biomarker studies. Even with this limitation, subset analysis found that pretreatment plasma VEGF receptor 2 levels appeared to predict improved invasive disease–free survival only in those treated with bevacizumab, a finding that mirrors other studies.

Conclusions So, where does targeting breast cancer vasculature stand in 2013? Several large adjuvant and neoadjuvant studies of bevacizumab have not yet been reported, but the negative results of BEATRICE must lead one to agree with the study authors that without an effective predictive biomarker, this drug cannot be recommended in triple-negative breast cancer. There is no surprise here. Since the beginning, bevacizumab studies have been plagued by the difficulty in identifying patients most likely to benefit, which is particularly important given the drug expense. It appears that breast cancer subtyping is unlikely to be of much help; antiangiogenic drugs actually target the tumor microenvironment, so breast cancer subtypes may be far less relevant than identification of patient- and normal organ-level factors affecting response to these drugs. While the BEATRICE study was disappointing in that it failed to give the “home run” of a well-tolerated targeted therapy that could augment adjuvant therapy in triple-negative breast cancer, the effort to identify predictive biomarkers beyond tumor-based markers provides some hope for the future. Clinical trials that include heavily embedded predictive biomarker endpoints, such as CALGB 40603, will be key to better understanding whether we can identify those patients for whom antiangiogenic therapy is worthwhile. n

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

References 1. Miles DW, Diéras V, Cortés J, et al: First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: Pooled and subgroup analyses of data from 2447 patients. Ann Oncol July 25, 2013 (early release online). 2. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299-309, 2012. 3. Bear HD, Tang G, Rastogi P, et al: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012.

NOW ENROLLING A Phase 2 Trial of Rindopepimut in Patients With Relapsed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ReACT is a phase 2 study being conducted in the United States that will evaluate if rindopepimut is effective in extending progression-free survival (PFS) in patients with relapsed EGFRvIII-expressing glioblastoma, when added to standard bevacizumab

1:1 Randomization

Blinded Rindopepimut Group 1 Bevacizumab Naïve (n=70)

1st or 2nd relapse EGFRvIII-positive glioblastoma

Bevacizumab Blinded KLH Control

Bevacizumab

Treat until tumor progression, intolerance, or withdrawal of consent

Rindopepimut

Group 2 Bevacizumab Refractory

Bevacizumab

(n=25)

KLH=keyhole limpet hemocyanin.

N=95

Key Inclusion Criteria

Key Exclusion Criteria

• Previous treatment must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy, and temozolomide

• Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• First or second relapse of glioblastoma. Patients enrolling into group 2 must have progressed while receiving bevacizumab

• Clinically significant increased intracranial pressure, uncontrolled seizures, or requirement for immediate palliative treatment

• Documented EGFRvIII-positive tumor status. A tumor sample from either the initial diagnosis or more recent relapse will be acceptable. Only patients with the EGFRvIII mutation can participate in the trial

• History, presence, or suspicion of metastatic disease

Key Trial Endpoints • Primary: PFS rate at 6 months (PFS 6) • Secondary: Objective response rate, overall PFS, and overall survival

For more information visit www.celldextherapeutics.com, www.clinicaltrials.gov/show/NCT01498328, or e-mail info@celldextherapeutics.com. 1. Pelloski CE et al. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH et al. J Clin Oncol. 2010;28(31): 4722-4729. 3. Sampson JH et al. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics, Inc.

J2A

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Women in Oncology Lidia Schapira, MD: Bridging Communication Gaps Between Oncologists and Patients By Ronald Piana

Lidia Schapira, MD

ommunicating the intricacies of oncology care to vulnerable patients with cancer and their caregivers requires a firm grasp of the nuances of language. One of the oncology community’s true champions in the art of breaking down communication barriers is Lidia Schapira, MD, a medical oncologist at the Gillette Center for Breast Oncology at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School, Boston.

Medical Footsteps Dr. Schapira was born and reared in Buenos Aires, Argentina. Her father was an Austrian physician who fled to Argentina to escape the Nazis at the beginning of World War II. “My father was probably the wisest and kindest person in my life, and I strongly identified with him,” said Dr. Schapira. She remembers running to the scene of an accident when she was just 5 or 6 years old to see if she could help. Perhaps Dr. Schapira’s decision to follow in her father’s medical footsteps was subconsciously preordained. After graduating high school, Dr. Schapira said that her academic options at the time in Buenos Aires were fairly limited. “I actually wanted to study philosophy, but my father suggested that I should first get a real profession, then I could philosophize all I want,” said Dr. Schapira. A career in medicine was not only real, it offered Dr. Schapira an opportunity to satisfy her intellectual and scientific interests while fulfilling her desire to give something back to society. Dr. Schapira said that she was

drawn to the special challenges offered in oncology. “I loved problemsolving, and two areas of medicine that offered that challenge were infectious diseases and hematology. I also thought of pursuing psychiatry, but there just wasn’t enough action there for me. So I chose hematology, which was tied to the hip of oncology. Once I finished my medical training, I found oncology was a natural fit for someone also interested in psychology. It allowed me to care for patients with cancer and find out how they emotionally dealt with their illness,” explained Dr. Schapira. Dr. Schapira went to the University of Buenos Aires School of Medi-

father when I told him I wanted to pursue a career in philosophy.” “After fulfilling all the requirements, I became a card-carrying hematologist/oncologist. Although I enjoyed the scientific component of oncology, I still didn’t have a clear vision about my career path. This period of indecision coincided with two major events in my life: My father died, and my first child was born,” said Dr. Schapira. With a new baby at home, Dr. Schapira went on a self-described part-time track for about a decade, during which her practice began to focus on patients with breast cancer. “I also kept the academic piece of my career alive by doing a lot of

As I learned more, I began to foster educational programs about what we now call the ‘patient experience.’ These initiatives raised awareness … about the need to treat cancer from diagnosis to the last breath in a way that really pays attention to all the complex needs of the patient. —Lidia Schapira, MD

cine for 3 years, and then transferred to Dartmouth Medical School, receiving her MD in 1982, after which she trained in medicine at the Beth Israel Hospital in Boston until 1985. She then took a “gap year,” working in a community hospital until 1986, when she entered a hematology fellowship at Brigham and Women’s Hospital. It was there that her interest in doctor-patient communication began to take form.

Career Juggling “I was fascinated to learn how patients experienced day-to-day chronic illness, from diagnosis through the continuum of care. I remember asking my program director if there was a way I could study how patients reacted to hearing the news that they had a disease like leukemia. He gave me a puzzled look and told me that no such area of study existed,” said Dr. Schapira, adding, “It was sort of the same reaction I got from my

teaching. But I juggled my career to maintain a presence in my home life, which was very important to me,” said Dr. Schapira. She continued, “Although I was very organized in both my home and professional life, what I didn’t anticipate was that the emotional aspect of caring for patients with cancer was impossible to separate from my personal life. I spent many years cultivating my knowledge and skills in communicating with patients about their deepest concerns as they went through cancer treatment,” said Dr. Schapira.

Diving Deeper “During those transitional years, an opportunity developed through a patient of mine, a lovely young women who was dying of breast cancer. We became friends, and largely because of our relationship, I dived deeper into the dynamics of the doctor-patient relationship in the set-

ting of cancer and other life-threatening illnesses,” said Dr. Schapira. Her patient’s name was Julie Goldman. “We made a short film exploring how Julie’s diagnosis of cancer affected our own relationship. The film is called ‘One Story, Two Voices’; it is still available and continues to be used for medical and nursing education. It highlighted the opportunities for collaboration between cancer patients and their oncologists so that the relationship itself had therapeutic potential, regardless of the outcome of treatment,” said Dr. Schapira. “We gave lectures to draw attention to the lost potential that exists within the doctor-patient relationship. We were showing the community how better communication skills can translate into better clinical outcomes, using support groups and other methods of shared communication.” In 2002, Dr. Schapira became more involved with ASCO and other cancer organizations, developing innovative curriculum for postgraduate medical education and led workshops designed to improve the knowledge and skill set of clinicians. “Cancer organizations such as ASCO gave me a more formal venue to help train physicians in the skills that help them respond to and communicate better with their patients,” said Dr. Schapira. She also became more involved with the advocacy community, seeking to find better ways to integrate and strengthen the bond between patient groups and professional organizations.

Return to Academia As Dr. Schapira’s children became full-time students, she was able to return to academia, which gave her the venue to research and pursue her interest in the art of oncology communication. “As I learned more, I began to foster educational programs about what we now call the ‘patient experience.’ These initiatives raised awareness among the scientific and clinical communities about the need to treat cancer from diagnosis to the last breath in a way that really pays attention to all the complex needs of the patient,” she stressed.

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Women in Oncology Dr. Schapira served on the Board of Directors of the American Psychosocial Oncology Society (APOS). She described her work with APOS as a natural extension of her ongoing work in the field of communication. “We share a common interest in advancing the science of oncology and disseminating the important message of caring for the whole person, not just the disease,” said Dr. Schapira. At the 2011 Annual Meeting, she received ASCO’s Statesman Award for her years of extraordinary volunteer service, dedication, and commitment.

Branching Out As a communication specialist, Dr. Schapira has also branched out into the challenging field of medical interpreters—professionals who play a crucial role in mediating language-discordant encounters between patients with cancer and oncologists. “I grew up in a multilingual family. And because I immigrated to the United States, that helps me relate to patients from other countries who might feel like outsiders. The nuances of different languages truly affect conversations that involve clinical life or death decisions,” said Dr. Schapira. “So my work in this area is dedicated to demonstrating to the oncology community the importance of really paying attention to language preferences of our patients.” Dr. Schapira considers her work with medical interpreters a calling, bordering on a labor of love. “I feel that I have made a solid contribution in elevating the standards of professional medical interpreters. To that

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end, I convened an NCI-sponsored retreat of professional interpreters from all the NCI-designated cancer centers. For 2 full days we discussed ways to standardize the practice of medical interpretation and raise the level of specialized interpretation. The terminology in oncology exceeds the knowledge of most interpreters, and

this kind of intervention can make a huge difference in the quality of care we deliver,” said Dr. Schapira. Asked what she does to decompress from such a challenging career, Dr. Schapira responded, “If I have time, I’ll get in an early morning workout. But having quality time with my family is most crucial. I still

have one child still at home and if I have time to see him in the morning before going to work, that’s a good day. Then there’s my 4-year-old golden retriever, Teddy. I walk him every morning, which is a great way for me to start my day.” n Disclosure: Dr. Schapira reported no potential conflicts of interest.

The ASCO Post | SEPTEMBER 15, 2013

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Expert’s Corner Technology

H. Jack West, MD continued from page 1

for instance, with a conventional brickand-mortar oncology consultation is not only much less, in some cases it doesn’t exist. And second, there are still arcane jurisdictional rules for doctor-patient relationships that extend across state lines.

If a patient from Alaska wants a consult with me via a telemedicine portal, because it would take him 9 hours of travel to see me in person, I need to have an Alaskan medical license to legally participate in the telemedicine conference. I can practice telemedicine in the outer reaches of Washington, but not across the border

into Oregon. In part, this jurisdictional issue is just a way for the states to protect their medical revenue stream. But stifling telemedicine is certainly not in keeping with delivering the best medical care possible. Proactive telemedicine has been shown to reduce costs, for example, in preventing

unnecessary ER visits for patients with cancer who need advice on how to manage treatment-related side effects. Any thoughts on this issue? Telemedicine offers huge cost- and time-saving opportunities, but unfortunately they are being missed. For instance, there are large employers like Boeing, which is now contracting all its cardiac care with the Cleveland Clinic. It would be beneficial for Boeing to facilitate telemedicine conferences for routine cancer care and follow-up visits that don’t need an intervention. When you tally up the costs of employees traveling to the doctor’s office, the waiting time, and the visit itself, it really adds up. Any large employer who could substantially reduce the time of a 30-minute appointment to 30 minutes via telemedicine instead of half a day due to driving and wait times should be eager to improve “presenteeism” by facilitating telemedicine opportunities when possible. Now, just imagine how much Boeing would save by having an onsite telemedicine terminal. This would hold true for any large company like Amazon or Microsoft. The advantages of using telemedicine in the proper settings are substantial.

Keeping Up The Internet has changed the way doctors gather information, but there are still more than 200 print journals focused on cancer. Do you have a sense of which way all this digital and paper-based information is trending? I don’t believe there are data that truly capture the extent of usage or the breakdown between where doctors harvest their information. However, even the most motivated physicians— oncologists in particular—spend more and more time trying to stay up to date with the latest therapy, ending up buried in the avalanche of new clinical information. The volume of new material becoming available has been escalating rapidly, more than doubling over the past 20 years. It’s reached the point where it is infeasible to expect any single physician to remain updated on the emerging treatment options and clinical research opportunities across anything other than the most subspecialized patient population. In this era of information overload, we need to create a relationship with our patients and acknowledge on both sides that it is impossible, especontinued on page 59

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PAGE 59

Prevention Thoracic Oncology

Lung Cancer Alliance Launches National Campaign to Increase Public Awareness of Lung CT Screening

ollowing the recent recommendation by the U.S. Preventive Services Task Force (USPSTF) that individuals most at risk for lung cancer be screened, Lung Cancer Alliance has launched a national multimedia public education campaign urging individuals to assess their risk for lung cancer. The “Moments” campaign is appearing in cities nationwide and focuses on the inherent beauty of everyday, potentially missed moments.

Reduction in Mortality The campaign follows USPSTF’s July announcement recommending scans for those considered at highrisk for lung cancer. In making its rec-

H. Jack West, MD continued from page 58

cially for the general oncologist, to know all the information on one given subject. It’s better if patients and their caregivers partner in the informationgathering process. This way we can come together in the exam room and have a truly informed discussion, and ferret out all the clinical possibilities. This type of bidirectional exchange removes the unrealistic expectation that a single busy practitioner is the sole source of information in a field that is producing new markers and new agents every few months.

Impact of Online Information Sharing information is a good thing, but how does unfettered access to online medical information affect the doctorpatient relationship? It affects the relationship dramatically, cutting across many directions. Online medical information undermines any pretense toward paternalism that there might have been. It’s very easy now for patients to go to “Dr. Google” and learn about the latest study or new agents and markers that might not have been discussed by their doctor. That said, the great challenge we face from patients seeking informa-

ommendation, the panel considered facts from the National Lung Screening Trial, which concluded that computed tomography scans were more effective than x-rays in detecting lung cancer and that lung cancer, if caught early enough, could see a great reduction in mortality rates. The Moments campaign alerts individuals to include factors beyond smoking when considering their own risk for disease. The effort includes television and Facebook ads, out-ofhome placements, online video ads, and a “Map Your Moment” tool.

‘Monumental Move’ Laurie Fenton-Ambrose, President and CEO of Lung Cancer Allition online is that patients are not experts in culling through the vast amount of information, and, as we know, there’s a lot of misinformation available. So, it can create false expectations as they walk into the exam room. Also, there’s the overblown expectancy that the doctor should be up to date on every new data point

ance, called USPSTF’s recommendation “a monumental move in the fight against lung cancer,” cautioning that “now people need to know if they are at risk and if they are, take action.” Ms. Fenton-Ambrose added, “Lung cancer is the top cancer killer in the United States and we know scanning those at risk can and will save lives. Gaining this recommendation has been our top priority and we will continue to do everything we can to reach the public with this important health information.” Lung Cancer Alliance, which has been advocating for better lung can-

cer screening protocols for over 10 years, uses its most recent campaign to direct people to its online Risk Navigator, www.atriskforlungcancer. org. The site features questions that the user answers in order to determine his or her own risk for lung cancer. n

Role of Chat Rooms

Future of Telemedicine

The Internet is also full of online medical chat rooms. Do they play a role in the changing doctor-patient relationship? Absolutely. Cancer patients on these chats sometimes urge other patients to demand this particular clinical trial or new drug, whether it’s appropriate or not. However, there are online chat communities that are very constructive,

What do you see as the future of telemedicine? There are several models that could work well. For instance, many leading academic centers, ranging from Harvard to Johns Hopkins to the Cleveland Clinic, are now offering remote second opinions and report information or an actual interactive clinical discussion via video. This is something that’s likely to increase. Hopefully, payers will see the value of doing remote clinical work in situations that don’t need interventions. I also think we’ll see large networks like Kaiser Permanente moving toward having a major specialist available to do remote consults with the patient and his or her doctor within the same network to help shape the big picture clinical plan. It would be a very efficient way to ensure that patients enrolled in a broad network are getting the same care they would in a big tertiary center in the middle of a major city. This model also melds with the direction in which health care is moving— having a handful of major networks across the country. n

ASCO’s Cancer.Net [is] important because [the website gives] patients timely and credible information. We can’t stand on the sidelines; we need to ensure that we are providing online venues that deliver the best information possible for patients. —H. Jack West, MD

on the Internet. Doctors should not self-flagellate about not knowing the newest 1% marker that’s just come out in a press release. A patient might have a Google search set up to automatically return to specific sites that give them the latest cancer news, and much of this information will have no relevance to their particular clinical issue. The access to unlimited medical information is a double-edged sword that we need to learn to live with.

giving patients and caregivers support and instructing patients on how to have a constructive bidirectional conversation with their doctors about clinical approaches. I think that’s a good thing. That’s why websites like ASCO’s Cancer.Net are important, because they give patients timely and credible information. We can’t stand on the sidelines; we need to ensure that we are providing online venues that deliver the best information possible for patients.

Laurie Fenton-Ambrose

Disclosure: Dr. West reported potential conflicts of interest.

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The ASCO Post | SEPTEMBER 15, 2013

PAGE 62

Journal Spotlight Neuro-oncology

Postresection Adenovirus-Mediated Gene Therapy Improves Time to Death/Reintervention but Not Survival in Adult Glioblastoma By Matthew Stenger

n an open-label phase III trial (ASPECT) reported in Lancet Oncology, Manfred Westphal, MD, of University Hospital Eppendorf in Hamburg, and colleagues assessed the effects of locally applied adenovirus-mediated gene therapy with sitimagene ceradenovec followed by IV

for age (median, 58 and 57 years), sex (59% and 65% male), histopathology diagnosis (glioblastoma multiforme in 94% and 95%), location of tumor (right in 60% and 51%), ventricular opening (23% and 15%), time since clinical diagnosis (median, 7 and 8.5 days), Karnofsky score (90–100 in

Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. —Manfred Westphal, MD, and colleagues

ganciclovir after surgical resection in patients with newly diagnosed resectable glioblastoma.1 They found that the sitimagene ceradenovec treatment plus standard care significantly improved the composite endpoint of time to reintervention or death but not overall survival compared with resection plus standard care.

Study Details The trial involved 38 European sites with recruitment between November 2005 and April 2007. In total, 250 patients aged 18 to 70 years with newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection and a Karnofsky performance score ≥ 70 were randomized to surgical resection of the tumor and intraoperative perilesional injection of sitimagene ceradenovec (1 × 10¹² viral particles) followed by ganciclovir (postoperatively, 5 mg/ kg IV twice a day) in addition to standard care (n = 124) or resection and standard care alone (n = 126). Temozolomide was not a standard treatment in all participating countries at the time of the study and was allowed at the discretion of the treating physician. The primary endpoint was the composite of time to death or reintervention, adjusted for temozolomide use. Patients in the sitimagene ceradenovec group and the standard care group were generally well matched

66% and 71%), estimate of resection during surgery (radical in 83% and 81%), and estimated extent of resection from postoperative MRI (≥ 90% in 67% and 68%). For those with available data, 65% of patients in the sitimagene ceradenovec group and 76% in the control group had non-

methylated MGMT (the DNA repair gene O6-methylated-DNA methyltransferase). Temozolomide was used by more patients in the control group overall (65% vs 49%) and among those with nonmethylated MGMT (67% vs 45%).

