TAP Vol 4 Issue 4 by Harborside Press LLC

Lisa M. DeAngelis on Neuro-oncology

| Beta-blockers and Lung Cancer Survival

| Late Effects of Treatment

VOLUME 4, ISSUE 4

MARCH 1, 2013

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

ASCOPost.com

Gastrointestinal Cancers Symposium

FOLFOXIRI Plus Bevacizumab Is Superior to FOLFIRI Plus Bevacizumab in Metastatic Colorectal Cancer

On Radiation and Cancer Risk

By Caroline Helwick

or the treatment of metastatic colorectal cancer, better outcomes were achieved when bevacizumab (Avastin) was added to FOLFOXIRI (leucovorin, fluorouracil [5-FU], oxaliplatin, irinotecan), rather than FOLFIRI (leucovorin, Fotios Loupakis, MD, PhD 5-FU, irinotecan), in the phase�� III TRIBE trial conducted at 35 Italian centers and reported at the 2013 Gastrointestinal Cancers Symposium by Fotios Loupakis, MD, PhD, an oncologist at the Istituto Toscano Tumori in Pisa, Italy. “The trial achieved its objective of confirming the superiority of FOLFOXIRI vs FOLFIRI in terms of progression-free survival, also in combination with

bevacizumab,” Dr. Loupakis said. “FOLFOXIRI plus bevacizumab compared to FOLFIRI plus bevacizumab moderately increases specific side effects, but the overall safety profile is acceptable.”

By Robert Peter Gale, MD, PhD, Eric Lax, and F. Owen Hoffman

See Page 36

Study Background Dr. Loupakis noted that first-line FOLFOXIRI has demonstrated superior activity and efficacy compared to FOLFIRI in a previous phase III trial, while at the same time other studies showed that the addition of bevacizumab to first-line doublets improves outcomes. A phase II study of FOLFOXIRI plus bevacizumab, furthermore, showed promising activity and manageable toxicities. The present Italian trial compared FOLFOXIRI/ bevacizumab to FOLFIRI/bevacizumab as first-line

continued on page 54

continued on page 8

Adolescent and Young Adult Oncology

Study Finds Young Cancer Survivors Often Skip Checkups

High health-care costs discourage follow-up, jeopardizing early detection of late treatment effects and cancer recurrence. By Jo Cavallo

e owe our life to radiation. The universe was created in a thermonuclear explosion, and continued existence of life on Earth depends on plants using chlorophyll to capture light energy emitted by the sun (and exploding supernovas) and converting it into chemical energy, with the subsequent conversion of carbon dioxide and water to oxygen and sugar. Röntgen’s discovery of x-rays in 1895 substantially changed this equation. It was now possible to see things within the living body, but at what cost? It is difficult to overestimate the transforming effect of the discovery of x-rays on human health. Illnesses could be quickly and noninDr. Gale is Visiting Professor in the Section of Haematology, Division of Experimental Medicine, Department of Medicine, Imperial College, London. Mr. Lax is a writer in Los Angeles. Their book, Radiation: What It Is, What You Need to Know, was published January 2013 by Alfred A. Knopf. Mr. Hoffman is President of SENES Oak Ridge, Inc, and an expert in radiation risk assessment.

MORE IN THIS ISSUE

lthough the majority of the more than 69,000 adolescents and young adults (AYAs) diagnosed with cancer each year will survive their disease, many of them will experience interruptions in their education and a derailment in their career tract, curtailing their lifetime earning potential and reducing their

access to health insurance. It is the lack of affordable health insurance and the inability to cover out-of-pocket costs associated with routine care that are keeping adolescents and young adults from seeking follow-up care once their cancer is in remission. This is according to a recent study by Anne C. Kirchoff, PhD, MPH, Assistant Professor of Pediatrics at the University of Unfortunately, there is a lack of Utah School of Medicine; Investigator at the Huntsawareness by young adult survivors man Cancer Institute in of the problems that can emerge over the Cancer Control and Population Sciences Retime, so they may not realize that they search Program; and lead need to get in to see their doctor and author of the study published with colleagues rehave that coordinated care. cently in Cancer.1 —Anne C. Kirchoff, PhD, MPH

Oncology Meetings Coverage Gastrointestinal Cancers Symposium �� 3 San Antonio Breast Cancer Symposium �� 15, 16, 18 ASH Annual Meeting �� 27, 32 FDA Update �� 2, 52 Direct from ASCO �� 23-26 Bevacizumab in Colorectal Cancer: Expanded Indications �� 38

continued on page 36

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A Harborside Press® Publication

The ASCO Post | MARCH 1, 2013

PAGE 2

FDA Update Hematology

FDA Approves Pomalidomide for Advanced Multiple Myeloma Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Associate Editors Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

E. David Crawford, MD University of Colorado

International Editors

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

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

George D. Demetri, MD Dana-Farber Cancer Institute

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

Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bishoy Morris Faltas, MD Weill Cornell Medical College John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

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

he FDA approved pomalidomide (Pomalyst) an oral immunomodulatory agent, to treat patients with multiple myeloma whose disease progressed after being treated with other cancer drugs. Pomalidomide is intended for patients who have received at least two prior therapies, including lenalidomide (Revlimid) and bortezomib (Velcade), and whose disease did not respond to treatment and progressed within 60 days of the last treatment (relapsed and refractory). “Pomalidomide is the third drug in a class of immunomodulatory agents that includes lenalidomide and thalidomide [Thalomid], and is the second drug approved in the past year to treat multiple myeloma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “Treatment for multiple myeloma is tailored to meet individual patient’s needs, and today’s approval provides an additional treatment option for patients who have not responded to other drugs.”

Accelerated Approval In July 2012, FDA approved carfilzomib (Kyprolis) to treat multiple myeloma. Similar to carfilzomib, pomalidomide is being approved under the agency’s accelerated approval program, which provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use. The therapy was also granted orphan product designation because it is intended to treat a rare disease or condition. Pomalidomide’s safety and effectiveness was evaluated in a clinical trial of 221 patients with relapsed or refractory multiple myeloma. The trial was designed to measure the number of patients whose cancer completely or partially disappeared after treatment (objective response rate). Patients were randomly assigned to receive pomalidomide alone or pomalidomide with low-dose dexamethasone. Results showed 7.4% of patients treated with pomalidomide alone achieved objective response rate. The median duration of response has not continued on page 9

Jacek Jassem, MD Medical University of Gdansk, Poland 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 Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

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Contributing Writers: Charlotte Bath, Jo Cavallo, 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.