Time to Death or Reintervention Median time to death or reintervention was significantly longer in the sitimagene ceradenovec group (308 vs 268 days, hazard ratio [HR] = 1.53, P = .006). The effect of sitimagene ceradenovec was greater among the subgroup of patients with nonmethylated MGMT (HR = 1.72, P = .008). Sitimagene ceradenovec also increased time to death or reintervention among patients who never used temozolomide (HR = 1.58, P = .0398). There was no difference between groups in overall survival (median, 497 vs 452 days, HR = 1.18, P = .31). There was evidence of a better effect of sitimagene ceradenovec treatment on overall survival among patients with nonmethylated MGMT, but the

effect was not significant (HR = 1.40, P = .112). Two-year overall survival was 25% in sitimagene ceradenovec group and 21% in the control group. An analysis of outcome by baseline antiadenoviral antibody status suggested a greater effect of sitimagene ceradenovec treatment in patients with higher titers of neutralizing antibodies. Among patients with titers > 100, 100, the hazard ratio for time to death or reintervention was 2.17 (P = .047) vs the control group. Among patients with antibody titers > 0, 0, the hazard ratio for time to all-cause mortality was 1.79 (P = .025) vs the control group. The proportion of patients who were antibody-positive and antibody titers initially increased in the sitimagene group and then declined over time.

Adverse Events More patients in the sitimagene ceradenovec group had one or more treatment-related adverse events of any grade (71% vs 41%), treatment-

Sitimagene Ceradenovec/IV Ganciclovir in Glioblastoma: Legitimizing the Gene Therapy Approach for Brain Tumors By William T. Curry, MD

he ASPECT study,1 a randomized, open-label, phase III trial examining adenovirus-mediated gene therapy with sitimagene ceradenovec followed by IV ganciclovir for patients with operable high-grade glioma, is an important achievement for both neuro-oncology and gene therapy. As vector engineering became more sophisticated in the 1990s and the molecular bases of disease were beginning to become unraveled, great enthusiasm drove the field of gene therapy as the expected therapeutic approach of the future for much of disease, including cancer. This enthusiasm was signifiDr. Curry is Associate Professor of Neurosurgery, Harvard Medical School, and Attending Neurosurgeon, Massachusetts General Hospital, Boston.

cantly dampened by the initial clinical experiences, which were hampered by lack of efficacy, low transduction efficiency of the targeted cells, and occasional severe toxicities, including treatment-associated mortality.2

Suicide Gene The delivery of the HSV thymidine kinase (HSV-tk) suicide gene as an anticancer therapeutic is a concept that has been examined preclinically and in clinical trials for nearly 20 years, and is attractive for several reasons. The tk gene, when delivered to cancer cells, phosphorylates the prodrug ganciclovir to ganciclovir triphosphate, which is a directly cytotoxic nucleoside analog. Cells expressing tk are therefore killed after administration of drug; also, the toxic metabolite can be

passed to adjacent cells via gap junctions, which allows for further spread of the effect. This is mechanistically straightforward and nontoxic to neurons and normal glia that are not undergoing cell division. The HSV-tk/ganciclovir paradigm has been previously examined in a randomized clinical trial in patients undergoing surgery for newly diagnosed glioblastoma.3 In 2000, Rainov and colleagues reported a phase III trial in which the treatment group underwent post-resection intracavity injection of vector-producing cells that released retrovirus- expressing HSVtk into the surrounding environment. There was no impact of the therapy on either progression-free or overall survival. The authors deduced that treatment failure was due to low genetic

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Journal Spotlight

related severe adverse events (23% vs 3%), treatment-related adverse events of grade 3 or higher (43% vs 9%), and serious adverse events (60% vs 43%). The most common grade 3 or 4 adverse events were hemiparesis (6.5% vs 2.4%) and aphasia (4.8% vs 1.6%). Seizure was more common in the experimental group during days 5 to 19, but the overall incidence was similar in the two groups (31% and 35%). Overall, 87% of patients in the experimental group and 86% of patients in the control group experienced nervous system disorders, 53% and 44% had transduction of the tumor cells, which was likely limited by the inability of the vector-producing cells to migrate.

Replication-Deficient Adenovirus Concurrently, replication-deficient adenovirus was being developed as an alternative vector, and preclinical data showed improved transduction efficiency as compared to retroviruses. After dosing and in vivo transduction were established in early-phase trials,4,5 a replication-deficient adenovirus containing the cDNA for HSV-tk was examined in a randomized phase II study,6 confirming safety and showing improved survival using the composite end point of time to death or surgery for recurrence, and leading to the current phase III study. In summary, the much-anticipated findings of this trial are that the study treatment of sitimagene ceradenovec followed by IV ganciclovir was associated with improved time to death or reintervention, the primary endpoint. Overall survival, however, was not significantly improved. Treatment had a greater effect on the subset of patients with unmethlyated MGMT promoters as measured by the primary endpoint. There were more significant adverse events in the treatment group, most consisting of neurologic morbidity. In the experimental group, having elevated antiadenovirus antibodies prior to treatment was associated with better outcome.

Design Limitations Though the ASPECT Study Group is to be commended for executing this randomized study, there are two design issues that are of concern. First, as enrollment began in 2005, the use of temozolomide was left to the discretion of the treating physicians, and the

Sitimagene Ceradenovec/IV Ganciclovir in Glioblastoma

be further developed, especially for patients who are unlikely to respond to standard chemotherapy.” n

■ Sitimagene ceradenovec followed by IV ganciclovir significantly

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

■ There was no difference between groups in overall survival.

Reference 1. Westphal M, Ylä-Herttuala S, Martin J, et al: Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): A randomised, open-label, phase 3 trial. Lancet Oncol 14:823833, 2013.

prolonged time to death or reintervention among all patients, those with nonmethylated MGMT, and those who did or did not use temozolomide.

gastrointestinal disorders, and 41% and 34% had infections. Treatment was discontinued due to an adverse event in 2% of sitimagene ceradenovec patients. The investigators concluded, “Our findings suggest that use of sitimagene ceradenovec and ganciclovir

after resection can increase time to death or reintervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should

distribution of temozolomide use was unequal between the two arms (49% in the treatment arm vs 65% in the control arm). However, we would expect this to bias outcome against the therapy. Second, the fact that this was an open-label study might bias the time to reintervention. An aptly named “reintervention committee”—members of which were blinded to treatment—retrospectively analyzed decision-making at the time of perceived progression and reintervention and determined that there was no bias. While the authors offer an explanation as to why a blinded trial was not feasible, there may have been alterna-

the highest antiadenoviral antibody titers were more successfully treated than those without baseline responses. Patients with more active immune systems (that are able to overcome glioblastoma-mediated immunosuppression) may more effectively mount antitumor immune responses after treatment, a phenomenon that has been observed in patients undergoing HSV-tk/ganciclovir treatment for malignant glioma.7 On balance, while sitimagene ceradenovec followed by IV ganciclovir will not become the standard of care for patients with newly diagnosed resected glioblastoma, this trial is an

With the appropriate technology and study design, gene therapy approaches to glioblastoma are deserving of serious attention and further investigation in large-scale clinical trials. —William T. Curry, MD

tives. Ideally, patients in the control arm would have received injections of a replication-deficient adenovirus that did not express HSV-tk, followed by ganciclovir. Currently, we could postulate that the observed effect was secondary to an adenovirus-induced inflammation.

Noteworthy Sidelights Several noteworthy sidelights further support activity of the treatment. Unexpected radiographic changes in the treatment group were regularly present at 19 days and were classified as pseudoprogression, necessitating a change in the radiographic interpretation of disease activity. Also, while preexisting antiadenoviral humoral immunity might be expected to abrogate the effects of treatment, subjects with

important advance and legitimizes a gene therapy approach for brain tumors. More robust efficacy will likely require vectors that more efficiently transduce target cells, stimulate antitumor immunity, or utilize vehicles that home to infiltrating tumor cells, such as mesenchymally derived stem cells.8 Viral oncolytic approaches, as opposed to the use of replication-deficient vectors, are under intensive study and have shown activity in a phase III trial in patients with advanced melanoma.9 With the appropriate technology and study design, gene therapy approaches to glioblastoma are deserving of serious attention and further investigation in large-scale clinical trials. n Disclosure: Dr. Curry reported no potential conflicts of interest.

References 1. Westphal M, Ylä-Herttuala S, Martin J, et al: Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): A randomised, open-label, phase 3 trial. Lancet Oncol 14:823-833, 2013. 2. Marshall E: Gene therapy death prompts review of adenovirus vector. Science 286:2244-2245, 1999. 3. Rainov NG: A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 11:2389-2401, 2000. 4. Sandmair AM, Loimas S, Puranen P, et al: Thymidine kinase gene therapy for human malignant glioma, using replicationdeficient retroviruses or adenoviruses. Hum Gene Ther 11:2197-2205, 2000. 5. Puumalainen AM, Vapalahti M, Agrawal RS, et al: Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther 9:17691774, 1998. 6. Immonen A, Vapalahti M, Tyynelä K, et al: AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: A randomised, controlled study. Mol Ther 10:967-972, 2004. 7. Floeth FW, Shand N, Bojar H, et al: Local inflammation and devascularization-in vivo mechanisms of the “bystander effect” in VPC-mediated HSV-Tk/GCV gene therapy for human malignant glioma. Cancer Gene Ther 8:843-851, 2001. 8. Murphy AM, Rabkin SD: Current status of gene therapy for brain tumors. Transl Res 161:339-354, 2013. 9. Andtbacka RHI, Collichio FA, Amatruda T, et al: OPTiM: A randomized phase III trial of talimogene laherparepvec (TVEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Oncol 31(suppl):Abstract LBA9008, 2013.

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JCO Spotlight Hematology

Potential Prognostic Significance Shown for Interaction of Follicular Lymphoma Cells with Immune Microenvironment By Matthew Stenger

t has been shown that CD4 and CD8 tumor-infiltrating lymphocytes in follicular lymphoma have impaired function and suppressed recruitment of critical signaling proteins to the immunologic synapse, and a number of studies have indicated the prognostic importance of the immune microenvironment in follicular lymphoma. In a study reported in the Journal of Clinical Oncology,1 Shahryar Kiaii, PhD, of Barts Cancer Institute, London, and colleagues investigated the molecular mechanisms underlying changes in tumor-infiltrating lymphocytes in the follicular lymphoma microenvironment. They found that the cells exhibited altered gene expression and showed that changes in the microenvironment can affect overall survival and time to transformation in follicular lymphoma. The study involved gene-expression

profiling of highly purified CD4 and CD8 tumor-infiltrating lymphocytes from lymph node biopsies at time of diagnosis in treatment-naive patients with follicular lymphoma and from reactive tonsils and peripheral blood from healthy subjects. Diagnostic tissue microarrays from an independent patient set were used to verify protein expression and analyze the impact of tumor-infiltrating lymphocyte–expressed genes on outcome, and timelapse imaging was used to assess T-cell motility.

Upregulated Genes and Impaired Motility The most upregulated genes in both CD4 and CD8 tumor-infiltrating lymphocytes were PMCH, ETV1, and TNFRSF9. PMCH was not expressed in peripheral blood T cells, but its expression was highly induced when cells were cocultured with follicular lymphoma cells. Both CD4 and CD8 tumor-infiltrating lymphocytes from

New Findings in Follicular Lymphoma ■ Tumor-infiltrating lymphocytes in follicular lymphoma have altered gene expression and impaired motility.

■ Models incorporating number and location of T cells expressing PMCH,

NAMPT, and ETV1 showed prognostic significance for overall survival and time to transformation.

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

[O]ur findings improve our understanding of the impact of tumor-infiltrating T cells in the microenvironment, identify molecular pathways that are altered, and introduce novel genes that may affect follicular lymphoma biology and outcome. — Shahryar Kiaii, PhD, and colleagues

patients with follicular lymphoma exhibited significantly impaired motility compared with the healthy tumorinfiltrating lymphocytes from reactive tonsils, and impairment of motility could be induced in healthy T cells by exposure to follicular lymphoma cells.

Prognostic Models Models incorporating the number and location of T cells expressing PMCH, NAMPT, and ETV1 showed prognostic significance for overall survival and time to transformation. In particular, the best model for predicting improved overall survival consisted of the number of PMCH- and NAMPT-expressing cells in the interfollicular area plus the ratio of ETV1expressing cells in the interfollicular/ intrafollicular area; a high combined score identified patients with significantly improved overall survival (hazard ratio [HR] = 0.32, P = .007). A model combining the ratio of

PMCH-expressing cells in the interfollicular/intrafollicular area combined with high expression of NAMPT and low expression of ETV1 in the intrafollicular area best identified patients with longer time to transformation (HR = 0.19, P = .003). The investigators concluded, “[O] ur findings improve our understanding of the impact of tumor-infiltrating T cells in the microenvironment, identify molecular pathways that are altered, and introduce novel genes that may affect follicular lymphoma biology and outcome.” n

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Kiaii S, Clear AJ, Ramsay AG, et al: Follicular lymphoma cells induce changes in T-cell gene expression and function: Potential impact on survival and risk of transformation. J Clin Oncol. June 17, 2013 (early release online).

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KADCYLA®: The first antibody-drug conjugate for HER2-positive metastatic breast cancer 1

Indication

KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do Not Substitute KADCYLA for or with Trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception Please see the following pages for additional important safety information and brief summary of full prescribing information, including Boxed WARNINGS.

The next era of treatment KADCYLA contains 3 components: the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker1-3 In preclinical studies:

Trastuzumab (monoclonal antibody) Binds to HER2 at subdomain IV to suppress downstream signaling

DM1* (cytotoxic maytansinoid) Inhibits tubulin polymerization to induce cell-cycle arrest and cell death

MCC* (stable linker) Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

• Maintains the HER2 suppression and anticancer activities of trastuzumab1 • Delivers cytotoxic DM1 to target HER2-expressing cells1 — Many normal cells express HER24 — Some cancer cells overexpress up to 200 times more HER2 than normal cells4

*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.

Additional Important Safety Information

Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who had Left Ventricular Dysfunction (LVD) trastuzumab permanently discontinued due to infusion-related reactions • Patients treated with KADCYLA are at increased risk of developing (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLArecommended for these patients. In EMILIA, the overall frequency of IRRs treated group and in 3.3% in the comparator group. Permanently in patients treated with KADCYLA was 1.4% discontinue KADCYLA if LVEF has not improved or has declined • KADCYLA treatment should be interrupted in patients with severe further IRR and permanently discontinued in the event of a life-threatening Pregnancy Registry IRR. Patients should be closely monitored for IRR reactions, especially • Advise patients to contact their healthcare provider immediately if during the first infusion they suspect they may be pregnant. Encourage women who may Thrombocytopenia be exposed to KADCYLA during pregnancy to enroll in the MotHER • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in Pregnancy Registry by contacting 1-800-690-6720 the KADCYLA-treated group and 0.4% in the comparator group (overall Pulmonary Toxicity incidence 31.2% and 3.3%, respectively) • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate been reported in clinical trials with KADCYLA. In EMILIA, the overall Neurotoxicity frequency of pneumonitis was 1.2% • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% • Treatment with KADCYLA should be permanently discontinued in in the KADCYLA-treated group and 0.2% in the comparator group (overall patients diagnosed with ILD or pneumonitis incidence 21.2% and 13.5%, respectively) • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral © 2013 Genentech USA, Inc. All rights reserved. TDM0001944700 Printed in USA. (07/13) neuropathy until resolution to ≤ Grade 2

Superior efficacy with a single agent1 NEARLY 6-MONTH IMPROVEMENT IN MEDIAN OVERALL SURVIVAL (OS) 100

30.9 months

Proportion surviving (%)

90 80

HR=0.682 95% CI: 0.548, 0.849 P=0.0006

70 60 50

KADCYLA (n=495) No. of events: 149

25.1 months

40 30 20

lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

No. at risk: KADCYLA 495 lapatinib + 496 capecitabine

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months 485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,3

• 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P <0.0001)1 • The most common NCI-CTCAE (version 3) adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother

Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS. References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356. 3. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012; 367:1783-1791 and Supplementary Appendix. 4. Hicks DG, Kulkarni S. Review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129:263-273.

Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For more information on KADCYLA, visit KADCYLA.com.

The ASCO Post | SEPTEMBER 15, 2013

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Robert S. Miller, MD, FACP, Appointed Editor-in-Chief of Cancer.Net

obert S. Miller, MD, FACP, a medical oncologist and recognized authority in breast cancer, survivorship care, and consumer health informatics, has been appointed Editor-in-Chief of ASCO’s patient

information website, Cancer.Net (www.cancer.net). He assumed this role at the 2013 ASCO Annual Meeting in June and succeeds Diane Blum, MSW, Chief Executive Officer for the Lymphoma Research

Foundation, who served as Editorin-Chief for 10 years. “I have been fortunate to serve as S:6.875” an Associate Editor of Cancer.Net for the past several years, and am deeply honored to be taking on this new

KADCYLA® (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA®, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

role,” said Dr. Miller. “Cancer.Net is a cornerstone of ASCO’s patient advocacy and communication strategies, and I certainly want to see all of the resources the site offers flourish and reach an even wider audience.” and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)]. 5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

B:17

T:15

7.5”

5.5”

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Fostering a Dialogue “Dr. Miller has been a long-term advocate of measures that enhance cancer care, and as Editor-in-Chief of Cancer. Net, he will further that commitment by lending his vision to a resource that people with cancer and their loved ones trust to provide timely, oncologist-ap-

proved information,” said ASCO Immediate Past President Sandra M. Swain, MD, FACP. “We are eager to embrace his vision for Cancer.Net, and to advance ASCO’s mission of empowering S:6.875” those with cancer by providing resources that help them make informed decisions and advocate for their best care.”

A key component of Dr. Miller’s vision for Cancer.Net includes enhancing the site’s interactivity. Through expanding Cancer.Net’ social media capabilities—including hosting tweetchats and incorporating more guest blog posts by those with cancer—he aims to create more opportunities for Robert S. Miller, MD, FACP

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Table 7 Selected Laboratory Abnormalities Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

Blood and Lymphatic System Disorders

Increased bilirubin

Neutropenia

6.7

2.0

9.0

4.3

Increased AST

Anemia

14.3

4.1

10.5

2.5

Increased ALT

Thrombocytopenia

31.2

14.5

3.3

0.4

Decreased platelet count

Cardiac Disorders Left ventricular dysfunction

1.8

0.2

3.3

0.4

3.3

2.5

Eye Disorders Lacrimation increased Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

0 0.4

Gastrointestinal Disorders Dyspepsia

9.2

11.5

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5

Diarrhea

24.1

1.6

79.7

20.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5 0.2

General Disorders and Administration 8.2

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection

9.4

0.6

3.9

Investigations Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7 0

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

Decreased potassium

8.4 Pediatric Use Safety and effectiveness of KADCYLA have not been established in pediatric patients.

8.5 Geriatric Use Of 495 patients who were randomized to KADCYLA in the randomized 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients response to KADCYLA. ≥ 65 years old (n=138 across both treatment arms) the hazard ratios A total of 836 patients from six clinical studies were tested at for progression-free survival (PFS) and Overall Survival (OS) were multiple time points for anti-therapeutic antibody (ATA) responses 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post- Population pharmacokinetic analysis indicates that age does not dose time points. The presence of KADCYLA in patient serum at have a clinically meaningful effect on the pharmacokinetics of the time of ATA sampling may interfere with the ability of this assay ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. to detect anti-KADCYLA antibodies. As a result, data may not 8.6 Females of Reproductive Potential accurately reflect the true incidence of anti-KADCYLA antibody KADCYLA can cause embryo-fetal harm when administered during development. In addition, neutralizing activity of anti-KADCYLA pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and contraception while receiving KADCYLA and for 6 months following specificity of the test methods used. Additionally, the observed the last dose of KADCYLA. incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to KADCYLA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-KADCYLA antibodies is not yet known. 7 DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have been conducted. In vitro studies indicate that DM1, the cytotoxic component of KADCYLA, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) with KADCYLA should be avoided due to the potential for an increase in DM1 exposure and toxicity. Consider an alternate medication with no or minimal potential to inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying KADCYLA treatment until the strong CYP3A4 inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse reactions. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.3)] Risk Summary

If KADCYLA is administered during pregnancy or if the patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

8.7 Renal Impairment No dedicated renal impairment trial for KADCYLA has been conducted. Based on the population pharmacokinetics, as well as analysis of Grade 3 or greater adverse drug reactions and dose modifications, dose adjustments of KADCYLA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment In vitro studies in human liver microsomes indicates that DM1 is metabolized by CYP3A4/5. The influence of hepatic impairment on the pharmacokinetics of ado-trastuzumab emtansine conjugate has not been determined. 10 OVERDOSAGE There is no known antidote for overdose of KADCYLA. In clinical trials, overdose of KADCYLA has been reported at approximately two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal case, the patient incorrectly received KADCYLA at 6 mg/kg and died approximately 3 weeks following the overdose; a cause of death and a causal relationship to KADCYLA were not established.

KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of 17 PATIENT COUNSELING INFORMATION KADCYLA in pregnant women. No reproductive and developmental • Inform patients of the possibility of severe liver injury and advise toxicology studies have been conducted with ado-trastuzumab patients to immediately seek medical attention if they experience emtansine. Nevertheless, two components of KADCYLA symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (trastuzumab and DM1) are known or suspected to cause fetal harm (especially RUQ abdominal pain), jaundice, dark urine, generalized or death when administered to a pregnant woman. If KADCYLA is pruritus, anorexia, etc. [see Warnings and Precautions (5.1)]. administered during pregnancy, or if a patient becomes pregnant • Advise patients to contact a health care professional immediately while receiving KADCYLA, apprise the patient of the potential for any of the following: new onset or worsening shortness of breath, hazard to the fetus. Patients should be advised to use effective cough, swelling of the ankles/legs, palpitations, weight gain of contraception during treatment with KADCYLA and for 6 months more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.2)]. following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient • Advise pregnant women and females of reproductive potential that becomes pregnant while receiving KADCYLA, immediately report KADCYLA exposure can result in fetal harm, including embryo-fetal exposure to the Genentech Adverse Event Line at 1-888-835-2555. death or birth defects [see Warnings and Precautions (5.3), Use in Encourage women who may be exposed during pregnancy to enroll Specific Populations (8.1, 8.6)]. in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see • Advise females of reproductive potential to use effective Patient Counseling Information (17)]. contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA [See Warnings and Precautions (5.3) and Human Data In the post-marketing setting, treatment with trastuzumab during Use in Specific Populations (8.1, 8.6)].

pregnancy has resulted in cases of oligohydramnios, some • Advise nursing mothers treated with KADCYLA to discontinue associated with fatal pulmonary hypoplasia, skeletal abnormalities nursing or discontinue KADCYLA, taking into account the importance and neonatal death. These case reports described oligohydramnios of the drug to the mother [see Use in Specific Populations (8.3)]. in pregnant women who received trastuzumab either alone or in • Encourage women who are exposed to KADCYLA during pregnancy combination with chemotherapy. In some case reports, amniotic to enroll in the MotHER Pregnancy Registry by contacting fluid index increased after trastuzumab was stopped. In one 1-800-690-6720 [see Warnings and Precautions (5.3) and Use in case, trastuzumab therapy resumed after the amniotic fluid index Specific Populations (8.1, 8.6)]. improved, and oligohydramnios recurred. KADCYLA® (ado-trastuzumab emtansine) Animal Data There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No: 1048

Currently, Dr. Miller is an Assistant Professor of Oncology at the Johns Hopkins University School of Medicine and Clinical Associate of the Breast Cancer Program and Oncology Medical Information Officer at the Sidney Kimmel Comprehensive Cancer Center. He earned his medical degree from the Medical College of Virginia School of Medicine, completed a residency in Internal Medicine at the University of California at San Francisco, a fellowship in Medical Oncology at Stanford University School of Medicine, and received his graduate certificate in biomedical informatics at Oregon Health and Science University. Dr. Miller has been an active ASCO member and volunteer since 1992. He currently serves on the Health Information Technology Workgroup, the Cancer Education Committee, and the editorial boards of Cancer.Net and the Journal of Oncology Practice (JOP), where he is a consultant editor and producer of the JOP podcast series. He is Chair of the ASCO Integrated Media and Technology Committee and an active ASCOConnection.org blogger. Previously, he was a member of the ASCO Board of Directors. For his dedication to the Society, ASCO awarded Dr. Miller a Fellow of the American Society of Clinical Oncology (FASCO) Award in 2011. He is a past recipient of an ASCO Travel Award from the Conquer Cancer Foundation. Dr. Miller is also a member of the American College of Physicians and the American Medical Informatics Association. He is a former member of the Oncology Workgroup of the Certification Commission for Health Information Technology (CCHIT). n B:11.5”

7.6

Longtime ASCO Member

T:10.5”

7.1

Chills

Decreased neutrophils

8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)].

dialogue between well-known, prominent cancer researchers and people with the disease.

S:9.875”

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Decreased hemoglobin

the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings.

The ASCO Post | SEPTEMBER 15, 2013

PAGE 70

Direct from ASCO

ASCO Congratulates QOPI-Certified Practices

QCP™: Recognizing Excellence The QOPI® Certification Program (QCP™) recognizes medical oncology and hematology/oncology practices that are committed to delivering the highest quality of cancer care. QCP evaluates an individual practice’s performance in areas that affect patient care and safety. The QOPI Certification Program provides a 3-year certification for outpatient hematology-oncology practices. QCP validates processes that demonstrate to patients, payers, and the medical community, a practice’s commitment to quality.

Western Region

Southern Region

ARIZONA • Palo Verde Hematology Oncology, Ltd.

FLORIDA • Arizona Oncology Associates, P.C.

CALIFORNIA • The Chao Family Comprehensive Cancer Center (Division of Hematology/Oncology) • Santa Monica Hematology-Oncology Consultants • Palo Alto Medical Foundation for Health Care, Research and Education • St Jude Heritage Medical Group/ Virginia K Crosson Cancer Center • Diablo Valley Oncology and Hematology Medical Group

• Marin Cancer Care, Inc. • Cancer Care Associates • Pacific Cancer Medical Center • Moores UCSD Cancer Center • Epic Care • Soborato Cancer Center at Santa Clara Valley Medical Center • Woodland Healthcare • Breastlink Network of Comprehensive Breast Centers

COLORADO • Southwest Oncology, P.C. The Queen’s Medical Center, Cancer Center

IDAHO • Mountain States Tumor Institute MONTANA • Billings Clinic NEVADA

• Columbia Basin Hematology & Oncology, PLLC • Washington Hematology-Oncology • Puget Sound Cancer Centers • Northwest Medical Specialties

• Atlanta Hematology & Oncology Associates, P.C. • Harbin Clinic

LOUISIANA • Louisiana Oncology Associates - Lafayette

• Alamance Regional Cancer Center • Cancer Care of Western North Carolina, PA - Asheville • Cornerstone Hematology/Oncology and Cornerstone Hematology/Oncology at Premier • Matthews Hematology Oncology Associates • Oncology Specialists of Charlotte • Hanover Medical Specialists P.A.

• Louisiana Hematology Oncology Associates • Raab Specialty and Oncology Clinic at Carteret General Hospital • Randolph Cancer Center • Cancer Centers of North Carolina • Mecklenburg Medical Group Oncology • Gaston Hematology and Oncology Associates • Carolinas Hematology Oncology Associates • Regional Cancer Care

SOUTH CAROLINA

• UNM Cancer Research and Treatment Center • Presbyterian Medical Group - Medical Oncology

• Coastal Cancer Center • Palmetto Hematology Oncology

• Hematology Oncology Associates, P.C.

• The Jones Clinic • The West Clinic

OREGON WASHINGTON

• Medical Oncology, LLC • Longstreet Cancer Center

• Auxilio Breast Cancer Center

NEW MEXICO

• NCCCP- Providence Cancer Center

GEORGIA

PUERTO RICO

• Comprehensive Cancer Centers of Nevada • New Mexico Oncology Hematology Associates, Ltd. • Hematology Oncology Associates, P.C.

• Holy Cross Hospital, Michael and Dianne Bienes Comprehensive Cancer Center • Florida Hospital Cancer Institute Cancer Institute of Florida and Premier Hematology & Oncology • MD Anderson Cancer Center Orlando

NORTH CAROLINA

HAWAII • OnCare Hawaii, Inc. • OnCare Hawaii -

• Space Coast Medical Associates, LLP • University of Miami - Sylvester Comprehensive Cancer Center • Cancer Care of North Florida, PA • Florida Oncology Association • Advanced Medical Specialties

• Self Regional Healthcare Cancer Center

TENNESSEE

TEXAS • The Center for Cancer & Blood Disorders • Oncology Consultants • MD Anderson Regional Care Center • The Don & Sybil Harrington Cancer Center

• Tennessee Oncology

ASCOPost.com | SEPTEMBER 15, 2013

PAGE 71

Direct from ASCO Midwestern Region

Eastern Region

ILLINOIS • CGH Medical Center • North Shore Oncology-Hematology Associates, Ltd. • Dreyer Cancer Center • Edward Hematology Oncology Group • Joliet Oncology-Hematology Associates, Ltd. • Oncology Specialists, S.C. • Center for Cancer Care at OSF Saint Anthony Medical Center • Springfield Clinic Oncology • Division of Hematology/OncologyNorthwestern University Feinberg School of Medicine • Affiliated Oncologists, LLC • Physicians East, P.A. • NorthShore University HealthSystem

CONNECTICUT Medical Group Kellogg Cancer Centers • Oncology Hematology Associates of Northern Illinois, Ltd. • Cancer Care Specialists of Central Illinois, SC • Northwest Oncology and Hematology, S.C. • Illinois CancerCare, P.C. • Creticos Cancer Center Advocate Illinois Masonic Medical Center • Hematology Oncology Consultants, Ltd. • Illinois Cancer Specialists • Ira J Piel MD, FACP, SC • LaGrange Oncology Associates, P.C. • Mid Illinois Hematology & Oncology Associates, Ltd. • Carle Foundation

INDIANA • Michiana Hematology-Oncology, P.C. • IU Simon Cancer Center Hematology

Oncology

Rapids • Physician’s Clinic of Iowa- Hematology/ Oncology

KANSAS • Kansas City Cancer Center

• The University of Kansas Cancer Center

KENTUCKY • Pikeville Medical Center Oncology Practice • Louisville Oncology

• CBC Group Consulting in Blood Disorders & Cancer

MICHIGAN • Northern Michigan Hematology/Oncology • Sparrow Regional Cancer Center • West Michigan Cancer Center • University of Michigan Cancer Center • Southwest Michigan Oncology Associates, PLLC

• Marquette General Hematology/Oncology • Charach Cancer Treatment Center • Center for Cancer Care & Blood Disorders • IHA Hematology Oncology Consultants • Allegiance Hematology Oncology

MINNESOTA • Park Nicollet Frauenshuh Cancer Center • HCMC Comprehensive Cancer Center

• University of Minnesota Medical Center, Fairview • SSM Cancer Care

NEBRASKA • Nebraska Hematology-Oncology PC • St. Francis Cancer Treatment Center

• The Urology Cancer Center

NORTH DAKOTA OHIO

SOUTH DAKOTA • Sanford Hematology & Oncology WISCONSIN • Fox Valley Hematology & Oncology, SC • Gundersen Lutheran Center for Cancer and Blood Disorders • Mayo Clinic Health System, Franciscan Healthcare

• Beebe Medical Center/Tunnell Cancer Center

MAINE • Harold Alfond Center for Cancer Care • CMMG Hematology Oncology Associates • CancerCare of Maine - Lafayette Family

Cancer Center • Maine Center for Cancer Medicine & Blood Disorders

MARYLAND • Carolyn B. Hendricks, MD, PA • Oncology Hematology Associates Weinberg Cancer Institute • AAMC Oncology Hematology

• Saint Agnes Hospital • Sandra & Malcolm Berman Cancer Institute at GBMC

• Commonwealth Hematology Oncology • Mass General North Shore Cancer Center • New England Hematology Oncology Associates • Baystate Regional Cancer Program • Hematology Oncology Specialists of Cape Cod

• Beth Israel Deaconess Medical Center Cancer Center • Southcoast Centers for Cancer Care • Dana-Farber/Brigham and Women’s Cancer Center at Milford Regional Medical Center • Dana-Farber Cancer Institute Inc. Londonderry & South Shore

NEW HAMPSHIRE • New Hampshire Hematology-Oncology • Norris Cotton Cancer Center-

Kingsbury Pavilion

NEW JERSEY • Saint Barnabas Cancer Center • Frederick B. Cohen, M.D. Comprehensive

Cancer and Blood Disorders Center • RCCA-Central Jersey Oncology Center

NEW YORK • Crystal Run Healthcare, LLP • Hematology Oncology Associates of Brooklyn • Pluta Cancer Center • WestMed Medical Group • Buffalo Medical Group, PC • Hematology Oncology Associates of

Central New York • Roswell Park Cancer Institute • James P. Wilmot Cancer Center/URMC • Maimonides Cancer Center • Winthrop Oncology and Hematology Associates, P.C.

• Vita Medical Associates, P.C. • Hematology & Oncology Associates of Northeastern PA, PC • Berks Hematology Oncology Associates • Hematology Oncology Associates • Consultants in Medical Oncology and

Hematology, PC • UPMC Cancer Center • Geisinger Clinic • Good Samaritan Oncology & Hematology Associates

RHODE ISLAND

• Roger Maris Cancer Center • Oncology Hematology Care, Inc. • Lake Health/University Hospitals Seidman Cancer Center • Toledo Clinic Cancer Centers • Ohio Cancer Specialists Inc.

DELAWARE • Regional Hematology and Oncology, P.A. • Medical Oncology Hematology Consultants, PA

PENNSYLVANIA

MISSOURI • Truman Medical Center

• Connecticut Multispecialty Group Division of Hematology, Oncology • Oncology Associates PC

MASSACHUSETTS

IOWA • Medical Oncology and Hematology Associates • Medical Associates Clinic Oncology • Oncology Associates at Mercy Cedar

• Norwalk Medical Group, P.C. • Western Connecticut Medical Group P.C.; Department of Medical Oncology and Hematology

• Summit Oncology Associates, Inc. - Akron • Genesis Hematology and Cancer Treatment Center • HOA Cancer Center Promedica Hematology Oncology

• Adele R. Decof Comprehensive Cancer Center • Rhode Island Hospital, The Comprehensive Cancer Center

• Roger Williams Medical Center • The Cancer Center at Memorial Hospital of Rhode Island

VIRGINIA • Lynchburg Hematology Oncology • Blue Ridge Cancer Care • Virginia Cancer Specialists • Hahn Cancer Center - Hematology

Oncology Associates • Virginia Cancer Institute • Peninsula Cancer Institute • Virginia Oncology Associates

WASHINGTON, D.C. • Washington Cancer Institute WEST VIRGINIA • David Lee Cancer Center

QOPI-certified practices as of August 6, 2013 The practices listed herein currently hold QOPI® Certification and have given their permission to be identified as a QOPI® Certified practice. This list is provided for informational purposes and is not an endorsement or a warranty by the QOPI® Certification Program or ASCO of any specific practice or the care provided by any practice or the practice’s doctors.

The ASCO Post | SEPTEMBER 15, 2013

PAGE 72

Direct from ASCO

Sustainable Growth Rate Bill Advances in the House

he U.S. House Energy and Commerce Committee has unanimously approved the Medicare Patient Access and Quality Improvement Act of 2013, which replaces

Medicare’s sustainable growth rate formula. The law would provide 5 years of stable Medicare payments beginning in 2014, with reimbursement rates increasing 0.5% for each

year between then and 2018. Beginning in 2019, physicians

Sandra M. Swain, MD

Immediate Past President ASCO MeMber SinCe 1986

Allen S. Lichter, MD

ASCO Chief Executive Officer

ASCO MeMber SinCe 1980 Clifford A. Hudis, MD ASCO President

ASCO MeMber SinCe 1991

Join AsCo’s leadership development program

shApe your Future & ours If you completed your final subspecialty training between 2004 and 2009 and are interested in becoming a future leader in ASCO, our Leadership Development Program is for you. Participants in this year-long program will learn valuable leadership skills and gain exposure to the roles and mission of ASCO and the Society’s powerful place in developing the future of cancer care. This program requires a time commitment for travel and training. IF seleCted you wIll: • Network with and receive mentorship from AsCo leadership

• enhance leadership skills through interactive sessions

• Interact with AsCo committees and government research agencies

• receive first-hand advocacy experience on Capitol hill

To apply today or view the full eligibility requirements for ASCO’s Leadership Development Program, visit www.asco.org/leadership ApplicAtions must be received by september 26, 2013.

Apply todAy www.asco.org/leadership

can choose to report certain quality measures and have traditional feefor-service payments adjusted based on how providers compare to peers on those measures. Physicians would be eligible for a 1% bonus if they meet or exceed quality measures, and could be subject to payment penalties for failure to meet the standards. The law also provides an alternative to the quality-incentive program as physicians may opt out if they participate in an alternative payment model such as a patient-centered medical home or accountable care organization. House members have yet to determine how to pay for the $140 billion cost of an SGR repeal, and the Senate has yet to signal its position on the House bill. A full House vote is expected sometime this year, before a 25% cut to Medicare payments goes into effect on January 1, 2014. n © 2013. American Society of Clinical Oncology. All rights reserved.

“

The ASCO Leadership Development Program strives to teach its participants how to build a team and then lead that team to greatness. As participants in this program, we have been challenged to define a strategic issue and work together to reach a desired outcome. I see this program as a springboard for future leadership opportunities in my clinic and oncology.

”

— Melissa Dillmon, MD, FACP, HArbin CliniC

Order Updated ASCO Answers Fact Sheets for Your Office or Waiting Room

SCO Answers fact sheets give a onepage introduction to more than 40 types of adult and childhood cancers, as well as types of treatments and side effects. Each fact sheet provides an overview of the topic, a list of helpful terms, and a list of questions to ask the doctor. Download the fact sheets at www.cancer.net/factsheets or order them through the ASCO University Bookstore at www.cancer.net/estore. All fact sheets ship for free, and ASCO members receive a 20% discount. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | SEPTEMBER 15, 2013

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Communicating the Promise Science Offers to Society

SCO President Clifford Hudis, MD, FACP, will be serving during a particularly notable year: 2014, the Society’s 50th anniversary. This occasion brings with it much to reflect on, from the advances in the field of oncology to the growth of ASCO’s influence, but Dr. Hudis takes a moment to simply ponder the milestone—in fact, the concept of milestones in general. “Perhaps we attach too much importance to specific years,” he reflected. “But it is also true that from time to time we have to pause, look around at our environment and ourselves and make sure we know what we aim to accomplish, and that we are working optimally toward our agreed-upon goals. Our 50th year seems like as good a time as any for this exercise!”