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $259; Individual International: $499; Institutional Domestic: $319; Institutional International $559. Contact subscriptions@harborsidepress.com. Correspondence: Address general inquiries to Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

ASCOPost.com | MARCH 1, 2013

PAGE 3

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Outcomes Comparable for Panitumumab and Bevacizumab in Metastatic Colorectal Cancer By Caroline Helwick

n patients with KRAS wild-type metastatic colorectal cancer, outcomes were comparable whether patients received the epidermal growth factor receptor (EGFR) inhibitor panitumumab (Vectibix) or the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin). This was shown both in the first-line and second-line settings, in randomized phase II studies presented at the 2013 Gastrointestinal Cancers Symposium. While bevacizumab is FDA-approved for the first-line treatment of patients with metastatic colorectal cancer in conjunction with a fluorouracil (5-FU)–based regimen or FOLFOX (leucovorin, 5-FU, oxaliplatin)/FOLFIRI (leucovorin, 5-FU, irinotecan), panitumumab is indicated as a monotherapy for the treatment of EGFRexpressing metastatic colorectal cancer with disease progression on or following FOLFOX/FOLFIRI regimens. In the European Union, panitumumab is indicated for wild-type KRAS metastatic colorectal cancer in the first- and second-line settings with FOLFOX and FOLFIRI, respectively, or in third-line treatment as a monotherapy. The phase�� II PEAK study compared the drugs in 285 treatment-naive patients with metastatic unresectable KRAS wild-type colorectal cancer, in conjunction with modified FOLFOX6.1 The phase II SPIRITT trial evaluated both drugs paired with FOLFIRI for the second-line treatment of 182 patients with KRAS wild-type disease previously treated with bevacizumab.2 Both were labeled “estimation studies” and were not formal, hypothesis-testing trials. The senior author for both investigations was William Go, MD, PhD, Clinical Research Senior Medical Scientist in Hematology-Oncology at Amgen, Thousand Oaks, California. “To our knowledge, the PEAK study is the first prospective trial comparing an anti-EGFR agent to bevacizumab in combination with an oxaliplatin-based regimen in KRAS wild-type patients with treatmentnaive advanced colorectal cancer,” said Lee S. Schwartzberg, MD, Senior

Lee S. Schwartzberg, MD

Partner and Medical Director of The West Clinic in Memphis.

Key Data Median progression-free survival was 10.9 months with panitumumab and 10.1 months with bevacizumab (HR = 0.87; P = .35). Median overall

survival has not been reached with panitumumab and was 25.4 months with bevacizumab (HR = 0.72; P = 0.14). The overall response rates were 58% and 54%, and the resection rates were 13% and 11% for panitumumab and bevacizumab, respectively. Treatment exposure to the individual agents and number of cycles received were the same between the arms. In the subgroup analysis of treatment hazard ratios (HR), no clear differences were observed, although there was a suggestion that progression-free survival may be better with panitumumab among patients with three or more metastatic sites (HR = 0.52). For overall survival, patients who were young, with a high tumor bur-

den and with high levels of lactate dehydrogenase—which often cluster together, he said—appeared to fare better with panitumumab as well, though these are hypothesis-generating observations only, according to Dr. Schwartzberg. The safety profile in both treatment arms was similar to previous studies, and the treatment discontinuation rates due to adverse events were similar between the arms: 24% with panitumumab and 27% with bevacizumab. Grade 3/4 adverse events occurred in 86% and 76%, respectively. “Based on these findings, I am very comfortable treating a KRAS wild-type patient with panitumumab first-line with FOLFOX,” Dr. Schwartzberg said. continued on page 8

EXPERT POINT OF VIEW

wo gastrointestinal cancer experts commented on the findings in interviews with The ASCO Post. Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, Minnesota, noted, “The PEAK and SPIRITT trial were decently designed, decently powered randomized phase II trials, and the results are surprisingly Axel Grothey, MD similar to what we expected. The data are interesting, and they suggest there is probably not a real difference between panitumumab [Vectibix] and bevacizumab [Avastin] in patients with KRAS wild-type disease. The definitive answers will come from phase III trials.” He said he would select the drugs based on patient profiles. Eric Van Cutsem, MD, PhD, Professor at the University of Leuven in Belgium and Head of Digestive Oncology at University Hospital Gasthuisberg, added a note of caution. “Though these are important studies, they are randomized phase II trials and therefore not practice-changing.” The two studies showed the drugs to be comparable “quantitatively,” he said, “but the benefit of each drug may be different for different patients. Some will benefit from panitumumab and some from bevacizumab. At this point, we have no way of selecting those patients. Biomarkers [also under investigation in these studies] will help us do that.” He proposed that the EGFR ligands amphiregulin and epiregulin, and potentially BRAF and NRAS expression, may someday help identify patients best treated with EGFR inhibitors. “And patients who have low expression of

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

these ligands or mutants for different genes may be better off with bevacizumab in this setting,” he suggested.

Drug Sequence Important The sequence in which the two agents are applied is also important, he added. “We have data showing that bevacizumab is more active in early lines of treatment, and this is how I use it in most patients, but there are exceptions,” Dr. Van Cutsem said. “In KRAS wild-type patients where we want to go for a response and render the patient resectable, an anti-EGFR antibody usually gives a higher response upfront, though this was not seen in the PEAK trial.” Eric Van Cutsem, MD, PhD Dr. Van Cutsem elaborated on Dr. Grothey’s reference to the phase III comparisons and said they should be very informative as to the optimal use of the antiEGFR and anti-VEGF agents in colorectal cancer. The GermanAustrian FIRE trial has enrolled more than 900 patients for the comparison of cetuximab (Erbitux) and bevacizumab; results are expected at the 2013 ASCO Annual Meeting. The Cancer and Leukemia Group B (CALGB) is also comparing cetuximab and bevacizumab first-line, with overall survival as the primary endpoint, he said. In addition, he looks forward to seeing results of the biomarker analyses from the current phase II trials. n Disclosure: Dr. Grothey reported no potential conflicts of interest. Dr. Van Cutsem has received research funding paid to his institution by Amgen, Merck Serono, and Roche.

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.

NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated

with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

I N T R O D U C I N G More than 20,000 patients with mCRPC have received ZYTIGA® (post-chemotherapy with docetaxel) to date.†1

MECHANISM OF ACTION ZYTIGA® is a CYP17 (17 -hydroxylase/C17, 20-lyase) inhibitor that inhibits androgen production at 3 sources: the testes, adrenal glands, and the prostate tumor tissue itself.

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.* Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy containing docetaxel.*

ZytigaOne™ is your single source for personalized access services for you and your patients: Visit www.zytigaone.com or call 1-855-998-4421. *Study Designs: ZYTIGA®, in combination with prednisone, was evaluated in 2 Phase 3, randomized, double-blind, placebo-controlled, multicenter trials in patients with mCRPC. Study 1 enrolled patients who received prior chemotherapy containing docetaxel (N = 1,195), whereas Study 2 enrolled patients who had not received prior chemotherapy (N = 1,088). In both studies, patients were using a luteinizing hormone-releasing hormone agonist or were previously treated with orchiectomy. In the active treatment arms, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the control arms, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In Study 1, the primary efficacy endpoint was overall survival. In Study 2, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. † Estimate based on sales and use data from May 2011 to November 2012. Reference: 1. Data on file. Janssen Biotech, Inc.

www.zytigahcp.com Please see adjacent pages for brief summary of full Prescribing Information.

K08Z121176

Adverse Reactions—The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 12/12 08Z12264B

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castrationresistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot ﬂush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) Grade 3-4 All Grades1 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

7.6

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse

events graded according to CTCAE version 3.0 terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 2 Includes 3 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Laboratory Abnormality Hypertriglyceridemia High AST Hypokalemia Hypophosphatemia High ALT High Total Bilirubin

Abiraterone (N=791) All Grades Grade 3-4 (%) (%) 62.5 0.4 30.6 2.1 28.3 5.3 23.8 7.2 11.1 1.4 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Prednisone (N=542) Grade 3-4 System/Organ Class All Grades1 Adverse reaction % % General disorders Fatigue 39.1 2.2 Edema2 25.1 0.4 Pyrexia 8.7 0.6 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 Groin pain 6.6 0.4 Gastrointestinal disorders Constipation 23.1 0.4 Diarrhea 21.6 0.9 Dyspepsia 11.1 0.0 Vascular disorders Hot ﬂush 22.3 0.2 Hypertension 21.6 3.9 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 Dyspnea 11.8 2.4 Psychiatric disorders Insomnia 13.5 0.2 Injury, poisoning and procedural complications Contusion 13.3 0.0 Falls 5.9 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 Nasopharyngitis 10.7 0.0 Renal and urinary disorders Hematuria 10.3 1.3 Skin and subcutaneous tissue disorders Rash 8.1 0.0 1 Adverse

events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Placebo with Prednisone (N=540) All Grades Grade 3-4 % % 34.3 20.7 5.9

1.7 1.1 0.2

25.2 4.1

2.0 0.7

19.1 17.8 5.0

0.6 0.9 0.2

18.1 13.1

0.0 3.0

13.5 9.6

0.2 0.9

11.3

0.0

9.1 3.3

0.0 0.0

8.0 8.1

0.0 0.0

5.6

0.6

3.7

0.0

ZYTIGA® (abiraterone acetate) Tablets

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Storage and Handling: Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 30oC (59oF to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations].

Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Laboratory Abnormality Hematology Lymphopenia Chemistry Hyperglycemia1 High ALT High AST Hypernatremia Hypokalemia 1Based

Abiraterone (N = 542) Grade 1-4 Grade 3-4 % %

Placebo (N = 540) Grade 1-4 Grade 3-4 % %

38.2

8.7

31.7

7.4

56.6 41.9 37.3 32.8 17.2

6.5 6.1 3.1 0.4 2.8

50.9 29.1 28.7 25.0 10.2

5.2 0.7 1.1 0.2 1.7

on non-fasting blood draws

Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: December 2012 2000005445 K08Z121174A

The ASCO Post | MARCH 1, 2013

PAGE 8

Gastrointestinal Cancers Symposium Panitumumab and Bevacizumab continued from page 3

Same Conclusion in Second-line Study The drugs also were comparable in the second-line setting, reported J. Randolph Hecht, MD, Professor of Medicine and Director of the UCLA Gastrointestinal Oncology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles. He presented the results of the SPIRITT trial, which enrolled 182 patients with KRAS wild-type colorectal cancer who had previously received bevacizumab and oxaliplatin-based treatment but no prior irinotecan or anti-EGFR therapy. The biologics were given along with FOLFIRI. Median progression-free survival was 7.7 months with panitumumab and 9.2 months with bevacizumab (HR = 1.01). Median overall survival was 18.0 and 21.4 months, respectively (HR = 1.06), Dr. Hecht reported. Median progression-free survival and overall survival were both higher than was found in previous secondline treatment studies of these agents, he noted.

Bevacizumab plus FOLFOXIRI continued from page 1

treatment in 508 patients with unresectable metastatic colorectal cancer. The vast majority of the population had synchronous metastases and had more than one metastatic site (liver only was just about 20% in the two arms). Patients were randomly assigned to bevacizumab at 5 mg/kg plus either FOLFIRI or FOLFOXIRI.

Key Results At a median follow-up of 26.6 months, FOLFOXIRI/bevacizumab reduced the risk of progression by 27% (P = .0012), a benefit consistently seen across all subgroups. Median progression-free survival was 12.2 vs 9.7 months. The combination also increased response rate from 53% to 65% (P = .005). Cycles were delayed in

J. Randolph Hecht, MD

Twice as many bevacizumabtreated patients received subsequent anti-EGFR treatment vs panitumumab-treated patients (54% vs 26%). Subsequent anti-VEGF therapy was received by 20% of the panitumumab arm and 24% of the bevacizumab arm.

Treatment Considerations Response rates were higher with

panitumumab/FOLFIRI vs bevacizumab/FOLFIRI: 32% vs 19%. This difference, along with the difference in toxicity, can be used to guide treatment decisions, according to Dr. Hecht. “These drugs are both reasonable options,” he commented. “Off study, my decision to use one or the other partly depends on the patient’s need to achieve a response. If the patient has a large tumor burden and is progressing rapidly, this is where I might use panitumumab. On the other hand, if I am concerned about skin toxicity, I may use bevacizumab.” More toxicity attributed to known side effects of anti-EGFRs (skin toxicity, hypomagnesemia) was noted for panitumumab in the SPIRITT trial—30% of patients had skin toxicity

Panitumumab vs Bevacizumab in Metastatic Colorectal Cancer ■■ Two randomized phase II trials compared panitumumab and bevacizumab in patients with KRAS wild-type metastatic colorectal cancer.

■■ No significant differences were shown in progression-free or overall survival. ■■ Phase III studies are underway to more clearly define the relative efficacy of these agents.

16% of the FOLFOXIRI group and 6% of the FOLFIRI arm, and there were slightly more dose reductions, “but these did not compromise the overall dose intensity of the treatment plan,” he noted. The combination was, however, associated with more grade 3/4 diarrhea (19% vs 11%, P = .012), stomatitis =� �� .048), �� and neutrope(9% vs 4%, P �� nia (50% vs 20%, P < .001), but not febrile neutropenia, serious adverse events, treatment-related deaths, or early deaths. Serious adverse events were reported by approximately 20% in each arm. Analyses of secondary resections, postprogression treatment, overall survival, and biomarkers are ongoing.

of at least grade 3. The worst of grade 3/4 adverse events were recorded for 78% of the panitumumab arm vs 65% of the bevacizumab arm, which did not appear to impact discontinuation rates (29% vs 25% rates of discontinuation due to adverse events, respectively). n

Disclosure: Dr. Schwartzberg has served as a consultant or advisor for Amgen. Dr. Hecht has received research funding from Amgen. Dr. Go is in a leadership position at and owns stock in Amgen.

References 1. Schwartzberg LS, Rivera F, Karthaus M, et al: PEAK (study 20070509): A randomized phase II study of mFOLFOX6 with either panitumumab or bevacizumab as first-line treatment in patients with unresectable wild-type KRAS metastatic colorectal cancer. 2013 Gastrointestinal Cancers Symposium. Abstract 446. Presented January 26, 2013. 2. Hecht JR, Cohn A, Dakhil S, et al: SPIRITT (study 2006014): A randomized phase II study of FOLFIRI with either panitumumab or bevacizumab as secondline treatment in patients with wild-type KRAS metastatic colorectal cancer. 2013 Gastrointestinal Cancers Symposium. Abstract 454. Presented January 26, 2013.

EXPERT POINT OF VIEW

ordan D. Berlin, MD, Ingram Professor of Cancer Research and Clinical Director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center, Nashville, commented on the findings of TRIBE. “This study is outstanding, and while we don’t have overall survival data yet the findings suggest that we can very well use FOLFOXIRI with bevacizumab,” Dr. Berlin said. “Particularly interesting though not surprising is the finding that throwing all the drugs into the mix at once does increase the Jordan D. Berlin, MD response rate. We therefore hope that this regimen would be useful prior to hepatic resection, to increase the possibility of resection for patients who are not quite there yet. While the findings do not yet change the standard of care, they give us more leeway in how we look at these patients and more options for individualizing their treatment.” n Disclosure: Dr. Berlin reported no potential conflicts of interest.

Conclusions “Based on these results, we believe that FOLFOXIRI plus bevacizumab

FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer ■■ As a backbone for the addition of bevacizumab in first-line metastatic

colorectal cancer, FOLFOXIRI was superior to FOLFIRI in the phase III Italian TRIBE study.

■■ FOLFOXIRI/bevacizumab reduced the risk of progression by 27%, vs FOLFIRI/bevacizumab.

■■ Median progression-free survival was 12.2 months, vs 9.7 months, respectively.

may represent a new option for the treatment of patients with metastatic colorectal cancer. We don’t think this is for all patients, but especially for patients selected according to the eligibility criteria of this study,” Dr. Loupakis said. “Obviously, it will be important to see the overall survival data and the data in light of second-line treatments [an ongoing analysis],” Dr. Loupakis added. n

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

Reference 1. Loupakis F, Cremonlini C, Masi G et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as firstline treatment of metastatic colorectal cancer: Results of the phase III randomized TRIBE trial. 2013 Gastrointestinal Cancers Symposium. Abstract 336. Presented January 26, 2013.