50 Years of Advances in Oncology Fifty years ago, our Society’s founders were also looking around at their environment, which was one similar to ours. There were exciting advances in cancer treatment and patient care both realized and on the horizon. Heartened by these advances and the promise of more to follow, the founders sought to equip the fledgling field of oncology with a valuable resource: an educational and scientific forum in which oncologists could learn from one another. In the 50 years since ASCO’s birth, the founders’ optimism has been fulfilled in many ways. Since the 1970s, the 5-year survival rate across all cancers has increased from one-half to two-thirds of patients. Dr. Hudis noted, “Additionally, in many cases, quality of life during treatment is also better, as side effects that used to be severe have been minimized to the point that most patients can be treated in an outpatient setting and function close to normally.” “In other [areas of the field], we have made less progress,” he said. However, unanticipated advances have been made in a few areas, and Dr. Hudis contended that “This provides reason for even greater optimism than our founders had, [and serves as] a reminder that the path from point A to point B is sometimes circuitous and surprising.”

Bridging the Gap Thinking about were we were, where we are, and where we want to be, and as

members of our many local and global communities, Dr. Hudis has identified a challenge for ASCO, one from which he developed the theme of his term: “Science and Society.” The challenge arises from the environment that we find ourselves in: Although scientific advances in patient care and cancer treatment are growing at an increasing pace, society’s understanding of these developments is not. This limits the speed of innovation and in some cases the acceptance of the results of studies. Dr. Hudis explained, “There is evidence of a rift between the thinking of scientists and that of many other members of society, and I have been repeatedly struck by it. It’s frustrating to me that straightforward scientific advances are often poorly understood or even rejected by society while unscientific pronouncements can quickly

From time to time we have to pause, look around at our environment and ourselves and make sure we know what we aim to accomplish. —Clifford Hudis, MD, FACP

represents the oncology field, “ASCO is in a unique position to help guide society in critically examining lifestyles and nutritional standards in the same way it has studied the biology and genetic causes of cancer in the past,” he said. This is becoming critical as energy imbalance and obesity are approaching tobacco as the leading modifiable risk fac-

is already addressing this solution through CancerLinQ, a health information technology initiative that gathers and analyzes data on millions of patient experiences, but its further development is a critical and time-sensitive step. To make this happen, we will need to go beyond financial investment and achieve societal understanding of the value and utility of “big data” as it relates to health care, and we will have to work together to identify feasible strategies to gather and analyze it.

The Value of Research

gain traction.” To bridge this potential gap between science and society, Dr. Hudis has identified three aspects of our environment that must be transformed.

Lifestyle Choices and Cancer According to Dr. Hudis, the first aspect of our environment that must change is society’s awareness of how behaviors and lifestyle choices contribute to cancer. The effect of these modifiable lifestyle choices—such as overeating and smoking—has been supported by scientific evidence, but our behavior has not always followed suit. In light of this evidence, Dr. Hudis noted that science can assist society in recognizing the detrimental effects of these behaviors and in developing remedies. Additionally, as an organization that

tors for many cancers. ASCO can use its scientific standing to work with all of society to look for acceptable approaches to reducing the disease burden from this increasingly common problem.

Building a Better Health-Care System The second aspect of our environment that must be addressed is the country’s fragmented health-care system, which hinders scientific progress and advances in cancer treatment. Millions of patient experiences and outcomes are locked away in file cabinets and unconnected digital file servers. To address this, Dr. Hudis supports the idea of gathering, synthesizing, and analyzing every patient’s experience through a connected database. ASCO

The third aspect Dr. Hudis deems in need of change is the barriers that scientists—specifically, young investigators pursuing careers in cancer research— now increasingly face. Many of these prospective cancer treatment pioneers are unable to conduct their research and contribute to the field because they lack funding and resources. He explained, “Advancements in cancer care can’t be made without resources and commitment to research, and yet there is the constant threat that these foundational components of research will be curtailed.” Dr. Hudis stressed the importance of changing society’s view of the value of this research—and science in general—by emphasizing how science develops understanding and treatments that benefit everyone. He added, “This research should never be seen as discretionary or as a luxury. To change such views we need to engage all members of society in the scientific process. In the end, it all comes back to illuminating the intersection of science and society so that we all see clearly the importance of the other.” n © 2013. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | SEPTEMBER 15, 2013

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Direct from ASCO

Conquering Cancer by Encouraging Diversity in the Field of Oncology

s the Conquer Cancer Foundation Grants and Awards Program has grown over the last 30 years, so has its purpose. Not only does the Grants and Awards Program support young researchers, foster mentoring relationships, and improve the quality of cancer care around the world, it also works to increase diversity in the oncology workforce by providing financial support and career development opportunities for doctors in underrepresented populations who are interested in a career in oncology. “The importance of diversity in oncology cannot be over-empha-

Directors. “In a field where innovation is paramount, the exchange of ideas and experiences between doctors of diverse backgrounds has the power to inspire new research and improve care for patients.”

Award Opportunities for Underrepresented Populations

The Foundation offers two key diversity award opportunities. The first is the Medical Student Rotation (MSR) for Underrepresented Populations, which provides 8- to 10-week clinical or clinical research oncology rotations for U.S. medical students and pairs students with renowned oncologists for academic and career mentorship. In addition, the Resident Travel Award (RTA) for Underrepresented Populations provides financial support for residents who are undecided on their specialty choice to attend the ASCO Annual Jacquelyne Gaddy and W. Charles Penley, MD, FASCO Meeting in order to further explore sized,” said W. Charles Penley, the field of oncology. MD, FASCO, Chair of the Con“I watched several family memquer Cancer Foundation Board of bers pass away or suffer with can-

Final Publication of IOM Report on Learning Health Systems Available

he Institute of Medicine (IOM) has issued the final publication of its report, Best Care at Lower Cost: The Path to Continuously Learning Health Care in America. ASCO continues to support the IOM report’s core recommendations for establishing a “learning health system” in the United States and aims to achieve them through its development of CancerLinQ, the Society’s multiphase rapid-learning initiative. The report describes a rapid learning system that will use real-time knowledge to improve outcomes, engage patients and family mem-

cer,” says 2012 MSR recipient Jacquelyne Gaddy. “I knew coming into medicine that I wanted to do oncology, but after having 8

bers, create a new culture of care, and form a continuous cycle of quality improvement in cancer care. The report made 10 recommendations for developing the rapid learning system in health care. Through its work on CancerLinQ, ASCO is already working to address seven of these recommendations. To access the report and its additional materials, please visit the report’s webpage on the IOM’s website at http://www.iom.edu/ n © 2013. American Society of Clinical Oncology. All rights reserved.

weeks to really focus on that, I do honestly think it’s shaped my career and ultimately will put me where I need to be. To actually have daily

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

interactions with patients and develop relationships with them… solidified my decision to enter oncology,” said Ms. Gaddy. Visit ConquerCancerFoundation.org to learn more about these and other funding opportunities, and to make a donation in support of ambitious students like Ms. Gaddy who are eager to make a difference in the lives of people with cancer. Help make the next 30 years of the Grants and Awards Program possible by making a gift today. n © 2013. American Society of Clinical Oncology. All rights reserved.

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

What’s Hot in

JCO

JCO.org Prognosis of Women With Primary Breast Cancer Diagnosed During Pregnancy: Results From an International Collaborative Study By Frédéric Amant, et al

Pregnancy During or After Breast Cancer Diagnosis: What Do We Know and What Do We Need to Know? By Richard L. Theriault, et al

Fluorouracil, Doxorubicin, and Cyclophosphamide (FAC) Versus FAC Followed by Weekly Paclitaxel As Adjuvant Therapy for High-Risk, Node-Negative Breast Cancer: Results From the GEICAM/2003-02 Study By Miguel Martín, et al Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact on Outcome in the Medical Research Council Myeloma IX Study By Andy C. Rawstron, et al

Minimal Residual Disease in Multiple Myeloma By Nikhil C. Munshi, et al

When hemoglobin falls...

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks.5* • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo.2,3† • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W.6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa ACC trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.2,3

Aranesp® (darbepoetin alfa) Indication Aranesp® is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.

Limitations of Use: Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp® is not for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • As a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799 www.amgen.com

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks. • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. • Because of these risks, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/ or dispense Aranesp® to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions. • Use ESAs only for anemia from myelosuppressive chemotherapy. • ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • Discontinue following the completion of a chemotherapy course. • Aranesp® is contraindicated in patients with: − Uncontrolled hypertension − Pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs − Serious allergic reactions to Aranesp®

• In controlled clinical trials of patients with cancer, Aranesp® and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures. • Control hypertension prior to initiating and during treatment with Aranesp®. • For lack or loss of hemoglobin response to Aranesp®, initiate a search for causative factors. If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. • Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Aranesp®. − This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. − PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Aranesp® is not approved). − If severe anemia and low reticulocyte count develop during treatment with Aranesp®, withhold Aranesp® and evaluate patients for neutralizing antibodies to erythropoietin. − Permanently discontinue Aranesp® in patients who develop PRCA following treatment with Aranesp® or other erythropoietin protein drugs. Do not switch patients to other ESAs. • Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Aranesp®. Immediately and permanently discontinue Aranesp® if a serious allergic reaction occurs. • Adverse reactions (≥ 1%) in clinical studies in cancer patients receiving chemotherapy were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary of prescribing information, including Boxed WARNINGS, on the adjacent page. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

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*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP "NPOH BMM QMBDFCP DPOUSPMMFE TUVEJFT BCEPNJOBM QBJO WT BOE FEFNB WT XFSF SFQPSUFE NPSF GSFRVFOUMZ JO QBUJFOUT SFDFJWJOH "SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOE FEFNB WT JO UIF "SBOFTQ USFBUFE QBUJFOUT compared to those receiving placebo. 1PTUNBSLFUJOH &YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZ PS FTUBCMJTI B DBVTBM SFMBUJPOTIJQ UP ESVH FYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVT BMMFSHJD SFBDUJPOT Immunogenicity "T XJUI BMM UIFSBQFVUJD QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ /FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS &4"T DBO SFTVMU JO 13$" PS TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT *O DMJOJDBM TUVEJFT UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFE VTJOH UIF #JBDPSF┬о BTTBZ 4FSB GSPN QBUJFOUT XJUI $,% BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO QBUJFOUT XJUI $,% BOE DBODFS QBUJFOUT %VSJOH "SBOFTQ UIFSBQZ SBOHF UP XFFLT B GPMMPX VQ TBNQMF XBT UBLFO 0OF BEEJUJPOBM QBUJFOU XJUI $,% BOE BEEJUJPOBM DBODFS QBUJFOUT EFWFMPQFE BOUJCPEJFT DBQBCMF PG CJOEJOH "SBOFTQ /POF PG UIF QBUJFOUT IBE BOUJCPEJFT DBQBCMF PG OFVUSBMJ[JOH UIF BDUJWJUZ PG "SBOFTQ PS FOEPHFOPVT FSZUISPQPJFUJO BU CBTFMJOF PS BU FOE PG TUVEZ /P DMJOJDBM TFRVFMBF DPOTJTUFOU XJUI 13$" XFSF BTTPDJBUFE XJUI UIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZ PG UIF BTTBZ "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

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ASCOPost.com | SEPTEMBER 15, 2013

PAGE 79

Future of Oncology The Direction of Immunotherapy Over the Next Decade A Conversation With David L. Porter, MD By Jo Cavallo

he use of immunotherapy to target malignant cells in a variety of cancers—especially the PD-1 inhibitors lambrolizumab and nivolumab in the treatment of metastatic melanoma and the anti–PD-L1 agent MPDL3280A in the treatment of melanoma and lung, kidney, colorectal, and gastric cancers—made headlines at ASCO’s Annual Meeting in June. The success of these drugs in early-phase clinical trials builds on the momentum created by previous studies testing other therapies that use the body’s immune system to kill cancer cells. At the 2012 Annual Meeting of the American Society of Hematology, David L. Porter, MD, and colleagues at the University of Pennsylvania, presented their updated findings of a pilot study in 12 patients with leukemia, including 10 adults with advanced chronic lymphocytic leukemia (CLL) and two children with acute lymphoblastic leukemia (ALL) who had been treated with genetically engineered versions of their own T cells. Their findings showed that nine patients responded and three patients had no response to the therapy. Since then, a total of 24 adults with CLL and 10 children with ALL have been treated with gene-transfer therapy. In the longest follow-up to date, the first CLL patients treated with the therapy have remained in remission for 3 years, and the first child with ALL treated with the therapy has had a sustained remission of more than 1 year. The treatment, known as CTL019 (previously known as CART19), was pioneered by the University of Pennsylvania researchers and involves isolating a patient’s own T cells, genetically modifying them with a lentiviral vector expressing an antibody-like protein called chimeric antigen receptor (CAR). The cells are designed to attack the protein CD19 expressed on the surface of certain B cells. The reengineered cells are expanded and then injected back into the patient. The ASCO Post talked with Dr. Porter, Director of Blood and Marrow Transplantation and Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania, about the progress being made in immune therapy approaches, espe-

cially in cell-based therapies, and how immunotherapy may be the answer to curing cancer in the future.

eliminate some of the off-target toxicities that you often see with nonspecific immunotherapy.

Dramatic Progress

Looking Ahead

Please talk about how far research has come in understanding how to harness the body’s immune system to fight cancer. There has been dramatic progress over the past decade in understanding how to use the immune system. We have known for more than 50 years that the human immune system has the potential to be a very powerful anticancer therapy. Part of the rationale for doing bone marrow transplantations was to give the patient a new immune system, which could help fight

What advances in cell-based therapy do you see happening over the next decade? We need a better understanding of the T-cell and other immune-cell populations that are needed to kill cancer cells. Our knowledge of the interactions among immune effector cells is increasingly complex, but we need an even better understanding of how these cells function and interact to maximize the response to cellular therapy. I think the biggest limitation that

Ultimately, it’s going to be important to develop randomized clinical studies to show that immunotherapy may be superior to other treatment modalities. But right now we are still in the early phases of trying to show that there is a role for these types of treatments. —David L. Porter, MD

the patient’s cancer, and I think that’s where so much interest in cellular immunotherapy originated. Over the years it has been possible to develop targeted therapy in the form of antibodies, and now in the form of cell-based therapy. There has also been tremendous progress in understanding very complicated interactions with the immune system. One can now manipulate and downregulate inhibitory signals or immune suppressors like regulatory T-cells. Researchers have also developed efficient methods that allow us to stimulate and grow immune effector cells for clinical use. From a cell-based therapy standpoint, one big advance have been in the ability to grow immune cells in the laboratory in numbers large enough so they could be used therapeutically. Now, particularly with some of the work that we have been doing to grow specific immune-cell populations, we can confer novel specificity to the T cells and make the immune function much more targeted and specific, and

has to be overcome is the identification of the appropriate targets on cancer cells. We have been treating ALL and CLL by targeting CD19, which is an ideal cancer target. The problem with many cancers is that they are too close to self and there aren’t easily identifiable target antigens that allow you to apply immune therapy without off-target toxicity. How will you be able to overcome that problem? I sincerely believe that over the next 5 to 10 years, some of the biggest advances will come from identifying new targets for various kinds of cancers and then applying vaccine therapy, antibody therapy, and cellular therapy against these specific targets. This will be done through extensive studies of cancer cell biology, DNA sequencing, and other techniques that will allow this type of immunotherapy to become increasingly personalized to a patient’s specific tumor and the tumor’s specific targets. I believe that it will be possible

to accomplish this for many, if not most, cancers over the next decade.

Immunotherapy vs Chemotherapy Will immunotherapy render conventional types of chemotherapy obsolete? It’s going to be a long time before chemotherapy is obsolete. Some chemotherapy may actually have a role concurrently with immunotherapy and may function to modulate the immune interactions. There may be instances where we use multimodality therapy, including chemotherapy, radiation therapy, and immunotherapy. The biggest downside to chemotherapy is its complete lack of specificity. If you could use less and use it more judiciously, or use it to modulate other therapy, presumably the toxicity will be less.

Curing Cancer Could immunotherapy be the answer to curing some cancers? Immunotherapy can already cure some cancers. Going back to the example of bone marrow transplantation, there are circumstances when patients with leukemia or lymphoma relapse after allogeneic transplant and can be cured with infusions of normal T cells from their original transplant donor (donor lymphocyte infusion). Immune therapies are the new frontier in cancer therapy, and the field is in its infancy. Although there are not many examples of immunotherapy curing cancer yet, I anticipate that the application of immunotherapy in the treatment of cancer will grow dramatically over the next decade.

CAR Technology Your current research is focused on using viral transfection to genetically modify T cells to express a chimeric antigen receptor (CAR) in patients with CLL and ALL. Are you planning studies in other hematologic cancers using CAR? We hope to be able to expand this therapy to patients with non-Hodgkin lymphoma very soon, but we believe that this approach is applicable to other targets as well. Our initial work is focused very heavily on CD19 and on expanding CD19 targets, and then we hope to use similar chimeric antigen recontinued on page 80

The ASCO Post | SEPTEMBER 15, 2013

PAGE 80

Patient’s Corner

Celebrating 2 Decades as a Cancer Survivor Faith, family, and wonderful medical care have allowed me to have a productive life. By Jim Taulman, as told to Jo Cavallo

his past June, I celebrated 20 years of being a cancer survivor by throwing myself a party. It was an interesting experience because I learned that many of the 100 guests I invited were also cancer survivors or were family members of cancer survivors, and so we celebrated their lives as well. Our pastor led us in a prayer of gratitude, and I was glad we could acknowledge in a public way how fortunate we are.

pecting to get such a life-threatening diagnosis—but as a person of faith, the prospect of death didn’t frighten me. Getting the diagnosis just gave me the privilege of an early warning, so I

2 more decades with my family and to continue the work I love—first, as an editor in a denominational publishing house, and currently, as a personal historian. I have no plans of retiring.

In addition to my faith and family, I’m sure I owe my continued good health to the two oncologists who have treated me over the past 20 years.

Early Warning I was 57 when I was diagnosed with low-grade non-Hodgkin lymphoma (NHL), and although I was told the cancer was incurable, my oncologist assured me it was treatable. Except for missing a half-day of work when I had a biopsy of an enlarged lymph node in my groin that was discovered during a routine medical exam, I’ve been able to go about my life uninterrupted by the cancer or its treatment side effects. It’s not that it wasn’t a shock to hear I had cancer—I had no symptoms of the disease and, therefore, wasn’t ex-

was able to prepare myself to die, if that was to be my fate, sooner than I might have expected. As it turned out, the treatments I was prescribed, first-line therapy with chlorambucil (Leukeran), which kept me in remission for 6 years, and then two treatments with rituximab (Rituxan), which has kept me in remission for the past 14 years, have allowed me to have

Living a Good Life

Immunotherapy

Wider Applicability

continued from page 79

Is cellular-based immunotherapy applicable to solid tumor cancers as well as blood cancers? The hope is that immunotherapy will be effective for solid tumors as well. Studies using targeted immune therapy in patients with breast and ovarian cancer are just getting underway, and other cell-based therapy trials are targeting brain tumors, sarcomas, and other cancers. We will know in several years whether we can target solid tumors effectively. But, again, the problem is identifying those unique targets.

ideal candidate for this type of therapy? We don’t know the answer to that yet. We have treated about 24 people, and we have not yet been able to identify factors that predict who may or may not respond to the therapy, but we are working very hard to do that.

ceptor technology to target other tumor types once targets can be identified. For example, we are hoping to open a study with multiple myeloma patients over the next few months. We are thinking very hard about how best to target myeloma cells and how we can apply similar chimeric antigen receptor technology to patients in the setting of stem cell transplant. In myeloma, we think the best strategy may be to prevent patients from relapsing, so we are initially hoping to target patients who are at high-risk for relapse or who have minimal residual disease, and would administer chimeric antigen receptor therapy early after a transplant.