ASCOPost.com | MARCH 1, 2013

PAGE 9

FDA Update

Pomalidomide Approved for Multiple Myeloma continued from page 2

yet been reached in these patients. In patients treated with pomalidomide plus low-dose dexamethasone, 29.2% achieved objective response rate with a 7.4-month median duration of response.

Safety Data Pomalidomide carries a Boxed Warning alerting patients and healthcare professionals that the drug should not be used in pregnant women because it can cause severe life-threatening birth defects, and that the drug can cause blood clots. Because of pomalidomide’s embryo-fetal risk, it is available only through the Pomalyst Risk Evalua-

Contact

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

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

Advertising

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

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

tion and Mitigation Strategy (REMS) Program. Prescribers must be certified with the Pomalyst REMS Program by enrolling and complying with the REMS requirements. Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients who are not pregnant but can be-

come pregnant must comply with the pregnancy testing and contraception requirements, and males must comply with contraception requirements. Pharmacies must be certified with the Pomalyst REMS Program, must only dispense to patients who are authorized to receive the drug and must comply with REMS requirements.

Both lenalidomide and thalidomide have similar REMS. Common side effects include a neutropenia, fatigue and weakness, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infections, back pain, and fever. Pomalidomide is marketed by Celgene, based in Summit, New Jersey. n

The ASCO Post | MARCH 1, 2013

PAGE 10

Expert’s Corner Brain Tumors

The Challenges and Rewards of Neuro-oncology A Conversation with Lisa M. DeAngelis, MD By Ronald Piana

also involves educational activities at the resident and fellow levels, and I help junior faculty develop their careers. I do not have a laboratory program, but I am very engaged in our ongoing clinical research projects.

Brain Imaging

Lisa M. DeAngelis, MD

espite the extremely difficult clinical challenges posed by brain tumors, mortality rates in this disease have decreased somewhat over the past several decades due, in part, to advances in surgical techniques and therapies. The ASCO Post recently discussed contemporary issues in neuro-oncology with Lisa M. DeAngelis, MD, Chair of the Department of Neurology and Co-Executive Director of the Brain Tumor Center at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. Dr. DeAngelis, who was elected to the Institute of Medicine last year, shed light on, among other things, the current state of brain tumor therapies.

Inside the Brain Tumor Center Please give the readers a glimpse into Sloan-Kettering’s Brain Tumor Center. It is a virtual multidisciplinary center that encompasses both clinicians and basic investigators from many of SloanKettering’s departments. On the clinical side, it includes neurology, neurosurgery, neuroimaging, neuropathology, and radiation oncology. On the laboratory side, we have translational scientists who work in tandem with our clinicians, as well as basic investigators conducting studies that pertain to brain tumors. So the Brain Tumor Center is truly an aggregate of multiple areas of expertise, all of which are intensely focused on advancing the treatment of brain tumors. As Executive Co-Director of the Brain Tumor Center, what do your daily duties encompass? I have a very varied set of responsibilities. I do see patients 1 full day a week and occasionally on our consult service. As Chair of the department, I do a fair amount of administrative work, which

Given the issues with false-positives in other clinical scenarios, where do we stand in brain imaging as it relates to detection? Brain imaging has undergone a revolution over the past couple of decades. We rely almost exclusively on MRI as our standard neuroimaging modality, and the technology is actually quite good at detecting early abnormalities in the brain, as far as anatomy and localization are concerned. In some scenarios, using advanced imaging tools such as spectroscopy or perfusion techniques, we can ac-

using intravenous contrasts. This lack of visual specificity on the scan consequently makes it harder to determine what’s happening clinically with the disease. Thus, most of our imaging challenges arise during the course of treatment delivery.

Under Investigation You mentioned an increased use of antiangiogenics in brain tumors. Do these agents show promise in gliomas? Bevacizumab recently received FDA accelerated approval for recurrent glioblastoma. So far, two large randomized phase�� III trials incorporating bevacizumab into initial therapy have been completed. One, the AVAglio study, predominantly conducted in Europe, has shown significant improvement in progressionfree survival when adding bevacizumab

We are rapidly enhancing our scientific understanding of the molecular abnormalities that drive these tumors, which will lead to the development of pathway-specific agents that will hopefully increase patient survival. —Lisa M. DeAngelis, MD

tually get an indication of the tumor type or grade. That said, there are no imaging techniques that replace tissue samples for diagnosis. The challenge in brain imaging comes not so much at the point of diagnosis but rather during the course of treatment. Imaging helps us to interpret disease response and progression and helps us differentiate tumor from the actual effects of treatment. This is important because when tumors are treated effectively, there is residual dead tissue and inflammatory debris in the area where the tumor was. The brain lacks a lymphatic system and lymph nodes to provide drainage, so it takes much longer for some of this material to clear than it would in other parts of the body. It can also incite an inflammatory response leading to edema and causing this remaining debris to look exactly like tumor tissue. This is a big challenge for us. Another imaging challenge is posed by our increasing use of bevacizumab (Avastin) and other antiangiogenic agents, which interfere with the scan’s ability to outline the tumor definitively

to upfront chemoradiation. We are currently waiting for overall survival data and the results from a Radiation Therapy Oncology Group (RTOG) phase III bevacizumab study. These trials will likely define the role of bevacizumab in the treatment of glioblastoma, and antiangiogenic agents still need further study in other grades of glioma. What’s currently under investigation at your center? One area of clinical interest is the epidermal growth factor receptor (EGFR) pathway that is upregulated in about 40% of glioblastomas and has been associated with a specific mutation called EGFRvIII, which is seen in about 20% of glioblastoma patients. However, our research has demonstrated that the standard anti-EGFR drugs are not effective in this disease. Recently published work by Dr. Ingo Mellinghoff at MSKCC points to several problems with studies looking at the EGRF pathway, such as not achieving adequate drug level in the brain.1 This suggests that high-dose pulsatile scheduling might be more effective. We are

looking at that in clinical trials. In addition, the anti-EGFR agents— like erlotinib (Tarceva)—that are useful in lung cancer do not bind very well to the specific EGFR conformation that we see in glioblastomas harboring the EGFRvIII mutation. Alternatively, drugs like lapatinib (Tykerb) bind more effectively and if given in a high-dose pulsatile schedule might prove more effective. This will be studied in a trial currently under development by Dr. Mellinghoff.

Growing Array of Clinical Successes Any last thoughts about your work in this very difficult clinical scenario? I have been optimistic about making a difference in brain tumors since the beginning of my career, which is one of the reasons I’ve been able to remain focused on my clinical work. This is a particularly exciting time in our understanding of brain tumors and our ability to translate that knowledge into a growing array of clinical successes. It’s important to note that when I began my career in neuro-oncology, nobody was interested in this field. Brain tumors were considered a terminal disease, and the mindset was that any treatment, even one that conferred survival benefit, would leave the patient compromised by brain-tissue destruction that was irreparable. However, what we’ve learned over the years is that our patients can do remarkably well when we control their disease in ways that are sensitive to quality-of-life issues. Moreover, we are rapidly enhancing our scientific understanding of the molecular abnormalities that drive these tumors, which will lead to the development of pathway-specific agents that will hopefully increase patient survival. Neuro-oncology is such an exciting field within cancer care, and I hope it will continue to attract enthusiastic young people from our medical schools. n Disclosure: Dr. DeAngelis reported no potential conflicts of interest.

Reference 1. Vivanco I, Robins HI, Rophie D, et al: Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2:458-471, 2012.

When hemoglobin fallsâ&#x20AC;Ś

For chemotherapy-induced anemia (CIA) in metastatic patients with Hb < 10 g/dL

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 Q3W6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa CIA 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.3

INDICATION and LIMITATIONS OF USE Aranesp® (darbepoetin alfa) is 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. Aranesp® is not for use: • In patients receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy • In patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • As a substitute for RBC transfusions in patients requiring immediate correction of anemia Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being.

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

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 • 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, and discontinue upon completion of a chemotherapy course

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • Prescribers and hospitals must enroll in the ESA APPRISE Oncology Program to prescribe or dispense Aranesp® to patients with cancer; to enroll, visit www.esa-apprise.com or call 1-866-284-8089 for assistance Do not use Aranesp® in patients with uncontrolled hypertension; control blood pressure prior to and during treatment. Do not use Aranesp® in patients with pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs. If severe anemia and low reticulocyte count develop during treatment, withhold Aranesp® and evaluate for PRCA. Do not use Aranesp® in patients with history of serious allergic reactions to the product, which may include anaphylaxis, angioedema, bronchospasm, skin rash, and urticaria. Immediately discontinue Aranesp® if such a reaction occurs. Adverse reactions in ≥ 1% of patients treated with Aranesp® in clinical studies were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary on following page for additional safety information, including Boxed WARNINGS. 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.

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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

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

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ASCOPost.com | MARCH 1, 2013

PAGE 15

News Breast Cancer

Final ‘Joint Analysis’ Confirms Life-saving Benefit of Trastuzumab in Patients with HER2-positive Early Breast Cancer By Caroline Helwick

T:14”

B:14.25”

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n the final planned joint analysis of overall survival from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials, the addition of trastuzumab (Herceptin) to paclitaxel following doxorubicin/cyclophosphamide (AC) reduced breast cancer deaths by 37%, according to Edward H. Romond, MD, Professor of Medicine at the University of Kentucky, Lexington. The studies from the National Surgical Adjuvant Breast and Bowel Project and the North Central Cancer Treatment Group evaluated the benefit of trastuzumab when added to adjuvant chemotherapy for women with HER2positive early breast cancer. The initial results were reported in 2005 and updated in early 2011. At the 2012 San Antonio Breast Cancer Symposium, Dr. Romond presented the final overall survival analysis.1

Benefit across All Subsets “The relative risk reduction benefit for both disease-free and overall survival was present and of similar magnitude in virtually all subsets of patients analyzed,” Dr. Romond noted. In the trials, a regimen of doxorubicin/cyclophosphamide followed by paclitaxel was assigned to 2,028 wom-

en, while doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab was assigned to 2,018. The majority of the population had one to three positive lymph nodes, and

Robust Disease-free Benefit Disease-free survival was 73.7% with doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab vs 62.2% with doxorubicin/cyclo-

The relative risk reduction benefit for both disease-free and overall survival was present and of similar magnitude in virtually all subsets of patients analyzed. —Edward H. Romond, MD

about half the women were hormone receptor–positive. At a median follow-up of 8.4 years (data lock as of September 15, 2012), the definitive overall survival analysis was performed after 704 events occurred. About 5% of women assigned to receive trastuzumab did not receive the drug because of cardiac symptoms or decrease in left-ventricular ejection fraction during AC, and 20% assigned to the control arm crossed over to receive trastuzumab after positive results from the first interim analysis; both these groups were included in the intent-to-treat analysis.

Final Analysis of Trastuzumab Trials ■■ The joint analysis of NSABP B-31 and NCCTG N9831, which evaluated the

benefit of adding trastuzumab to adjuvant chemotherapy, documented a 37% reduction in breast cancer mortality at 10 years.

■■ Disease-free survival events were reduced by 40%. ■■ All subgroups benefited from the addition of trastuzumab.

phosphamide followed by paclitaxel, for an absolute improvement of 11.5% at 10 years and 40% reduction in risk (P < .0001), Dr. Romond reported. “This was mostly due to a difference in distant recurrences,” he noted, which were seen in 11.2% and 19.4%, respectively. Among patients who were hormone receptor–positive, the cumulative incidence of distant recurrence as a first event was 12.7% with doxorubicin/cyclophosphamide followed by paclitaxel plus trastuzumab and 22.3% with doxorubicin/cyclophosphamide followed by paclitaxel. In the hormone receptor–negative subset, the incidence was 11.9% and 21.5%, respectively. “For patients with hormone receptor–positive disease, the absolute reduction in the rate of distant recurrence as a first event continues to improve over time with the addition of trastuzumab, and reaches 9.6% at 10 years. For patients with hormone receptor–negative disease,

the absolute risk of distant recurrence as a first event is reduced by 9.6% at 7 years, after which distant recurrence from breast cancer is unlikely,” Dr. Romond said.

Deaths Reduced by 37% Similarly, trastuzumab clearly saved lives. At 10 years, overall survival was 84.0% vs 75.2%, an 8.8% absolute improvement that reflects a 37% reduction in risk (P < .0001). Over time, the difference in survival has widened from 2.9% at 4 years to 5.5% at 6 years and to 7.6% See Page 36 at 8 years. Deaths due to breast cancer were observed in 10.3% of women who received trastuzumab vs 16.8% of those who did not. The risk reduction was of similar magnitude whether patients’ tumors were estrogen and/or progesterone receptor–postive or –negative. All subgroups benefited from trastuzumab. The absolute differences in overall survival differences were particularly striking for women ≥ 60 years old (13.7%), those with ≥ 10 positive nodes (15.6%), and those with tumors ≥ 5.0 cm (11.8%). n Disclosure: Dr. Romond reported no potential conflicts of interest.

Reference 1. Romond EH, Suman VJ, Jeong J-H, et al: Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. 2012 San Antonio Breast Cancer Symposium. Abstract S5-5. Presented December 7, 2012.

Don’t Miss These Important Reports in this Issue of The ASCO Post Robert Peter Gale, MD, on Radiation and Cancer Risk, see page1

Lee S. Schwartzberg, MD, on Panitumumab and Bevacizumab in Colorectal Cancer, see page 3

Visit The ASCO Post online at ASCOPost.com

Lisa M. DeAngelis, MD, on the Challenges and Rewards of Neuro-oncology, see page 10