—Jim Taulman

Not all the patients in your study responded to this treatment. Is there an

I know not everyone fares so well with this cancer. A friend of mine who was diagnosed with NHL soon after I was could not tolerate rituximab and died in 2000. Why I’ve done so well for so long is a mystery to me, but I’m using the time I’ve been given to be a better husband to my wife Mary—I think having cancer has been harder

Clinical Trials How will clinical trials need to be designed over the next decade to effectively test this type of therapy? Trials need to be designed so that we can initially test not just the level of activity of immunotherapy but its safety as well. There are unique issues with the long-term safety of immune therapy, particularly with gene therapy. Ultimately, it’s going to be important

on her than on me—and a better father and grandfather, as well as a more productive citizen. I’ve also spent the time engaging in satisfying work that brings joy to the lives of the people that hire me to record and publish their personal histories.

Being Part of the Team In addition to my faith and family, I’m sure I owe my continued good health to the two oncologists who have treated me over the past 20 years. From my initial diagnosis, I explained to my medical team that I wanted to be included in all treatment decisions and kept informed about my progress. It was important for me to be treated as a person and not just a name on a medical chart. Both my oncologists honored my requests and I consider them my friends. I don’t know what the future will hold, but I have no regrets or fear. I just have gratitude for the life—and the time—I’ve been given. n Jim Taulman lives in Franklin, Tennessee.

to develop randomized clinical studies to show that immunotherapy may be superior to other treatment modalities. But right now we are still in the early phases of trying to show that there is a role for these types of treatments. At the University of Pennsylvania, we plan to open a Center for Advanced Cellular Therapies, where we can take immunotherapy from the basic research of target identification, vector development, and cell manufacturing all the way through the clinical trial process. n

Disclosure: Dr. Porter receives research support from Novartis and has IP interests on technology licensed to Novartis. Conflict of interest is managed in accordance with oversight and policies of the University of Pennsylvania. Dr. Porter’s spouse is employed by Genentech.

Visit The ASCO Post website at

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The ASCO Post | SEPTEMBER 15, 2013

PAGE 82

Survivorship

Cancer: Survivors in Focus Photo Exhibit Honors Cancer Survivors By Jo Cavallo

n June, the David J. Sencer Centers for Disease Control and Prevention (CDC) Museum in Atlanta, Georgia, opened a new photo exhibit featuring the faces of people living through and beyond a cancer diagnosis. The exhibit: Cancer: Survivors in Focus, tells the stories of cancer survivors while raising awareness of how the public health community can ease the burden of cancer on patients and society through support, surveillance programs, and the investigation of effective cancer therapies. The exhibition of more than 100 photos, a collaboration of the David

J. Sencer CDC Museum and the CDC’s Division of Cancer Prevention and Control, explored the lives of

CDC’s Stories of Survivorship. Two of the photographers whose work was showcased in the exhibit: John

It has been very meaningful both to us at the CDC and to people outside of the agency. The focus on survivorship gave a different angle to looking at cancer, and the message is so hopeful. I think it is that sense of hope and optimism that has reverberated out of this exhibit. —Louise E. Shaw, Curator, David J. Sencer CDC Museum

survivors in three themes: Not As I Pictured; Without Borders: The Global Face of Cancer; and Close to Home:

Kaplan, Not as I Pictured, and Carolyn Taylor, Without Borders: The Global Face of Cancer, are cancer survivors.

The show closed in early September but not before it was viewed by more than 25,000 people; because of the positive response, the exhibit may be traveling to other cities in the fall. “The exhibit exceeded my expectations,” said Louise E. Shaw, Curator of the David J. Sencer CDC Museum. “It has been very meaningful both to us at the CDC and to people outside of the agency. The focus on survivorship gave a different angle to looking at cancer, and the message is so hopeful. I think it is that sense of hope and optimism that has reverberated out of this exhibit.” n

WITHOUT BORDERS: THE GLOBAL FACE OF CANCER Carolyn Taylor is a survivor of ovarian and endometrial cancers. In March 2010, Ms. Taylor began a photo documentary project that took her over 100,000 miles around the world to photograph and interview cancer survivors, caregivers, and medical professionals. The following year, Ms. Taylor launched the Global Focus on Cancer, a nonprofit organization dedicated to raising cancer awareness, providing support, and creating an international network of communication for cancer patients, survivors, caregivers, and medical professionals.

Dar es Salaam, Tanzania. He is diagnosed with leukemia.

Dr. Francesco DeLorenzo, Rome, Italy, colon cancer survivor.

Yusra, The West Bank, breast cancer survivor.

Harmala Gupta, New Delhi, India, Hodgkin lymphoma survivor. Hassan Dar es Salaam, Tanzania, skin cancer survivor.

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PAGE 83

Survivorship

CLOSE TO HOME: CDC’S STORIES OF SURVIVORSHIP Bryan Meltz is a documentary photographer based in Atlanta, Georgia. She specializes in projects dealing with social and humanitarian concerns. “My hope is that people seeing this exhibit will be transformed much in the same way I have been. Instinctively, the word ‘cancer’ terrified me, but by working on this project, I was able to set aside that fear. By seeing people confront this disease head on, summon amazing amounts of strength and move forward with dignity, we can all learn so much. Because of their stories, we can feel a little more empowered to take a more active role in our own health care and to advocate for others with less fear and greater understanding. We learn that cancer is not a death sentence, but simply a life challenge.”

“I am extremely grateful that [Adrienne] has responded as well as she has [to treatment], and she had done so with a positive attitude and fighting spirit.” —Cheryl, Epidemiologist at the CDC Division of HIV/ AIDS Prevention-Surveillance and Epidemiology, is the mother of Adrienne, who was diagnosed with neuroblastoma at 21 months old.

—Bryan Meltz

“When the doctor told me I had breast cancer I was shocked, but I wasn’t surprised. I wasn’t surprised because I know enough about it to know that anyone can get it, and I’m no different than anyone else when it comes to this disease. Being the single mother of two young children, my primary concern was how I was going to deal with this diagnosis and take care of them at the same time. “I transformed from a person who was totally devastated by my diagnosis to someone extraordinarily grateful that I had been diagnosed early. I now see my early diagnosis as a gift, and that’s really what I want other women to see. You can be diagnosed, you can survive, you can thrive, and you can go through all of it and look like nothing has ever happened.” —Marcella, Captain, US Public Health Service, National Center for Chronic Disease Prevention and Health Promotion, breast cancer survivor

“I don’t try to look back and say woe is me, I simply try and look forward and ask, what is the best course of action in dealing with what is present?” —Jim, Health Scientist, Division of Preparedness and Emerging Infections, prostate cancer survivor

All photos courtesy of the David J. Sencer Centers for Disease Control and Prevention (CDC) Museum.

“I come from a strong family history of women diagnosed with breast cancer—mother, grandmother, great grandmother, sister, aunt, first cousin. In 2007, I found a lump and immediately sought medical attention. Through biopsy results, I was diagnosed with breast cancer. I went through 5 months of chemo, and opted for a double mastectomy. Four years later I was diagnosed again, same diagnosis, despite having the surgery. I endured another 4 months of chemo and 35 rounds of radiation. Lessons learned from my experience are: 1. Know your body; 2. Trust your instinct and seek a second or third opinion if necessary; and 3. Actively participate in your own health care. Those actions can make all the difference.” —Denise, Management & Program Analyst, Office of the Associate Director for Science, breast cancer survivor

continued on page 87

To prevent SREs in patients with BREAST CANCER and bone metastases

vs zoledronic acid

Better prevent SREs1 MEDIAN TIME TO FIRST SRE IN BREAST CANCER1*

27 26.4 At

Months (study end)

median time not yet reached

Months

XGEVA® 120 mg Q4W (n = 1,026)

XGEVA® acts precisely to bind RANK Ligand, a key mediator of bone resorption, and inhibit osteoclast formation, function, and survival1

zoledronic acid 4 mg Q4W (n = 1,020)

HR = 0 0.82; 82; P = 0 0.010, 010 0 superiority

• XGEVA® reduced the risk of first SRE by 16% vs zoledronic acid in patients with other solid tumors or multiple myeloma (P < 0.001, noninferiority; P = 0.060, NS for superiority)1* XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma Convenient 120 mg subcutaneous injection administered once every 4 weeks1 Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia1 Approximately 70% of patients are expected to have $0 out-of-pocket cost for XGEVA®2† *Data from the international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046) and in patients with bone metastases from other solid tumors (excluding breast and prostate cancer) or multiple myeloma (N = 1,776). The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1 † Estimated amount of Medicare beneficiaries with supplemental coverage and commercially insured patients with no OOP cost; based on XGEVA® payor mix and coverage of XGEVA® and other similar products. Does not include costs related to office visit, physician, staff, or administrative charges associated with administering XGEVA®.

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypersensitivity • XGEVA is contraindicated in patients with clinically signiﬁcant hypersensitivity to any component of the product. ®

Hypocalcemia • XGEVA® can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct preexisting hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia. • Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ) • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®.

• Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture • Atypical femoral fracture has been reported with XGEVA®. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. A number of reports note that patients were also receiving treatment with glucocorticoids at the time of fracture. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Interruption of XGEVA® therapy should be considered, pending a risk/ beneﬁt assessment, on an individual basis.

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. XGEVA® (denosumab) prescribing information, Amgen. 2. Data on ﬁle, Amgen.

S:9.5”

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypersensitivity. Xgeva is contraindicated in patients with clinically signiﬁcant hypersensitivity to any component of the product (see Adverse Reactions). WARNINGS AND PRECAUTIONS: Hypocalcemia. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth (see Use in Specific Populations). There are no adequate and well controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneﬁts in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other ﬁndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone a Table 1. Per-patient Incidence of Selected Adverse Reactions of Any Severity growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth (Trials 1, 2, and 3) malalignment; and decreased neonatal growth. At birth out to one month of age, infants Xgeva Zoledronic Acid had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and Body System n = 2841 n = 2836 strength returned to normal; there were no adverse effects on tooth eruption, though % % dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; GASTROINTESTINAL and minimal to moderate mineralization in multiple tissues was seen in one recovery Nausea 31 32 animal. There was no evidence of maternal harm prior to labor; adverse maternal Diarrhea 20 19 effects occurred infrequently during labor. Maternal mammary gland development was GENERAL normal. There was no fetal NOAEL (no observable adverse effect level) established for Fatigue/ Asthenia 45 46 this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis INVESTIGATIONS and led to postnatal impairment of dentition and bone growth. Pregnant RANKL 18 9 Hypocalcemiab knockout mice showed altered maturation of the maternal mammary gland, leading Hypophosphatemiab 32 20 to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in NEUROLOGICAL full Prescribing Information). Headache 13 14 Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, a decision should be made whether to discontinue nursing or discontinue the drug, 2, and 3, and meeting one of the following criteria: taking into account the importance of the drug to the mother. Maternal exposure • At least 1% greater incidence in Xgeva-treated patients, or to Xgeva during pregnancy may impair mammary gland development and lactation • Between-group difference (either direction) of less than 1% and more than based on animal studies in pregnant mice lacking the RANK/RANKL signaling 5% greater incidence in patients treated with zoledronic acid compared to pathway that have shown altered maturation of the maternal mammary gland, placebo (US Prescribing Information for zoledronic acid) leading to impaired lactation postpartum. However, in cynomolgus monkeys treated b with denosumab throughout pregnancy, maternal mammary gland development Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; (0.71 – 0.9 mmol/L) for phosphorus] however, development and lactation have not been fully evaluated (see Nonclinical Severe Mineral/Electrolyte Abnormalities Toxicology [13.2] in Full Prescribing Information). • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment of patients treated with zoledronic acid. Of patients who experienced severe with Xgeva may impair bone growth in children with open growth plates and hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) Use in Specific Populations). at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than eruption. Adolescent primates treated with denosumab at doses 5 and 25 times 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of (10 and 50 mg/kg dose) higher than the recommended human dose of patients treated with zoledronic acid. 120 mg administered once every 4 weeks, based on body weight (mg/kg), had Osteonecrosis of the Jaw abnormal growth plates, considered to be consistent with the pharmacological In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Warnings and Precautions). When events occurring during an extended treatment decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and phase of approximately 4 months in each trial are included, the incidence of mesenteric lymph nodes. Some bone abnormalities recovered once exposure was confirmed ONJ was 2.2% in patients who received Xgeva. The median time to ONJ ceased following birth; however, axillary and inguinal lymph nodes remained absent was 14 months (range: 4 – 25). 6 months post-birth (see Use in Pregnancy). Postmarketing Experience. Because postmarketing reactions are reported Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) voluntarily from a population of uncertain size, it is not always possible to reliably were 65 years of age or older. No overall differences in safety or efficacy were estimate their frequency or establish a causal relationship to drug exposure. observed between these patients and younger patients. The following adverse reactions have been identified during post approval use of Xgeva: Renal Impairment. In a trial of 55 patients without cancer and with varying • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. degrees of renal function who received a single dose of 60 mg denosumab, Immunogenicity. As with all therapeutic proteins, there is potential for patients with a creatinine clearance of less than 30 mL/min or receiving dialysis immunogenicity. Using an electrochemiluminescent bridging immunoassay, less were at greater risk of severe hypocalcemia with denosumab compared to than 1% (7/2758) of patients with osseous metastases treated with denosumab patients with normal renal function. The risk of hypocalcemia at the recommended doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to dosing schedule of 120 mg every 4 weeks has not been evaluated in patients 3 years tested positive for binding antibodies. No patient with positive binding with a creatinine clearance of less than 30 mL/min or receiving dialysis (see antibodies tested positive for neutralizing antibodies as assessed using a Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] chemiluminescent cell-based in vitro biological assay. There was no evidence of in full Prescribing Information). altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly OVERDOSAGE: There is no experience with overdosage of Xgeva. dependent on the sensitivity and specificity of the assay. Additionally, the observed HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. incidence of a positive antibody (including neutralizing antibody) test result may be Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. influenced by several factors, including assay methodology, sample handling, timing Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to of sample collection, concomitant medications, and underlying disease. For these temperatures above 25°C/77°F or direct light and must be used within 14 days. reasons, comparison of antibodies to denosumab with the incidence of antibodies Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted shaking of Xgeva.

RESPIRATORY Dyspnea Cough

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PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva on ﬁndings in animals. In utero denosumab exposure in cynomolgus monkeys Advise patients that denosumab is also marketed as Prolia®. Patients should resulted in increased fetal loss, stillbirths, and postnatal mortality, along inform their healthcare provider if they are taking Prolia. with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva Amgen Manufacturing Limited, a subsidiary of Amgen Inc. in pregnant women. Women should be advised not to become pregnant when One Amgen Center Drive taking Xgeva. If this drug is used during pregnancy, or if the patient becomes Thousand Oaks, California 91320-1799 pregnant while taking this drug, the patient should be apprised of the potential ©2010-2013 Amgen Inc. All rights reserved. hazard to the fetus. Women who become pregnant during Xgeva treatment Printed in USA. 68257-R2-V2

with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There ADVERSE REACTIONS: The following adverse reactions are discussed below and was no evidence that various anticancer treatments affected denosumab systemic elsewhere in the labeling: exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 • Hypocalcemia (see Warnings and Precautions) months were not altered by concomitant chemotherapy and/or hormone therapy. The • Osteonecrosis of the Jaw (see Warnings and Precautions) median reduction in uNTx/Cr from baseline to month 3 was similar between patients The most common adverse reactions in patients receiving Xgeva (per-patient receiving concomitant chemotherapy and/or hormone therapy (see Clinical incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, Pharmacology [12.2] in full Prescribing Information). and nausea (see Table 1). The most common serious adverse reaction in patients USE IN SPECIFIC POPULATIONS: receiving Xgeva was dyspnea. The most common adverse reactions resulting in Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: discontinuation of Xgeva were osteonecrosis and hypocalcemia. Xgeva can cause fetal harm when administered to a pregnant woman based Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reﬂect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were

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Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-ﬁve percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-ﬁve percent of patients who received Xgeva received concomitant chemotherapy.

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Survivorship Cancer: Survivors in Focus continued from page 83

NOT AS I PICTURED Pulitzer Prize-winning photographer John Kaplan was diagnosed with non-Hodgkin lymphoma in 2008 when he was 48. His self-portraits reflect his personal journey while going through treatment. “At first taking pictures was a way to cope with my own fear, distracting myself from the tough reality I faced, along with my family. I soon realized that if I was able to go into remission, and we hoped and prayed that I would, I knew our family’s story could lend hope and courage to others facing a cancer diagnosis.

John Kaplan took this selfportrait soon after getting a diagnosis of non-Hodgkin lymphoma.

“My ‘visual journal’ captured a new routine; anti-nausea drugs, growing fatigue, and a changing physical self I no longer recognized in the mirror. With so many difficult adjustments surrounding us, my wife, Li, and I were determined to provide as much normalcy as possible for our children. Carina was then only 4-years-old, and her little brother, Max, just 2.” —John Kaplan

Using a camera remote hidden in his hand, John photographs his bone marrow biopsy, calling it the worst pain he has ever endured.

John tips his cap to students in his international journalism class at the University of Florida after explaining he had been diagnosed with cancer.

John finds strength with wife, Li, and children, Carina and Max.

John and his wife, Li, get good news from his oncologist, James W. Lynch, Jr. MD, Professor of Medicine, Division of Hematology & Oncology at the University of Florida: “You are in complete remission.”

The photographer uses humor is these self-portraits to give viewers an emotional break from the intensity of his cancer treatment process.

The ASCO Post | SEPTEMBER 15, 2013

PAGE 88

Book Review

The Trials and Tribulations of a Revolutionary Cancer Drug By Ronald Piana

modest brass plaque above a booth in the Eagle Pub in Cambridge, notes, “On this spot, on February 28, 1953, Francis Crick and James Watson declared the discovery of DNA with these words: ‘We have discoverewd the secret of life.’” Announcing a major scientific advance over a pint of ale is a far cry from the standing-room-only crowd at the 2006 ASCO Annual Meeting, where Brian Drucker, MD, presented data from the 5-year follow-up of patients taking imatinib (Gleevec) for chronic myeloid leukemia (CML). It wasn’t the secret of life, but the

The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level.