The ASCO Post | MARCH 1, 2013

PAGE 16

News Breast Cancer

Dose-dense Chemotherapy in Breast Cancer: Epirubicin-based Regimens Studied in German and UK Trials By Caroline Helwick

to epirubicin (100 mg/m2 × 4) every 3 weeks or accelerated epirubicin (100 mg/m2 × 4) plus pegfilgrastim (Neulasta) at 6 mg on day 2 every 2 weeks, followed by classical CMF every 4 weeks for four cycles or capecitabine (2,500 mg/m2/d × 14) every 3 weeks for four cycles. Other adDavid Cameron, MD Volker J. Moebus, MD juvant treatment for HER2-positive or hormone receptor–posin the treatment of early breast cancer, tive disease was given as needed. dose-dense regimens (given every For patients whose HER2 and estro2 weeks) have proven superior to congen receptor status was known, 61% had ventionally dosed chemotherapy (given estrogen receptor–positive/HER2-negevery 3 weeks), but data on long-term ative tumors, 19% were HER2-positive survival are lacking. Two studies preand 20% were estrogen receptor–negasented at the San Antonio Breast Cantive/HER2-negative. cer Symposium evaluated the benefit of At a median follow-up time of 49 dose-dense epirubicin-based regimens, months, the primary endpoint—time to but they may have raised more questions recurrence—was not significantly differthan answers. ent for the two treatment strategies, Dr. Cameron reported. At 3 years, recurUK TACT2 Trial rence rates were 90.9% with standard The phase III UK TACT2 trial comchemotherapy and 91.0% with accelerpared standard chemotherapy with epiated epirubicin; at 5 years, recurrence rubicin plus CMF (cyclophosphamide, rates were 85.2% and 86.4%, respectively methotrexate, fluorouracil) to acceler(P = .60). Overall survival was similar as well, ated (dose-dense) epirubicin in noderates being 95.4% and 94.4%, respecpositive or high-risk node-negative early tively, at 3 years and 89.3% and 88.6%, breast cancer.1 It tested the hypotheses that accelerated epirubicin improves outrespectively, at 5 years (P = .23). comes, and that capecitabine (Xeloda) “There was no evidence of any imgives similar efficacy with better tolerprovement in disease outcomes,” Dr. ability than CMF. The current report Cameron said. “The hazard ratio for time focused on the impact of accelerating to recurrence was 0.96. And there was no epirubicin therapy. differential effect by subgroup.” David Cameron, MD, Professor The dose-dense approach was associof Oncology at the University of Edinated with less myelosuppression (growth burgh, Scotland, presented the first effactors were mandatory), but more ficacy results of standard vs accelerated hand-foot toxicity, he noted. epirubicin. The capecitabine compari10-Year Follow-up of iddETC son is still awaited. On the other hand, the phase III The study included 4,391 patients ranGerman AGO Breast Study Group’s domly assigned between 2005 and 2008

Dose-dense Chemotherapy in Breast Cancer ■■ In the UK TACT2 trial, an accelerated (dose-dense) epirubicin-based

regimen did not result in better relapse-free or overall survival than a standard epirubicin-based regimen. Overall survival at 3 years was approximately 95% per arm.

■■ In the German iddETC trial, which evaluated a dose-dense plus dose-

intense epirubicin-based regimen, a 10% absolute difference in overall survival was shown, vs standard chemotherapy.

■■ Further, in the German iddETC trial, epoetin alfa reduced the need for red

blood cell transfusions by about 50%, but was associated with a doubling in the rate of venous thromboembolism.

iddETC (intense dose-dense epirubicin, paclitaxel, cyclophosphamide) trial showed that a dose-dense and dose-intense regimen was superior to standard chemotherapy.2 “At 10 years, recurrence-free survival and overall survival continue to be significantly superior, with an absolute difference in overall survival of 10%,” said Volker J. Moebus, MD, Director of the Breast Center and Chief of the Department of Obstetrics and Gynecology at the Klinikum Frankfurt Höchst in Ger-

many. “This is quite remarkable for a chemotherapy trial.” The iddETC trial enrolled 1,284 patients with at least four positive lymph nodes (median, eight). In contrast to other dose-dense trials, the iddETC regimen is dose-dense and dose-intensified. In the experimental arm, patients received three courses each of epirubicin (150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2,500 mg/m2) every 2 weeks with growth factor support. In the stan-

EXPERT POINT OF VIEW

andra Swain, MD, FACP, Medical Director of the Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, moderated the San Antonio session where the dose-dense chemotherapy studies were presented, and commented on the findings of the two studies.

iddETC Trial With regard to the iddETC trial, Dr. Swain joined several listeners in questioning whether the benefit was Sandra Swain, MD, FACP due to the dose intensification or to other factors, in particular, the taxane schedule. Other studies have shown, she said, that increasing the dose intensity of anthracyclines and also cyclophosphamides does not improve outcomes. “So, it’s probably the taxane that is making the difference [in the iddECT arm],” she suggested. In the iddETC trial, paclitaxel was given either every 3 weeks, which is known to be inferior, or every 2 weeks at the higher dose, she noted. While a 10% difference in overall survival is “striking,” she acknowledged, because of the study design “you can’t determine if the benefit is due to the dose and schedule of the taxane or, in fact, whether it’s the dose-dense approach that makes the difference.” She also pointed out that the estrogen receptor–positive patients benefited from the dose-dense, dose-intense strategy, whereas Cancer and Leukemia Group B (CALGB) 9741 did not show a benefit for dose-dense treatment in this subgroup. “I think this is interesting,” she said.

UK TACT2 Trial As for the UK TACT2 trial, she pointed out that the study included “all comers” and half the patients were node-negative; therefore, this was a better population than the iddETC trial cohort with at least four positive nodes. This does not necessarily mean, she added, that dose-dense regimens are better in more high-risk patients. “We also need to see the results of the randomization between capecitabine and CMF,” she added. Dr. Swain further noted that the rate of venous thromboembolism in iddETC (13%) was much higher than what was observed in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38, a study she led, but as in B-38 the use of epoetin alfa was not detrimental to clinical outcomes. “This is reassuring,” she said. Meanwhile, she said the results of the trials should not change practice. For physicians who like to use dose-dense chemotherapy, “don’t change anything,” Dr. Swain suggested. n Disclosure: Dr. Swain reported no potential conflicts of interest.

ASCOPost.com | MARCH 1, 2013

PAGE 17

News

dard arm, they received four courses of conventionally dosed epirubicin/ cyclophosphamide (90/600 mg/m2) followed by four courses of paclitaxel (175 mg/m2), all in 3-week intervals without growth factor support. At a median follow-up of 122 months, time to relapse, which was the primary endpoint, was reduced by 26% in the iddETC arm (P = .00014). “We observed 604 disease-free survival events, 282 with iddETC and 322 with standard chemotherapy,” Dr. Moebus said. “We saw that iddETC improved disease-free survival irrespective of nodal status, HER2 status, and estrogen receptor status.” Deaths were reduced by 28% in the iddETC arm, having occurred in 201 of those patients vs 245 in the conventional arm. This yielded 10-year overall survival rates of 69% and 59%, respectively (P = .0007). In patients with four to nine positive nodes, deaths were reduced by 23% (P = .061), and 10-year survival rates were 74% and 66%, respectively. Greater benefit was observed in patients with ≥ 10 positive nodes, where mortality was reduced by 34% (P = .0016) and 10-year survival rates were 62% and 48%, respectively, Dr. Moebus said.

Epoetin Alfa Reduces Need for Transfusions but Increases Risk of Venous Thromboembolism The trial also evaluated the safety of epoetin alfa as prophylaxis against anemia, and randomly assigned the iddETC cohort to epoetin alfa (n = 319) or not (n = 324). Dosedense regimens with growth factor support require red blood cell transfusions in up to one-fourth of patients, Dr. Moebus pointed out. In the second randomization to epoetin alfa or not, red blood cell transfusions were significantly less among patients who received epoetin alfa (13%) compared with those who received no prophylaxis (28%, P < .0001). This protection occurred without more recurrences or deaths. Relapses occurred in 146 patients in the prophylaxis group and in 136 of patients not receiving epoetin alfa (P = .69). The 10-year relapse-free survival rates were 57% and 55%, respectively, and overall survival rates were 70% and 68%, respectively (P = .45). The use of epoetin alfa, however, was associated with an increase in venous thromboembolism: 13% vs 7% (P = .029). “Epoetin alfa diminished the percentage of red blood cell transfusions, and

primary prophylaxis avoided a decline in hemoglobin values. Negative impacts on recurrence-free and overall survival were not found,” he said. “We also confirmed the known elevated risk for venous thrombotic events by [erythropoiesisstimulating agent] use.” In conclusion, Dr. Cameron noted that iddETC is a feasible regimen with

a manageable toxicity profile. “We observed no therapy-related deaths or longterm toxicity such as congestive heart failure or peripheral neuropathy, and no increases in myelodysplastic syndrome or acute myeloid leukemia. The iddETC regimen should be considered a standard regimen for high-risk breast cancer patients with node-positive disease.” n

Disclosure: Dr. Cameron reported no potential conflicts of interest. Dr. Moebus is a speaker for Amgen and Roche, has received research support See Page 36 from Johnson & Johnson and Amgen, and is a member of the advisory board for Sanofi-Aventis.