Tall Order The audience for this type of science-based book is generally known as the “smart lay public.” The allure of science books depends on intellectual nourishment served in a compelling narrative, which is a tall order. The challenge for the author is to walk a delicate information line—giving just enough science to nourish readers with knowledge while keeping the book rolling along

This can be heady content, and Ms. Wapner is at her best when she sharpens her descriptions of biology and oncology so the layperson can be challenged but not overwhelmed. development of imatinib revolutionized the treatment of CML. A diagnosis of CML was once a death sentence. These days, if CML is diagnosed early, it can be managed as a chronic disease, giving patients many years of good-quality life. The deadly leukemic cells these patients harbor in their bone marrow are kept corralled by the tyrosine kinase inhibitor drug imatinib. And it almost didn’t happen. Early on, CML was thought to be too uncommon to justify the huge investments in research, development, and regulatory costs needed to bring it to market. Obviously, the visionaries won out over the bean counters. And that story, in a nutshell, is the basis of Jessica Wapner’s new book,

without a surfeit of facts and theory bogging down the pace. The Philadelphia Chromosome has an added challenge as the author charts the discovery of the gene that led to the development of imatinib: There are no zany characters, exciting locales, or juicy anecdotes. Even the hero, Dr. Drucker, is painted in the most neutral of colors, leaving the reader wanting a tad more. These limitations don’t make for a bad book; they just narrow the potential readership down to those who are thrilled by a story that Robert A. Weinberg, PhD, describes in the forward thusly: “The story that this book relates vindicates those who dreamed that one day cancers could be treated through rationally

designed drugs—and in fact remains the major success story to this day…. This book makes good reading for those interested in the work of the heroes who pushed this drug forward to its truly brilliant successes.” Jessica Wapner is a sturdy writer who has good command of a difficult subject. The book has been well researched and benefits from first-hand accounts of more than 35 interviews. This can be heady content, and Ms. Wapner is at her best when she sharpens her descriptions of biology and oncology so the layperson can be challenged but not overwhelmed. For example, here she teaches something in plain language: “Finding a way to turn a compound into a drug that would not be immediately rejected or disintegrated by the body would not be easy. To enter the body, the molecule had to be stable in water without dissolving. To leave the body, the drug, having done its work, had to penetrate the portal vein, which goes through the liver, where the remnants could be broken down for excretion.” Her sections on tyrosine kinase inhibitors, however, risk overload, and many of those passages become overwhelming.

Select Audience Readers of The ASCO Post will appreciate the step-by-step process that produced one of modern oncology’s greatest success stories. Some of the most compelling sections deal with the battle to get the drug into the pipeline. In those parts, the true heroes of this tale emerge as

Title: The Philadelphia Chromosome: A Mutant Gene and the Quest to Cure Cancer at the Genetic Level Author: Jessica Wapner Publisher: The Experiment, LLC Length: 302 pages Price: $25.95

champions for patients with cancer. But be prepared, years drag by before imatinib finally receives FDA approval. In that regard, The Philadelphia Chromosome also leaves us wanting more. At the book’s close, Dr. Drucker said of his hope for the future, “There would be a Gleevec for every cancer.… [I]t’s all about target. Identifying the right target, getting a good drug to market, and not worrying about [the size of the market].” The Philadelphia Chromosome can be a challenging read at times, but for a select audience, it is worth the effort. n

News and Views from the World of Clinical Oncology and Hematology Visit The ASCO Post website at

www.ASCOPost.com

ASCOPost.com | SEPTEMBER 15, 2013

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News

ASCO Launches New Site to Seek Feedback from Cancer Community on Clinical Practice Guidelines

SCO has launched a new wiki site to engage the cancer community in its clinical practice guideline development process. The new site will provide oncologists, practitioners and patients with an opportunity to provide feedback or submit evidence on individual published guidelines and can be accessed at: www.asco.org/guidelineswiki. “Cancer treatment has advanced based on clinical trials conducted in a surprisingly small number of patients. With new laboratory insights and a massive expansion of potential drugs, we have to begin to gain knowledge from every treatment experience if we are to accelerate progress and continuously improve quality of care,” said Clifford A. Hudis, MD, FACP, President of ASCO.

ment to quality of life. Guidelines can address specific clinical situations or the use of approved medical products, procedures, or tests. Using the best available

evidence, ASCO expert panels identify and develop practice recommendations for specific areas of cancer care that would benefit from using practice guide-

lines. All ASCO Guidelines are published in the Journal of Clinical Oncology. To learn more about ASCO’s guidelines, please visit www.asco.org/guidelines. n

WHAT IF ENGINEERING THE ANTIBODY COULD IMPROVE ADCC? Glycoengineering a monoclonal antibody may improve ADCC1-4 In preclinical studies, the modification of certain sugar molecules via glycoengineering has been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by enhancing the ability of monoclonal antibodies to activate immune effector cells. Fc Region

SUGARS MAY COMPROMISE IMMUNE EFFECTOR–ANTIBODY BINDING 4

Based on preclinical models, the ability of an antibody to bind to immune effector cells may be compromised by the presence of certain sugar residues on the antibody’s Fc region.

Clifford A. Hudis, MD, FACP

Sugar Modification

“ASCO guidelines are intended to help improve cancer care and this new site will enhance our ability to do so by learning from the experiences of our colleagues,” Dr. Hudis said.

Offer Comments, Provide Evidence Individuals will have the opportunity to comment on published guidelines and provide new evidence, which will be reviewed by the site administrator and forwarded to the individual guideline panel co-chairs for consideration. In addition, the site will provide an overview of the evolution of the recommendations of each guideline. All information is open for viewing. However, to comment or submit new evidence, an ASCO Guidelines Wiki user account is needed. To receive your user account, please contact guidelines@asco.org. ASCO published its first clinical practice guideline in 1994 and has since issued numerous guidelines on areas of care that range from prevention to treat-

GLYCOENGINEERING MAY INCREASE BINDING AFFINITY 1,3,4

GLYCOENGINEERING COULD LEAD TO IMPROVED ADCC 2,5

The modification of certain sugar residues via glycoengineering may result in enhanced binding affinity to immune effector cells that activate ADCC.

Preclinical data have demonstrated that certain glycoengineered antibodies may induce a greater level of ADCC than non-glycoengineered antibodies.

Glycoengineered antibodies have been or are being studied across a panel of molecular targets5 Immune Effector Cell

Glycoengineered antibodies have been or are being investigated in clinical trials across multiple disease states, including cancer, inflammation, and asthma.

Target Protein Target Cell

For more information, visit ResearchBcell.com

References: 1. Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human FcγRIII and antibody-dependent cellular toxicity. J Biol Chem. 2002;277(30):26733-26740. 2. Ogorek C, Jordan I, Sandig V, von Horsten HH. Fucose-targeted glycoengineering of pharmaceutical cell lines. Methods Mol Biol. 2012;907:507-517. 3. Herbst R, Wang Y, Gallagher S, et al. B-cell depletion in vitro and in vivo with an afucosylated anti-CD19 antibody. J Pharmacol Exp Ther Ther. 2010;335(1):213222. 4. Ferrara C, Grau S, Jäger C, et al. Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose. Proc Natl Acad Sci USA. 2011;108(31):12669-12674. 5. Beck A, Reichert JM. Marketing approval of mogamulizumab: a triumph for glyco-engineering. MAbs. 2012;4(4):419-425.

*Based on preclinical models.

The ASCO Post | SEPTEMBER 15, 2013

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2013

2013 Oncology Meetings September Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp Continuum Cancer Centers of New York Conference on Quality of Care in Oncology September 20 • New York, New York For more information: www.chpnet.org/cme

ASH Consultative Hematology Course September 27 • Chicago, Illinois For more information: www.hematology.org Second Annual Update on Gastrointestinal Cancers September 27 • New York, New York For more information: www. columbiasurgery.org/cme/event_ gastrointestinal_cancer_20130927. html Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences

Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee For more information: www.tops-tennessee.com

2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org

Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org

The Art and Science of the New Melanoma Landscape September 27-28 • Houston, Texas For more information: www. ProvaEducation.com/Melanoma

NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 Amsterdam, The Netherlands For more information: www.ecco-org.eu

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences Progress Towards Individualised Cancer Treatments September 26-27 • London, United Kingdom For more information: www.rsm. ac.uk/academ/rpd16.php

28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications October 3-6 • San Diego, California For more information: www.aacr.org

Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/ conferences

Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia For more information: www.cancereducationconsortium. org/programs_paaw.html

Second Annual Conference Global Biomarkers Consortium October 4-6 • Boston, Massachusetts For more information: www. globalbiomarkersconsortium.com

9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/

15th Annual Scientific Meeting of the Australasian GastroIntestinal Trials Group October 8-10 • Melbourne, Australia For more information: http:// www.agitg.asnevents.com.au

2nd Annual Oncology Clinical Development Congress October 14-15 • Manchester, United Kingdom For more information: www. oncologyclinicaldevelopmentcongress.com

Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ ASCOv2/About+ASCO/ International+Affairs/Internationa l+Clinical+Trials+Workshops

17th Annual Interdisciplinary Conference on Supportive Care, Hospice, and Palliative Medicine October 11-12 • Houston, Texas For more information: www.mdanderson.org/ conferences

64th Annual Scientific Meeting of The Royal Australian and New Zealand College of Radiologists October 17-20 • Auckland, New Zealand For more information: http:// www.ranzcr2013.com/index International Stereotactic Radiotherapy Conference October 19-20 • Houston, Texas For more information: www.mdanderson.org/ conferences

2013 ASH State-of-the-Art Symposium October 11-12 • Los Angeles, California For more information: http:// hematology.org/Meetings/Stateof-the-Art-Symposium 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/

4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 continued on page 92

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2013

2013 Oncology Meetings continued from page 90

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 19-23, 2013 • Boston, Massachusetts For more information: www.aacr.org 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 2013 International Society of Geriatric Oncology Congress October 24-26 • Copenhagen, Denmark For more information: www.siog.org 51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de

New York Lung Cancer Symposium

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/

Academy of Oncology Nurse

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences Georgia Society of Clinical Oncology 4th Annual Winship Gastrointestinal Cancers Symposium November 2 • Atlanta, Georgia For more information: http:// www.gasco.us/meetings-topic. php?meetingid=92

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com Twelfth Annual International Conference on Frontiers in Cancer Prevention Research October 27-30, 2013 • National Harbor, Maryland For more information: www.aacr.org

Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

November 9 • New York, New York For more information: www.gotoper.com/conferences

Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information:

SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

www.aortic2013.org

December 55th ASH Annual Meeting

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/

December 7-10 • New Orleans, Louisiana For more information: www. hematology.org

International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences

Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro

JANUARY 24–26, 2014

Renaissance Vinoy St. Petersburg • St. Petersburg, FL

Chair: Pamela Hallquist Viale • Co-Chairs: Sandra E. Kurtin and Wendy H. Vogel

advancedpractitioner.com/jadprolive

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

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CREDITS/ CONTACT HOURS For nurses, physician assistants, and pharmacists

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News

St. Jude Children’s Research Hospital Recognizes Childhood Cancer Awareness Month

hildhood cancer remains the leading cause of death by disease among young Americans. September marks Childhood Cancer Awareness Month, a time to highlight efforts to reduce the disease’s toll on children. At St. Jude, the past year has brought advances in understanding and treating childhood cancer, particularly in the areas of genomics and survivorship. “One child dying of cancer is one too many and the need to find better treatments is as critical as ever,” said William E. Evans, MD, St. Jude Director and CEO. “As we learn more and more about the genetic causes of pediatric cancer through genomic research, treating these cancers becomes more complex and challenging.”

Pediatric Cancer Genome Project discoveries during the past year include identifying missteps in two genes responsible for more than 50% of diffuse low-grade gliomas.

Late Effects an Issue Today’s cancer researchers also have to be concerned with enhancing the quality of life for children when treatment ends. “With more

childhood cancer patients surviving into adulthood, there is a growing need to study the late health effects of live-saving treatments,” Dr. Evans said.n

Pediatric Cancer Genome Project Genomic studies have shown researchers that diseases previously thought to be single entities actually include multiple subtypes that often don’t respond to standard treatment. The challenge now is determining the genetic missteps that cause these cancers and finding existing drugs or developing new drugs for targeted treatment. A number of significant discoveries related to these efforts have been made through the Pediatric Cancer Genome Project, a collaboration between St. Jude and Washington University to map the complete normal and cancer genomes of 700 young patients. This effort to understand what drives some of the most aggressive childhood cancers is the largest project of its type. When project data was made available in May 2012, it marked the largestever release of comprehensive human cancer genome data for free access by the global scientific community. The amount of information shared more than doubled the volume of highcoverage, whole-genome data available from all human genome sources combined. “The sequence data represent billions of clues, and the real detective work for researchers is figuring out what they mean for the bigger picture,” Dr. Evans said. “Ultimately, this information provides the foundation for the clinical trials that lead to more effective therapies.”

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The ASCO Post | SEPTEMBER 15, 2013

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Expert’s Corner

The Oncologist as Author: On Guiding Patients Through Cancer A Conversation With Kevin P. Ryan, MD, FACP By Caroline Helwick and afterward, and in a personal way. The book tries to envelop with knowledge the overwhelming sense of loss of control associated with cancer. I also wanted to pass on stories of patients I consider heroes. The project took me more than 4 years to complete. It required me to be introspective, and it was an affair of the heart.

Large Scope Kevin Ryan, MD

hen Tumor Is the Rumor and Cancer Is the Answer is the guidebook to cancer that Kevin P. Ryan, MD, FACP, COL, USAF (ret) wished his patients had during his 30 years of practicing oncology. The book, recently published by AuthorHouse, is an authoritative, inspiring, and even philosophical guide for individuals and families dealing with cancer. It is also the very personal reflection of a man who was not only a clinician—now retired—but who has been a researcher, Air Force colonel, musician, theater reviewer, and Mensa and Intertel member. Living in Fairfield, California, Dr. Ryan, currently focuses on teaching and writing. In a conversation with The ASCO Post, Dr. Ryan described his experience writing the book, and what he believes it offers to patients.

Patient Heroes Let’s start with the obvious question: Why did you write this book? I thought it had to be done. For oncologists, there are always patients who tug at your heart, or your head, or both, and if you admit to that, you want a way to deal with it and to record these experiences. When I looked around, I didn’t see any books like this. There were books on this tumor and that tumor, this therapy and that therapy—all were about different mouse traps. None seemed to take the patient from the anxiety of thinking it might be cancer, to the diagnosis, through treatment,

What does your book offer patients that they cannot get from their oncologist and oncology staff? There is an awful lot involved from diagnosis through treatment, and oncologists don’t have time to address in full detail the many questions their patients may have. Studies show that patients want time with their doctors, they want more psychosocial involvement,

ogy, principles of the various treatment modalities, side effects, alternative and unproven therapies, cutting-edge therapies, medical ethics (which figure into decision-making), and advice to family members on talking with their loved ones about their cancer. Other chapter titles include “Anxiety Versus Fear,” “When You Suspect the Diagnosis,” “Clinical Trials,” “The Problem of Pain,” “Biological Therapy and the Future,” “Spirituality,” “Medico-Legal Aspects of Oncology,” and “Internet”— which should give you an idea of just how wide-ranging the book is. I am also speaking to the oncology team, trying to relay what legions of patients have taught me about what works best in terms of respecting their autonomy, keeping them informed, and quenching their anxiety. I hope

I write in the first-person because this is an intimate conversation. I don’t want to distance myself from the patient by speaking as if it were a referential textbook. I was taught by my patients, and I am speaking back to them about what they taught me. —Kevin Ryan, MD

and they do better when they have it. Oncologists cannot possibly reach out and connect on all these levels with their patients—not that they are averse to this, but they don’t have time. Tell us what you included in your book. The book has a very large scope. It opens by addressing the hit-in-the-gut issues that arise immediately following a cancer diagnosis, and I have tried to give a way of achieving the right mindset for this. I titled the first chapter, “Read the Directions First,” and I include what I call “recipes” for mental and emotional success as patients gird up to weather this storm. I ask patients to “live the good life” and to maintain autonomy, in spite of cancer. Then I have a big overview of oncol-

the book will be useful for speaking to, counseling, and interacting with patients and families.

The Doctor’s Perspective Your book is not only informative about the biology and treatment of cancer, but it also describes the oncologist’s world to the patient. Patients ask us all the time, “How can you deal with cancer every day?” Well, whether oncologists are in institutional, academic, or private practices, I see the same traits in many of them: They are all boxing with God on “the Big C.” Oncologists are good at solving mysteries. We like getting to the answer, we are thrilled to get to the core of life, and with the emphasis on genetics, we are seeing these dreams come to fruition.

We want to win the prize, but we may not always be so good at handholding. That’s not our drive. We are driven by a need to beat what might be unbeatable. We also love systematic analysis of data, and so we are masters of clinical trials. Patients have a right to know who their doctors are and why we want to treat them, so I included this.

Personal Touch You also include stories of cancer survivors who touched your life, and you are a cancer survivor yourself. Obviously, personal stories hold a lot of weight for you. I had very early–stage melanoma a long time ago (I have dysplastic nevi syndrome). There is nothing quite like looking through a microscope with the head of pathology, “reading” your own cancer. It makes you more empathetic with your patients, for sure. My book concludes with a chapter called “Heroes,” which includes stories that are inspirational to patients and everyone involved in their care. I thought we could all learn from these individuals. You also write in a very personal way, using first-person narration, and you sprinkle the text with a good bit of philosophy. That’s somewhat unorthodox for a medical reference book. I had a Jesuit education through college. I suppose that is when I learned to speak about philosophical issues. I do like to “rhapsodize” on all aspects of life and, with regard to the book, I think it adds flavor and personality. I write in the first-person because this is an intimate conversation. I don’t want to distance myself from the patient by speaking as if it were a referential textbook. I was taught by my patients, and I am speaking back to them about what they taught me. If I were to detach myself, I would not be doing service to this relationship. I didn’t want this to be a textbook. It’s a dialogue. n Disclosure: Kevin P. Ryan, MD, is author of When Tumor Is the Rumor and Cancer Is the Answer.

Coming soon

Another option in short-acting G-CSF therapy » FDA approved Brought to you by Teva—a global leader experienced in developing and manufacturing biologics. Teva has a substantial portfolio of more than 50 oncology products in the US.

Learn more at GRANIXhcp.com Indication » GRANIXTM 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. » 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 treatmentemergent 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 Prescribing Information on adjacent page.

The ASCO Post | SEPTEMBER 15, 2013

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Announcements

Genitourinary Cancer Expert Walter M. Stadler, MD, Named Section Chief of Hematology/Oncology at the University of Chicago Medicine

alter M. Stadler, MD, an authority on prostate, kidney, bladder, and testicular cancers, has been named Chief of the Section of

Hematology/Oncology at the University of Chicago Medicine. This position became effective August 15, 2013. Dr. Stadler, the Fred C. Buffet

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 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)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] 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 nonUS-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. 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

Professor of Medicine and Associate Dean for Clinical Research, was selected for his clinical, research, and administrative achievements. He

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. 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 There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the 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 (AUC0-24) 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.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

joined the University of Chicago faculty more than 20 years ago and has served as interim Section Chief since January 2013. He succeeds Richard L. Schilsky, MD, who left in January to become the inaugural Chief Medical Officer for ASCO.

Walter M. Stadler, MD

“Walt Stadler has demonstrated exceptional leadership and thoughtful academic vision for the section,” said Everett Vokes, MD, Chairman of the Department of Medicine at the University of Chicago. “I am grateful for the excellent work that he has done and excited that he has accepted this important role. I look forward to working closely with him to improve the section’s clinical impact while continuing to enhance educational and research activities.”

Many Innovations Dr. Stadler studies innovative treatments for urologic cancers as well as clinical trial design. His work has led to better understanding of the role of several anticancer agents, including sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), and axitinib (Inlyta). He also researches ways to predict which patients will respond to targeted therapies and has helped design trials to evaluate those therapies. Among many innovations, Dr. Stadler collaborated with colleagues Mark Ratain, MD, and Marsha Rosner, PhD, to help develop the “randomized discontinuation trial,” a novel approach that is increasingly used to evaluate promising new drugs. He also helped develop new ways to monitor the effects of antiangiogenic therapy, including the use of dynamic contrast-enhanced MRI. “I’m humbled and honored to be selected for this position,” Dr. Stadler said. n

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Pioneers in Oncology Prominent Surgeon and Teacher LaSalle D. Leffall, Jr, MD, Promotes Hard Work and Education to Overcome Boundaries By Jo Cavallo

on his medical college admission test (MCAT), and was later rejected for admittance to Meharry Medical College. He was, however, accepted to Howard University College of Medicine. “The dean of the medical school at Howard and the admissions committee decided that with my college grades, I should do well in medical school and admitted me,” said Dr. Leffall. That decision proved to be the right one. “I graduated first in my class.” LaSalle Doheny Leffall, Jr, MD, FACS

eminiscing about his 65 years in medicine, LaSalle Doheny Leffall, Jr, MD, FACS, cites three events in his early childhood that would ultimately lead him to his position today as the Charles R. Drew Professor of Surgery at Howard University College of Medicine in Washington, DC. First, he was drawn to the compassion of the profession through the example of a family friend who was the only African American physician in his hometown of Quincy, Florida. In addition, he recalls an encounter with a wounded bird he nursed back to health when he was 9 (“my first patient”). And most important of all, he credits the unbridled encouragement of his parents. Martha and LaSalle Leffall, Sr, both schoolteachers, instilled in their son the belief that any obstacle could be overcome and any goal achieved.

Valued Credo “My father always told me, ‘with a good education and hard work, combined with honesty and integrity, there are no boundaries,’” said Dr. Leffall. “He also said medicine is an honorable profession and that I could help people, be proud of my work, and make a decent living so I could take care of my family. I like that last statement, because he wasn’t saying I could make a lot of money, he was saying I could make enough money to take care of my family.” Born on May 22, 1930, in Tallahassee, Florida, Dr. Leffall was a good student, graduating from high school at just 15, and summa cum laude from Florida A&M University 3 years later, in 1948. Despite graduating with high honors, he admits he did not score well

Breaking the Color Barrier Dr. Leffall’s strong work ethic and belief in the principle of “no boundaries” has carried him through a nearly 6-decade stellar career in surgical oncology—a career that broke the color barrier for others following in his footsteps, and is chronicled in

Americans1—and by 1960 the number of black physicians and surgeons nationwide numbered just 4,706.2 Fifty years later, the news is not that much better, with only 29,717 African Americans practicing medicine,3 4,340 of whom are oncologists.4 Although Dr. Leffall said he rarely encountered overt signs of prejudice or discrimination during his career, he does remember an incident, when he was a resident at Memorial SloanKettering, where a white patient being treated for cervical cancer refused to let him examine her. “The woman said, ‘I can’t let you examine me. I want somebody of my own race to examine me.’ When we made rounds later that afternoon, the attending physician told the patient she was being discharged because she

With ongoing basic and clinical research, we will continue to make progress that could eventually lead to a universal cure for cancer. When that happens, I’ll applaud from Heaven. — LaSalle D. Leffall, Jr, MD, FACS

his autobiography, No Boundaries: A Cancer Surgeon’s Odyssey (Howard University Press, 2006). He became the first African American President of the American Cancer Society in 1978, and the first African American President of the American College of Surgeons in 1995. Dr. Leffall was a protégée of Jack E. White, MD, the first African American to train in surgical oncology at Memorial Sloan-Kettering Cancer Center, and who in the 1950s launched the Tumor Clinic and Cancer Training Center, now the Howard University Cancer Center. In 1957, he would follow the path of his mentor and get his surgical training at Memorial Sloan-Kettering, the third African American to do so.

Civil Rights Struggle The late 1950s was a time of immense upheaval in the struggle for civil rights in the United States. It was also a time in which few African Americans were accepted into medical school. In 1957, only 14 of the 26 medical schools in the South admitted African

refused to be treated by his resident. The woman became so upset, she begged us to help her, which we did, and we later became friends,” he said.

Transcending Boundaries In addition to heeding his parents’ counsel that there would be no boundaries to his success if he worked hard and got a good education, Dr. Leffall’s oncology career has also been strongly influenced by the words of his professor at Howard, Charles R. Drew, MD, a pioneer in blood transfusions, who told him, “Excellence in performance will transcend artificial barriers created by man.” “I believed my parents and I believed Dr. Drew,” said Dr. Leffall. “The barriers Dr. Drew talked about were segregation and discrimination, but he said ‘if you do well enough, I don’t care what your race is, your ethnicity, or your religion, people will notice your hard work and accomplishments.’ And I took that advice to heart.” The writings of physician Sir William Osler also impacted Dr. Leffall’s career. “I read Aequanimitas early in

my career, which gave me my favorite quotation, ‘equanimity under duress,’ a concept emphasizing the importance of calmness and tranquility in confronting our daily problems,” he said.

A Lasting Legacy A surgeon specializing in colorectal, breast, and head and neck cancers, Dr. Leffall recognized early in his career the health disparities in the treatment of African American patients with cancer. During his tenure as President of the American Cancer Society, the organization launched a program focusing on the rise in cancer incidence and mortality rates in minority groups and had a major role in establishing the first conference in cancer health disparities to ensure that all patients receive the best cancer care. Wishing to combine his love of practicing medicine and teaching, in 1962 Dr. Leffall joined the faculty at Howard University College of Medicine, rising through the ranks from Assistant Professor of Surgery to Professor and Chairman of the Department of Surgery in 1970, and serving in that capacity for 25 years. In 1992, he was named the University’s Charles R. Drew Professor, the first endowed chair in the history of Howard’s Department of Surgery. Over the course of his career, Dr. Leffall estimates that he has taught more than 6,000 medical students and helped train more than 280 surgical residents. Although he gave up performing surgery the week before he turned 76 and stopped actively practicing medicine earlier this year, at 83, he has no plans to retire, and still arrives at Howard by 6:00 every morning, ready to teach his medical students and consult with colleagues on difficult cancer cases. When asked to name his greatest professional accomplishments, Dr. Leffall said there are two. The first is the number of new physicians he has sent into the world to treat patients with cancer. “I believe my greatest accomplishment is as a teacher because I will have a lasting effect on thousands of patients. I tell my students, ‘You must treat patients with respect and dignity and always give your best. You continued on page 98

The ASCO Post | SEPTEMBER 15, 2013

PAGE 98

Pioneers in Oncology LaSalle D. Leffall, Jr, MD continued from page 97

won’t be able to cure every patient, but you will be able to help most patients.’” And the second accomplishment he pointed to was being named Chairman of the President’s Cancer Panel from 2002 until 2011. Married to his wife Ruthie for 57

years, the couple has one son, LaSalle III, a lawyer and investment banker. Dr. Leffall is buoyed by the many advances he has seen in the treatment of cancer over his long career, especially in the increasing number of survivors and the attention paid to patients’ quality of life. However, what he really wants is an end to the disease.

Save the Date!

“With ongoing basic and clinical research, we will continue to make progress that could eventually lead to a universal cure for cancer,” he said. “When that happens, I’ll applaud from Heaven.” n References 1. Beardsley EH: A History of Neglect:

np For s a You nd r pa s

Health Care for Blacks and Mill Workers in the Twentieth-Century South. Knoxville, University of Tennessee Press, 1966. 2. U.S. Census of Population, Characteristics of the Population, U.S. Summary, vol 1, pt�1, 1, 1950�� vol 1, part 1, 1960. Washington, DC, U.S. Government Printing Office. 3. Association of American Medical Colleges: Diversity in the Physician Workforce: Facts & Figures 2010. Available at members. aamc.org. Accessed August 24, 2013. 4. Kirkwood MK, Kosty MP, Bajorin DF, et al: Tracking the workforce: The American Society of Clinical Oncology workforce information system. J Oncol Pract 9:3-8, 2013.

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PAGE 99

In the News Issues in Oncology

Tackling Overdiagnosis and Overtreatment, by Words and by Deeds By Charlotte Bath

“T

he complexity of the pathologic condition called cancer,” according to a Viewpoint article in the Journal of the American Medical Association,1 “complicates the goal of early diagnosis.” Failure to recognize that cancers are heterogeneous, and that not all progress to metastases and death, can lead to overdiagnosis and overtreatment. Recognizing the complexity of the disease “provides an opportunity to adapt cancer screening with a focus on identifying and treating those conditions most likely associated with morbidity and mortality.” The authors of the JAMA piece chaired a National Cancer Institute conference held to develop a strategy for improving the current approach to cancer screening and prevention, and they outlined their recommendations in the article. The recommendation that received the most attention in subsequent media coverage—which was considerable and included reports from The New York Times, The Washington Post, PBS, CBS, NBC, CNN, and FOX—concerned changing terminology so that the word “cancer” would be “reserved for describing lesions with a reasonable likelihood of lethal progression if left untreated.”

Reclassify Some Cancers as IDLE “There are 2 opportunities for change,” the authors wrote. “First, premalignant conditions (eg, ductal carcinoma in situ or high-grade prostatic intraepithelial neoplasia) should not be labeled as cancers or neoplasia, nor should the word ‘cancer’ be in the name. Second, molecular diagnostic tools that identify indolent or lowrisk lesions need to be adopted and validated. Another step is to reclassify such cancers as IDLE (indolent lesions of epithelial origin) conditions.” In an interview with The ASCO Post, Ian M. Thompson, Jr, MD, an article coauthor and working group Co-Chair, said that while he anticipated some resistance to the proposal to change cancer terminology, of all the recommendations, it is “probably the simplest to do.” Dr. Thompson noted that he and coauthor Laura J. Esserman, MD, MBA, initially proposed the term IDLE in an editorial published in JAMA in October 2009.2 “By changing our clinical and scientif-

ic priorities to focus on distinguishing indolent from aggressive disease, we can improve the value of screening, reduce morbidity of treatment, and prevent lethal outcomes of cancer,” they wrote. “What we were saying,” Dr. Thompson said, “is what everyone knows is an inherent truism—that there are a lot of indolent tumors, more so in some organ sites than in others, and that by detection of indolent tumors,

at Fred Hutchinson Cancer Research Center in Seattle.

Terminology Matters A study reported recently in JAMA Internal Medicine3 presented evidence that terminology can affect patients’ choice of treatment. In the study, 394 women without a history of breast cancer were presented with three scenarios that described ductal carcinoma in situ (DCIS) as noninvasive breast

We are facing significant challenges in managing a growing older population with limited resources. We can use those resources in a brute force manner ... and completely bankrupt our nation—and, in the process, not help health outcomes. Or we can be much more intelligent … and use those resources for net good. —Ian M. Thompson, Jr, MD

we don’t help our patients.” The working group co-chairs specialize in cancers that figure prominently in the discussion of overdiagnosis and overtreatment. Dr. Thompson is a urologic oncologist and Director of the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio, as well as Chair of the NCI Early Detection Research Network. Dr. Esserman is Director of the Carol

Laura J. Esserman, MD, MBA

Franc Buck Breast Cancer Center, Helen Diller Family Comprehensive Cancer Center, at the University of California, San Francisco. The third coauthor of the JAMA Viewpoint, Brian Reid, MD, PhD, is Director of the Seattle Barrett’s Esophagus Study

cancer, breast lesion, or abnormal cells. They were then asked to choose among three treatment options—surgery, medication, or active surveillance. When DCIS was described as noninvasive cancer, 53% of the study participants favored nonsurgical options, but that rose to 63% when the term used was breast lesion, and 69% when the term used was abnormal cells. “We conclude that the terminology used to describe DCIS has a significant and important impact on patients’ perceptions of treatment alternatives. Health care providers who use ‘cancer’ to describe DCIS must be particularly assiduous in ensuring that patients understand the important distinctions between DCIS and invasive cancer,” the study authors wrote. “That is the real world of this when you include the word ‘cancer,’” Dr. Thompson said. “Because the word ‘cancer’ has a connotation that is profoundly bad.” The word “precancerous” has that same connotation. “That means the shoe is going to drop sometime down the road and that you are irresponsible if you don’t do anything about it,” he continued. “A multidisciplinary effort across the pathology, imaging, surgical, ad-

vocate, and medical communities could be convened by an independent group (eg, the Institute of Medicine) to revise the taxonomy of lesions now called cancer and to create reclassification criteria for IDLE conditions,” the NCI working group stated.

Refocus Screening “Optimal screening frequency depends on the cancer’s growth rate,” the Viewpoint article noted. “If a cancer is fast growing, screening is rarely effective. If a cancer is slow growing but progressive, with a long latency and a precancerous lesion (eg, colonic polyps or cervical intraepithelial neoplasia), screening is ideal and less frequent screening (eg, 10 years for colonoscopy) may be effective. In the case of an indolent tumor, detection is potentially harmful because it can result in overtreatment. These observations provide an opportunity to refocus screening on reducing disease morbidity and mortality and lower the burden of cancer screening and treatments.” One way to refocus screening is to consider the characteristics of the individual patient, Dr. Thompson said. “Do you want to do a screening CT scan on a nonsmoker who is 25 years of age? Probably not.” Factoring in the life expectancy of the patient is also beneficial. “If a person has congestive heart failure, if you’ve looked at the life expectancy table, and the person has a life expectantly of 2 to 3 years, why would you draw a PSA test on that person?” Dr. Thompson asked. Another example involves colorectal cancer screening among the elderly. “That’s a classic example where the benefit, which might be 10 or 15 years down the road, is outweighed by the risks of the intervention,” Dr. Thompson said. “And then what do you do if you find something?”

Molecular Diagnostic Tools Molecular diagnostic tools that can identify indolent or low-risk tumors are now available for “virtually every organ site,” Dr. Thompson said. Some of these molecular diagnostics “are approved and some are ‘home-brew.’ So they are not [U.S. Food and Drug Administration] registered, but you can have them done. There are dozens and dozens of these tools for each of the organ sites, and the continued on page 105

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase

chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Iclusig (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients ™

IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. • Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity. Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusigtreated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver

function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated. Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients.

C H R O N I C P H A S E C M L (C P - C M L ) More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

44%

(144/267)

MCyR 95% CI: 48-60 (118/267)

CCyR 95% CI: 38-50 Most patients who achieved MCyR also achieved CCyR.

Median duration of follow-up was 10 months.1

Efficacy in T315I 70% of CP-CML patients with the T315I mutation (45/64) achieved MCyR (95% CI: 58-81), and 66% (42/64) achieved CCyR (95% CI: 53-77). Iclusig is a 45 mg oral tablet taken once daily with or without food.

Learn more about Iclusig’s efficacy in patients with the T315I mutation and all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Tablet is not shown at actual size. Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning. Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012. Reference: 1. Data on file.

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. 5.5

Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. 1

INDICATIONS AND USAGE

5.6

This indication is based upon response rate [see Clinical Studies (14)]. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig. CONTRAINDICATIONS

5.7

WARNINGS AND PRECAUTIONS

5.1

Thrombosis and Thromboembolism Arterial Thrombosis

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Serious arterial thrombosis occurred in 8% (34/449) of Iclusig-treated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

5.8

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery). Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations. Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

5.9

5.10 Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig. 5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts. The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing. 5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human 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. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)]. 5.3

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

5.4

Hypertension Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients

Myelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

5.2

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

None 5

Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)]. Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

Pancreatitis

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)]

• Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose. Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CPCML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%). Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%). Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 12 0 8 0 9 0 Insomnia 7

Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

N (%) 34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6). Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) 24 51 55 63 Leukopenia (WBC decreased) 14 35 53 63 Anemia (Hgb decreased) 9 26 55 34 Lymphopenia 10 26 37 22 ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

DRUG INTERACTIONS

8.7

Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)]. 7.1

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. 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. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/ day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3

Nursing Mothers It is unknown whether ponatinib 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 ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Renal Impairment

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally selfadministered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234

For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0513/0019/US

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In the News

Overdiagnosis/ Overtreatment continued from page 99

trick is going to be to integrate them into prospective trials for validation.” Using prostate cancer as an example, Dr. Thompson said, “If you select your patients properly for active surveillance—and that’s maybe 30% to 40% of all people diagnosed with prostate cancer—the risk of death in those patients is probably 1% to 2% in 10 to 12 years. The likelihood that any molecular diagnostic test will be able to pull out that 1% or 2% is incredibly low. So the molecular diagnostics need to be linked with current risk factors to determine when you use them. It is not just the molecular diagnostic, but it is the molecular diagnostic and its interaction with the patient and the tumor’s characteristics.”

Observational Registries The NCI working group also called for observational registries for lowmalignant-potential lesions. “Large registries for potentially indolent conditions would provide data linking disease dynamics (eg, tumor growth rate

over time) and diagnostics needed to provide patients and physicians with confidence to select less invasive interventions,” the authors stated. These large registries would be more representative of the entire population than current registries linked to academic centers, Dr. Thompson said. They could also provide information on how people in different parts of the country are responding to new recommendations about indolent cancers.

Not an Easy Undertaking Dr. Esserman told The ASCO Post, “Since there is a growing recognition of the likelihood that we can safely do less, the opportunity, especially with DCIS, where we have always recommended surgical intervention, is to study the impact of doing less and learn for whom less aggressive strategies would be as effective.” The NCI working group concluded, “Policies that prevent or reduce the chance of overdiagnosis and avoid overtreatment are needed, while maintaining those gains by which early detection is a major con-

tributor to decreasing mortality and locally advanced disease.” Now is the right time to do it, Dr. Thompson said, “simply because the science overwhelmingly says: As a nation, we overdetect disease. We are facing really significant challenges in managing a growing older population with limited resources. We can use those resources in a brute force manner without thinking about how we are helping people and completely bankrupt our nation—and, in the process, not help health outcomes. Or we can be much more intelligent, especially given the information that we know today, and use those resources for net good,” he continued. “I think all of us would acknowledge that the process of doing this is not easy and it would require consensus groups getting together,” Dr. Thompson said. “It would require input from patients, as well as healthy members of the community. It would probably need to include people whose lives have been saved by screening and people whose lives have been affected by screening in adverse ways,” Dr. Thompson said.

“So it is a really big undertaking,” Dr. Thompson concluded, but “if we don’t pay attention to the overdiagnosis of indolent cancers, our lives may be profoundly changed, because we are taking very precious resources and putting them into efforts that cause harm and produce no benefit,” he stated. “It will be an expensive undertaking, and it will require an investment in prospective research studies that may not be completed for 20 years, but just because it is hard doesn’t mean that we shouldn’t be doing it.” n

Disclosure: Drs. Thompson and Esserman reported no potential conflicts of interest.

References 1. Esserman LJ, Thompson IM, Reid B: Overdiagnosis and overtreatment in cancer: An opportunity for improvement. JAMA. July 29, 2013 (early release online). 2. Esserman L, Shieh Y, Thompson I: Rethinking screening for breast cancer and prostate cancer. JAMA 302:1685-1692, 2009. 3. Omer ZB, Hwang ES, Esserman LJ, et al: Impact of ductal carcinoma in situ terminology on patient treatment preferences. JAMA Intern Med. August 26, 2013 (early release online).

Expect Questions From Your Patients

“P

hysicians and patients should engage in open discussion” about the complex issues of cancer screening, overdiagnosis, and overtreatment, according to a report from the chairs of a National Cancer Institute working group tasked with developing a strategy to improve the current approach to cancer screening and prevention. Working group Co-Chair Ian M. Thompson, Jr, MD, told The ASCO Post that often when patients hear the terms cancer or malignancy, “the potential for their own mortality strikes them, and all of a sudden it becomes an emotional response instead of an intellectual response.” When that happens, he said, it is important that the patient be presented with precise data about long-term risks and that the physician “engage the patient in a conversation, so that the patient fully understands the risks of taking an aggressive vs a less aggressive approach.” Dr. Thompson, who is a urologic oncologist, said, “A good example is low-grade prostate cancer that is lowvolume. Almost nobody ever dies from

that disease. When the patient fully understands the risk, he may say, ‘You mean to tell me, I don’t have to do anything because not doing anything is just as good as doing something?’ That patient may leave the office having decided not to pursue any treatment. However, the physician should be pre-

nosis and overtreatment could cause concern about missed diagnoses, Dr. Thompson responded, “of course.” He said that he asks himself that question every time he sits down with one of his patients on active surveillance for prostate cancer. “Certainly at the beginning of the

Another challenge is that a lot of these conversations occur in the primary care office. So we have to educate our primary care physicians as well. —Ian M. Thompson, Jr, MD

pared for the patient calling the office after sharing his decision with his family. They might well have responded incredulously, “You have cancer, and the doctor is not going to do anything about it?”