References available at ASCOPost.com.

The ASCO Post | MARCH 1, 2013

PAGE 18

News Breast Cancer

Pathologic Complete Response Yields Long-term Benefits in Meta-analysis By Caroline Helwick

reast cancer patients who achieve a pathologic complete response to neoadjuvant therapy have more favorable outcomes than those who do not, according to a meta-analysis of neoadjuvant trials presented at the 2012 San Antonio Breast Cancer Symposium.1 Patients who achieved a pathologic

Patricia Cortazar, MD

complete response had a 52% reduction in the probability of an event (P < .001) and a 64% reduction in the probability of death (P < .001), in the meta-analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) presented by Patricia Cortazar, MD, Clinical Team Leader for the Breast Oncology Group of the U.S. Food and Drug Administration. “Pathologic complete response is a proposed surrogate endpoint for predicting long-term See Page 36 clinical benefit on endpoints such as disease-free survival, event-free survival, or overall survival. A meta-analysis has been needed to establish the magnitude of pathologic complete response improvement on a trial level that results in improved disease-free survival,” said Dr. Cortazar. The meta-analysis included 12 randomized controlled trials of neoadjuvant systemic therapy, including ECTO, EORTC 10994/BIG 1-00, GeparDuo, GeparQuattro, GeparTrio,

GeparTrio-Pilot, NOAH, NSABP B18, NSABP B27, PREPARE, and TECHNO. The total population included 12,993 patients. Trials were included if pathologic complete response was clearly defined, all the necessary data were collected, and data on event-free and overall survival with long-term follow-up were available. Three definitions of pathologic complete response, and the percentage of patients achieving them, were as follows: ■■ ypT0, ypN0: Absence of invasive cancer in the breast and axillary nodes, and absence of ductal carcinoma in situ (DCIS) (13%) ■■ ypT0/is, ypN0: Absence of invasive cancer in the breast and axillary nodes; DCIS is allowed (18%) ■■ ypT0/is: Absence of invasive cancer in the breast regardless of nodal involvement; DCIS is allowed (22%) The achievement of a pathologic complete response was positively associated with more favorable long-term outcomes, including event-free and overall survival, Dr. Cortazar reported. “The more favorable outcomes following pathologic complete response occurred regardless of whether DCIS was present or absent,” she said. Eradication of tumor from both the breast and the lymph nodes was better associated with improved event-free and overall survival than eradication from the breast alone. For consistency, a standard pathologic complete response definition should be used in future trials, preferably ypT0ypN0 or ypT0/isypN0, she suggested.

Results by Breast Subtype The achievement of pathologic complete response was highly variable by tumor subtype, with aggressive tumor subtypes more highly associated with event-free survival than smaller, less aggressive tumors. Pathologic

Pathologic Complete Responses and Long-term Outcomes ■■ The achievement of pathologic complete response after neoadjuvant

chemotherapy was associated with more favorable long-term outcomes, including event-free survival (52% risk reduction) and overall survival (64% risk reduction).

■■ A larger association was observed in patients with aggressive (vs less aggressive) tumor subtypes.

■■ Pathologic complete responses were uncommon (7%) in patients with low-grade hormone receptor–positive tumors.

EXPERT POINT OF VIEW

aura van’t Veer, PhD, Director of the Specialized Programs of Research Excellence (SPORE) of the University of California, San Francisco, commented on the meta-analysis. She said the study confirms that a pathologic complete response in the neoadjuvant setting is generally meaningful as it clearly relates to longterm outcomes. “This is even truer when you divide breast cancer into subtypes,” she said. For patients who are estrogen receptor– Laura van’t Veer, PhD negative or estrogen receptor–positive with higher-grade tumors, the correlation between pathologic complete response and long-term outcome is very strong, whereas the correlation is lacking in patients with low-grade estrogen receptor–positive tumors. “This is what my own research has shown in a smaller dataset, though including genomic information such as the 70-gene MammaPrint signature” she said. “And this strikes me as very important for our patients, who become concerned when they do not achieve a [pathologic complete response] with neoadjuvant treatment.” When the patient has a low-grade, indolent tumor, which has a low likelihood of recurrence, pathologic complete response is “of no relevance,” and clinicians can reassure these patients, she said. On the other hand, when patients have a high risk of recurrence and do not respond to neoadjuvant treatment, “you know you will have to do something extra.” She said there is no further point to evaluating pathologic complete response by estrogen receptor and HER2 status alone. Future studies should aim for “the next level” by evaluating pathologic complete response in discrete tumor subtypes. n Disclosure: Dr. van’t Veer is co-founder of Agendia Inc.

complete responses were uncommon in patients with low-grade hormone receptor–positive tumors (7%) and more common among tumors that were high-grade hormone receptor– positive (16%), triple-negative (34%), hormone receptor–positive/HER2positive (30%), and hormone receptor–negative/HER2-positive (50%). The hazard ratios (HR) for eventfree survival by subtypes, when pathologic complete response was achieved, were as following: ■■ Hormone receptor–positive patients: HR = 0.49 (P < .001) ■■ Hormone receptor–positive grade 3 patients: HR = 0.27 (P < .001) ■■ Hormone receptor–positive grade 1/2: HR = 0.63 (P = .07) ■■ HER2-positive patients: HR = 0.39 (P < .001) ■■ HER2-positive/hormone receptor–positive patients: HR = 0.58 (P = .001) ■■ HER2-positive/hormone receptor–negative: HR = 0.25 (P < .001) ■■ Triple-negative: HR = 0.24 (P < .001) Among HER2-positive patients,

the association between pathologic complete response and risk reduction was enhanced with trastuzumab (Herceptin) treatment. In HER2positive/hormone receptor–negative patients, hazard ratios associated with pathologic complete response were 0.35 (P < .001) without trastuzumab and 0.15 (P < .001) with trastuzumab treatment. The magnitude of pathologic complete response improvement that predicts long-term clinical benefit could not be established, possibly due to low pathologic complete response rates, heterogeneous populations, and lack of targeted therapies in most trials, Dr. Cortazar said. n Disclosure: Dr. Cortazar reported no potential conflicts of interest.

References 1. Cortazar P, Zhang L, Untch M, et al: Meta-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S1-11. Presented December 5, 2012.

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XGEVA®, THE FIRST AND ONLY RANK LIGAND INHIBITOR TO PREVENT SREs

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 Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. 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 hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• 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.

• 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.

• 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.

www.XGEVA.com

SUPERIORITY XGEVA® delayed the median time to ﬁrst SRE in a prespeciﬁed integrated analysis across 3 head-to-head studies vs zoledronic acid1

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients1,2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

HR = 0.83 (95% CI: 0.76–0.90) P < 0.0001†

0 0

Reduction in risk of ﬁrst SRE in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)3 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)3 • Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)3 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

STUDY MONTH Data from three 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), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. 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.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGEVA® acts precisely to bind XGEVA® is administered once to RANK Ligand, a key mediator every 4 weeks as a single, 120 mg of bone resorption, to inhibit subcutaneous injection3 osteoclast activity3

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3

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. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identiﬁed.