Concern About Missed Diagnoses? Asked if policies and programs intended to reduce the risk of overdiag-

conversation, before they opt for active surveillance, you have a very long discussion with them, and periodically you renew that discussion. As new data become available, you update them on the new data. So you are continuously asking yourself the question about missed diagnoses,” he said. “On the other hand, taking a patient to the operating room for an extraordinarily low-risk tumor—which

is an unusual circumstance for me personally—and putting the patient through the operative risk of that procedure and the potential side effects afterward, to me is a moral and ethical swamp where I don’t want to go,” Dr. Thompson commented. “In the case of the patient who opts for radiotherapy, where we know there may be a 1% to 2% risk of a secondary malignancy from that treatment, while the tumor itself poses less than a 1% risk, you are doing harm,” he continued. “We are always struggling with that possibility, and I think in every oncologic discipline, when you see someone with a potentially lethal tumor and you embark on a treatment, you always ask yourself if the net benefit of the treatment will be greater than the net harm. But the overarching principle underlying all this is, above all, don’t make them worse,” he said. “Another challenge is that a lot of these conversations occur in the primary care office. So we have to educate our primary care physicians as well,” he noted. n

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Awards

California Stem Cell Agency Awards More than $40 Million in New Research Grants, including Funds for Prostate Cancer Research

he California Institute for Regenerative Medicine recently announced approval by the agency’s governing Board, the Independent Citizens Oversight Committee, of $40 million in funding for researchers at 10 institutions as part of its Early Translational IV Research awards. Among the institutions included were Stanford, University of California, Los Angeles, University of California, San

evolve into clinical studies for treating some of the worst diseases we have in the community.” In this “early translation” phase

scientists are expected to do research that will result in the development of S:6.75” a new potential drug or cell therapy or make significant strides toward

such a therapy. The goal is to identify the most promising projects and move those good ideas out of the lab and into the clinic.

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

Robert Reiter, MD

Diego, Human BioMolecular Research Institute, Cedars-Sinai Medical Center, The Gladstone Institutes, SanfordBurnham Medical Research Institute, The Salk Institute, Numerate, Inc. and University of California, Irvine. These new Early Translational IV Research awards focus on turning basic discoveries about stem cells into potential therapies for prostate cancer, heart and liver disease, autism, HIV/ AIDS, and other diseases.

UCLA Recipient Focuses on Prostate Cancer Research Robert Reiter, MD, of the University of California, Los Angeles, was awarded approximately $4 million for research to develop human antibodies that can be used to target prostate cancer cells and to stop them spreading and growing. Other grants were awarded to researchers whose work is focusing on HIV/AIDS, heart disease, Huntington’s disease, amylotropic lateral sclerosis, autism, stroke, muscular dystrophy, hemophilia,�� sickle cell disease, and metabolic disorders.

From Bench to Bedside Alan Trounson, PhD, President of the stem cell agency, said “These awards are moving discoveries into the clinical pipeline for patients. The strategies are focused on problems where we think there is a very reasonable chance that they will

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. IMPORTANT SAFETY INFORMATION WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE • Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo

(3% vs 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs 3% and arterial thromboembolism: 2% vs 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

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Awards

The Board also approved changes to the stem cell agency’s intellectual property regulations that will change revenue sharing provisions to smooth out the payment process for companies that have a successful product. In addition the Board voted

to approve a new program designed to increase engagement between the stem cell agency and industry that will provide tens of millions of dollars in research awards to help move the most promising therapies into clinical trials.S:6.75” “The goal of our work is to do whatever we can to move treatments

out of the lab and into patients,” says Jonathan Thomas, PhD, JD, Chairman of the Independent Citizens Oversight Committee. The California Institute for Regenerative Medicine was established in November 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The

statewide ballot measure, which provided $3 billion in funding for stem cell research at California universities and research institutions, was overwhelmingly approved by voters, and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research. n

PROD

Intellectual Property Regulations

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

median

months

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ED AE/AS AD

4.0

COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, PPES, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

B:11.25”

S:9.75”

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

COMETRIQ.com

DATE

SIGNOFF

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

Disk release

Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

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

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Announcements

CancerCare Co-Payment Assistance Foundation Launches New Technology to Provide Cancer Patients with Same-Day Approval

ancerCare® Co-Payment Assistance Foundation recently announced the launch of its new website and customer relationship manage-

ment software, DiseaseTrak. Along with the implementation of DiseaseTrak, a customer-service platform, the Foundation will now

provide same-day determination and conditional approval. The technology will benefit people coping with cancer by allowing faster access to co-

COMETRIQ™ (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) 1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; reversible posterior leukoencephalopathy syndrome. In Patients with Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia hypocalcemia, fatigue hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving

payment assistance. “This tool will drastically improve patient access to treatment,” said the Foundation’s Director, Michele

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0

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Announcements

McCourt. “The process is easy, fast, and seamless.”

an enhanced level of customer service because the site closely monitors each individual’s unique treatment regimen, dispensing history, and medication usage. The site provides reminder tools and an interactive calendar to assist patients in managing their care. Grants and payments can also be closely tracked.

Real-Time Information Patients will also have real-time insight into their status and eliminate the wait and uncertainty regarding copayment assistance. Both patients and health-care providers will experience

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade All Grade Grades 3-4 Grades 3-4 CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 5 Palmar-plantar erythrodysesthesia syndrome 1

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose 1

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased singledose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be

Affiliated with CancerCare, the CancerCare Co-Payment Assistance Foundation is also able to provide immediate access to the full array of CancerCare’s free support services, including online and telephone counseling, support groups, resource referrals, publications, education, and financial assistance with treatment-

apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

related expenses such as transportation and child care. “We have found that co-payment assistance coupled with a network of professional emotional, and practical support improves quality of care for the patient and their loved ones. Combination of the two is the enhanced value the CancerCare Co-Payment Assistance Foundation brings to the table,” said John Rutigliano, CancerCare Chief Operating Officer. The new CancerCare® Co-Payment Assistance Foundation website will launch simultaneously to ensure easier navigation between it, CancerCare, and the new application system. For more information, visit http:// cancercarecopay.org/. n

Preventing Tobacco Use in Children

he U.S. Preventive Services Task Force recently released its final recommendation statement on primary care interventions to prevent tobacco use in children and adolescents.1 The Task Force recommends that primary care clinicians provide interventions, including education or brief counseling, to prevent initiation of tobacco use among school-aged children and adolescents.

Even Minimal Interventions Effective According to the recommendation statement, “The type and intensity of effective behavioral interventions substantially varied in the evidence review, ranging from no inperson interaction with a health care professional to seven group sessions totaling more than 15 hours. Even very minimal interventions, such as mailing materials to a youth’s home, had substantial effects on reducing smoking initiation.” n Reference 1. Moyer VA, on behalf of U.S. Preventive Services Task Force: Primary care interventions to prevent tobacco use in children and adolescents. Ann Intern Med. August 26, 2013 (early release online).

The ASCO Post | SEPTEMBER 15, 2013

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Letters to the Editor Ibrutinib Controversy

Clinical Trials, Crossover, and Clinical Equipoise

am writing with regard to two articles on the ethical imperative of clinical equipoise written by Susan O’Brien, MD, and Stephen J. Schuster, MD, and published recently in The ASCO Post.1,2 I was a victim of Pharmacyclics’ policies during one of their randomized ibrutinib trials (PCI32765) conducted in 2012. I was diagnosed with chronic lymphocytic leukemia (CLL) in 2002. Following a slow disease progression (CLL with a 13q deletion), I was treated with fludarabine, cyclophosphamide, and rituximab (Rituxan) during 2008 under the direction and protocol of physicians at The University of Texas MD Anderson Cancer Center in Houston, and Lehigh Valley Hospital in Allentown, Pennsylvania. I achieved complete remission, which lasted for approximately 3 years until October 2011, when my CLL returned with a more aggressive form (17p deletion and p53 inactivation). At that point, I started my research again to determine the latest and greatest treatment developments and options for patients with CLL. With information and guidance from a number of experts in the field, I decided to enroll in a Pharmacyclicssponsored ibrutinib trial. I initially qualified for a phase III randomized trial of

ibrutinib vs ofatumumab (Arzerra) with John Byrd, MD, at Ohio State University, but finally entered the trial with Dr. Schuster at the University of Pennsylvania (UPenn). At UPenn, I was assigned to the ofatumumab arm of the trial. I received 8 weekly ofatumumab infusions during August/September 2012. The ofatumumab treatment did not work, and I was left with a packed bone marrow,

The FDA and the biopharmaceutical drug companies cannot simply turn a blind eye to clinical trial patients who will otherwise die without the compassionate use of the most promising treatments and cures for cancer. multiple swollen lymph nodes, increasing cancerous lymphocytes, declining platelets, anemia, and neutropenia. I had become transfusion-dependent. Understanding my dire condition, I contacted Pharmacyclics to request a crossover to ibrutinib, which at that point was showing extremely favorable results for the effective management of CLL with a significant remission rate. Pharmacyclics denied my request and further excluded me from participating in any other ibrutinib trials because I was already a “data point” in one of their trials.

Clinical Trials, Crossover, and Clinical Equipoise

n a previous issue of The ASCO Post, Dr. Susan O’Brien wrote, “It is my understanding that the FDA strongly opposed allowing crossover [in the RESONATE trial]. I presume that is because the FDA also wants to see if there is a survival advantage.”1 The lack of crossover seems a valid concern to me in light of the “breakthrough designation” for ibrutinib and the fact that patients in the study drug arm can cross over on progression to receive the comparator, ofatumumab (Arzerra)—or any approved drug—by coming off study.

The actual response from the now former Chief Medical Officer of Pharmacyclics, Inc, was, “We agreed that we would follow all patients enrolled in the PCYC-1112-CA (RESONATE) trial for several important endpoints, and one of these is overall survival. This means we cannot allow patients who are randomized to receive ofatumumab on the trial to receive ibrutinib.” In effect, Pharmacyclics told me

It is my understanding that only the drug sponsor can explain the reason for not allowing the participants to cross over to receive their drug, and that the FDA, by regulation, cannot disclose anything about the deliberations, assuming this is a registered trial. n —Karl Schwartz Patient Advocate President, Patients Against Lymphoma Reference 1. O’Brien S: Ibrutinib CLL trial: Where is the equipoise? The ASCO Post 4(7):1, May 1, 2013.

that they had their data point from me and even if I died to achieve their “endpoint,” it was not their concern. In fact, a “dead” data point on ofatumumab furthered their case for fast-track FDA approval. Pharmacyclics cited FDA regulations as the reason for their position on “compassionate use” for dying trial participants. I contacted the FDA specifically to ask about their strict regulations on the Pharmacyclics ibrutinib trials. The FDA told me that the decision to restrict and exclude access to

ibrutinib for their clinical trial participants was entirely up to Pharmacyclics’ management. Something must be done for the ethical treatment of humans in an investigational environment. The FDA and the biopharmaceutical drug companies cannot simply turn a blind eye to clinical trial patients who will otherwise die without the compassionate use of the most promising treatments and cures for cancer. Survival on transfusions and/or bone marrow transplant seemed to be my only options following my Pharmacyclics trial on ofatumumab. Fortunately, due to the incredible research led by Carl June, MD, and the professional medical team at UPenn, I underwent CART19 T-cell therapy from February to April 2013, and I am now in complete remission and back to living my life. n —Bob Levis Allentown, Pennsylvania See related letters on page 111. References 1. O’Brien S: Ibrutinib CLL trial: Where is the equipoise? The ASCO Post 4(7):1, May 1, 2013. 2. Schuster SJ: The ethical imperative of clinical equipoise. The ASCO Post 4(7):25, May 1, 2013.

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 Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

Editors’ Note: The letters on pages 110-111 refer to articles published in the May 1, 2013, issue of The ASCO Post. To view these articles, visit www.ASCOPost.com or scan the QR code at right.

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Letters to the Editor

Pharmacyclics’ Reply

e acknowledge the letters submitted to The ASCO Post from a patient advocate and a chronic lymphocytic leukemia (CLL) patient enrolled on the RESONATE study (PCYC-1112-CA). At Pharmacyclics, we are committed to adhering to high scientific and ethical standards as we strive to develop novel therapies that help patients with unmet medical needs. RESONATE was the first randomized study in the ibrutinib clinical program. Prior to any patient receiving treatment on this clinical trial, the PCYC-1112 protocol was reviewed and approved by health-care authorities, ethics committees, institutional review boards, and signed off by the principal investigator at each clinical site. RESONATE was designed with guidance from health authorities and advisors to evaluate the potential benefit of ibrutinib in comparison with an appropriate control, ofatumumab (Arzerra), in relapsed or refractory CLL patients for global registration. Al-

though crossover was not a procedure in the original PCYC-1112 protocol, in December 2012, Pharmacyclics (as the sponsor of the study) released an amendment that would provide access to ibrutinib for patients randomized to ofatumumab once (and if) the favorable benefit-to-risk ratio of ibrutinib

Based on these mature data and with the recommendation of our Steering Committee, we have since approached global health-care authorities and the independent Data Monitoring Committee (DMC) with a plan to allow for earlier access to ibrutinib for patients who were randomly assigned to

On August 8, 2013, we released an amendment to the RESONATE study that allows crossover to ibrutinib treatment for patients who have shown disease progression on ofatumumab. over the control group has been demonstrated and following discussion and agreement with the health authority around the critical issues of patient safety and efficacy.

Protocol Update Since that time, additional phase I/II data have emerged and the durability of response to ibrutinib for CLL patients is now better understood.

the control arm than was previously planned. Discussions with the Food and Drug Administration confirmed that the agency supports crossing ofatumumab treated patients on PCYC1112 to ibrutinib treatment once disease progression has been confirmed by the Independent Review Committee (IRC), a process that will preserve the primary endpoint of IRC-

assessed progression-free survival. It is our fervent hope and goal that the results of the trial demonstrate sufficient patient benefit such that global regulatory authorities consider ibrutinib worthy of a defined label. On August 8, 2013, we released an amendment to the RESONATE study that allows crossover to ibrutinib treatment for patients who have shown disease progression on ofatumumab. Pharmacyclics maintains its relentless focus on bringing worldwide access to ibrutinib for patients who may receive benefit from this drug. For CLL patients on the control arm of PCYC-1112, we have worked continuously and tirelessly to implement this important study design change. We know full well that patients are waiting. We at Pharmacyclics feel it is both an honor and obligation to reach patients in need as soon as possible. n —Danelle James, MD, MS Senior Medical Director, Pharmacyclics —Jesse McGreivy, MD Chief Medical Officer, Pharmacyclics

FDA on CLL Drug Approval and Expanded Access

he ASCO Post article, “Ibrutinib CLL Trial: Where is the Equipoise?” published in May 2013, inaccurately conveyed that the Food and Drug Administration (FDA) requires an improvement in overall survival for chronic lymphocytic leukemia (CLL) drug approval and opposes allowing crossover in the RESONATE trial. To the contrary, the FDA recognizes the needs of patients with cancer and encourages drug companies to provide earlier patient access to promising therapies. The FDA understands the challenges of showing an overall survival improvement in CLL, given the long natural history of the disease and availability of multiple therapies. Therefore, while we may request drug companies to collect overall survival data to ensure there is no detrimental effect on overall survival and to observe any potential improvement, an improvement in overall survival is not necessary for approval in CLL. Recent FDA approvals for a CLL indication (bendamustine [Treanda] and rituximab [Rituxan]) were based on improvements in progression-free survival

together with a favorable benefit-risk profile. Crossover at the time of disease progression is acceptable to the FDA in these settings since the interpretation of progression-free survival would not be confounded by crossover. The 2013 approvals of dabrafenib (Tafinlar) and trametinib (Mekinist) in metastatic melanoma and the supplemental approval of erlotinib (Tarceva) in non–small cell lung cancer are additional examples of approvals based on progression-free survival where crossover was allowed at the time of progression.

Expanded Access Patients with cancer frequently have exhausted currently approved drugs and are willing to try investigational drugs that have not been approved by the FDA. In 1987, the FDA formally established rules that allow patients with serious or immediately life-threatening diseases access to investigational drugs outside of clinical trials for treatment use. This process is called expanded access. In 2009, the FDA revised its expanded access regulations by clarifying and broadening

these rules for both single-patient and larger-population access to investigational drugs. The FDA has encouraged drug companies to allow earlier patient access to promising therapies, such as ibrutinib, through the use of expanded access. However, drug companies must agree to provide these drugs to patients. The FDA cannot require a drug company to provide access to an investigational drug. In the past, FDA oncologists have agreed with patients and their physicians that an investigational drug could be used, only to find later that a company is unwilling to provide the drug. We recommend that drug companies, including those with drugs that have received a breakthrough therapy designation, provide clear and timely guidance on plans for expanded access, including specifying if and when access programs will be available after encouraging results are publicly announced. For companies that are unable or have decided not to offer expanded access programs, we recommend they publicly provide the rationale for the decision.

Coordination With ASCO The FDA has coordinated educational efforts with ASCO to inform health-care professionals and patients about expanded access programs. This includes providing information regarding appropriate patients for these programs and procedures to obtain expanded access to investigational drugs. These resources are available on the FDA and ASCO websites. As a next step, we recommend that ASCO develop a policy on the timely disclosure of information on expanded access programs when promising results are made public at ASCO meetings or in publications. This will provide clarity and transparency to patients and practicing oncologists. n —R. Angelo de Claro, MD, Edvardas Kaminskas, MD, Ann Farrell, MD, and Richard Pazdur, MD Office of Hematology and Oncology Products Center for Drug Evaluation and Research U.S. Food and Drug Administration

ADVERTISEMENT According to the CAP/IASLC/AMP Molecular Testing Guideline, EGFR and ALK testing is recommended for lung adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade in the setting of lung cancer resection specimens. In cases of limited specimen size (biopsies, cytology) where an adenocarcinoma component is not evident but cannot be ruled out, clinical criteria (e.g., young age, lack of smoking history) may be used to select patients for testing. However, patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics.4-6

THORACIC ONCOLOGY UPDATE:

New Molecular Testing Guideline for Non-small Cell Lung Cancer Patients The increasing momentum toward molecularly based classification and treatment of non-small cell lung cancer (NSCLC) is driven by our enhanced understanding of the molecular pathways involved in lung cancer pathogenesis, and of the proliferation and survival of cancer cells.1,2 This has given rise to important challenges in establishing and implementing standards: What biomarkers should we test for? Which patients should be tested? When is testing appropriate?

Guideline for Molecular Testing in NSCLC Last year, the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommended that all advanced or metastatic NSCLC that is determined by histology to be nonsquamous or NOS undergo biomarker testing for EGFR mutation and ALK gene rearrangement. These guidelines were recently updated to recommend EGFR and ALK testing in patients with squamous cell carcinoma if they never smoked and if small biopsy specimens were used to assess histology.3 And now a new guideline from the College of American Pathologists,