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

REFERENCES: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on ﬁle, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

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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 25Â°C/77Â°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: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. 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.

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 immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in SpeciďŹ c Populations). There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading. ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with 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 evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received 9HFWB XFSF GFNBMF &JHIUZ mWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP Asian, and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). SeventyďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

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 beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab 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 of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. 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 shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ÂŠ2012 Amgen Inc. All rights reserved. Printed in USA.

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Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants 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 GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor. NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk. 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information). Use in SpeciďŹ c Populations). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

ASCOPost.com | MARCH 1, 2013

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Philanthropy Spotlight A New Donor Shines with Conquer Cancer Foundation

o support all of our valuable programs for patients and physicians, the Conquer Cancer Foundation of the American Society of Clinical Oncology partners with organizations of every size and scale, and every partnership has a lasting impact. Recently, the Foundation began working with a new supporter, Shine for Scott, Inc, to provide four Merit Awards to bright young researchers presenting their work at the 2013 Gastrointestinal Cancers Symposium in San Francisco.

Shine for Scott Shine for Scott was founded in late 2010 following the death of the organization’s namesake, Scott Walden. Scott passed away from colon cancer on June 3, 2010, 18 months after his initial diagnosis. He was just 40 years old. After his diagnosis, it quickly became evident to Scott, his family, and his friends that Scott had several barriers to overcome as a young person dealing with this disease. First, there was a lack of understanding and knowledge among Scott’s peers regarding the symptoms, diagnosis, treatment, and prevention of colorectal cancer. Second, there was very little financial assistance available for middle-aged and middle-income individuals faced with a debilitating disease. Third, there were fewer medical treatments for colorectal cancer than there were for other types of cancers. Scott and his family and friends dedicated themselves to

making sure that Scott’s legacy would be to support and educate newly diagnosed patients, spread the word on screening and detection, and ultimately help in the search for a cure for colon cancer.

Supporting Key Researchers at the GI Symposium Colorectal cancer is the third most common cancer among both

cians, advocates, members of the press, and industry leaders from the oncology community attend the GI Symposium each year. This year’s Symposium featured nearly 600 abstracts on the latest research in gastrointestinal cancers. The Merit Awards are given to fellows and residents who submit high-quality abstracts selected for presentation at the GI Symposium.

We were motivated by the opportunity to support the best young research oncologists in presenting at this meeting dedicated to multidisciplinary approaches to GI cancers. —Ellen LeMosy, MD, PhD

men and women in the United States. It is also the third most common cause of cancer death among men and women separately (and the second most common cause of cancer death in men and women combined) in the United States. This year, an estimated 143,000 adults in the United States will be diagnosed with colorectal cancer. These numbers include over 103,000 new cases of colon cancer and over 40,000 new cases of rectal cancer. It is estimated that over 51,000 individuals will die of colorectal cancers in the United States in 2013. Over 2,000 researchers, physi-

Merit Award winners receive a monetary award, as well as complimentary registration for the 2013 Gastrointestinal Cancers Symposium and access to Symposium housing reserved for ASCO. Through four Merit Awards supported by Shine for Scott, the Conquer Cancer Foundation is able to recognize young researchers presenting superior research studies focused on colorectal cancer: ■■ Chiara Cremolini, MD, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori Circulating angiogenic factors as predictors of benefit from bevaci-

Oncology Career Fair at ASCO Annual Meeting

he 13th Annual Oncology Career Fair at the 2013 ASCO Annual Meeting offers a convenient way for attendees to learn more about employment opportunities available in the rapidly developing oncology profession. In addition, the Career Opportunities and Other Medical Meetings posting boards, located adjacent to the Career Fair, provide organizations with the opportunity to make readily available to the attendees information about job openings or other medical meetings held throughout the year.

In 2012, the Career Fair played host to over 30 exhibitors, ranging from medical centers, to private practices, to industry. Private interview booths are available on site to allow recruiters to speak with candidates in detail regarding potential opportunities. The 13th Annual Oncology Career Fair will be held on Saturday, June 1, and Sunday, June 2, at the rear of the Oncology Professionals Hall. n © 2013. American Society of Clinical Oncology. All rights reserved.

zumab beyond progression in metastatic colorectal cancer: Translational analyses from the phase III BEBYP trial. ■■ Aalok Kumar, BESc, MD, British Columbia Cancer Agency Use of adjuvant chemotherapy and outcomes in stage II colon cancer with versus without poor prognostic features. ■■ Van Morris, MD, The University of Texas MD Anderson Cancer Center Progression-free survival in metastatic, BRAF-mutated colorectal cancer. ■■ Andrea Russo, MD, Harvard Radiation Oncology Program Mutational analysis of locally advanced rectal cancer and response to neoadjuvant chemoradiation.

Working Together for Maximum Impact Shine for Scott sought to support Conquer Cancer Foundation because of its unique connection with ASCO. “We were motivated by the opportunity to support the best young research oncologists in presenting at this meeting dedicated to multidisciplinary approaches to GI cancers,” said Ellen LeMosy, MD, PhD, a member of the Shine for Scott Board of Directors. Ultimately, the team at Shine for Scott would like to do even more in the fight against colon cancer, both globally and locally. Specifically, their mission is to decrease colon continued on page 25

The ASCO Post | MARCH 1, 2013

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New ASCO Workforce Studies Release Preliminary Data on Oncology Workforce Environment

SCO has released the preliminary findings of a far-reaching research initiative to collect and analyze oncology workforce demographic and practice data. This initiative will help guide the Society’s response to the ever-changing business and political landscape in which oncologists care for people with cancer. This initiative comprises the three following research projects, the early findings of which reflect a mixed picture of an oncology community adapting to myriad stressors: ■■ ASCO Workforce Information System: The ASCO Workforce Information System (WIS) provides a mechanism for ongoing data collection and reporting on the current status of the oncologist workforce—specifically, for assembling the latest available data on oncologist supply and cancer

incidence and prevalence. ASCO plans to publish WIS findings annually, reporting on new data and tracking trends over time. ■■ ASCO National Census of Oncology Practices: This landmark nationwide initiative collected key data from U.S. oncology practices to address a lack of current and reliable information on how oncology practices are adapting to increasing administrative, financial, and political pressures, and to gather information about the existing and trending ownership structure of oncology practices. ASCO will collect, analyze, and report on the census each year, with plans to significantly expand U.S. practice participation in 2013. ■■ ASCO Study of Geographic Access to Oncology Care: ASCO

CONQUERING

contracted with the University of Iowa, with funding from Susan G. Komen for the Cure, to analyze data from the Iowa Cancer Registry, providing a means to review all newly diagnosed cancer cases within the entire state of Iowa to determine if geographic physician distribution and patient access to treatment sites contribute to disparities in cancer care. Iowa was chosen because of the combination of its robust physician database and cancer registry. As part of the project, the University of Iowa is helping ASCO understand how to analyze similar treatment trends and geographic

distribution of oncologists on a national scale.

Annual Report Coming in Fall 2013 ASCO plans to expand its research efforts on the state of cancer care, and summarize these efforts in an annual report in the fall of 2013. The original articles on these three studies were published in the January 18, 2013, issue of the Journal of Oncology Practice, and a detailed summary of key findings can be found at www.asco.org/stateofcancercare. n © 2013. American Society of Clinical Oncology. All rights reserved.

Cancer. Together, anything is possible. The Conquer Cancer Foundation. Our name says a lot. Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supporting the world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

DONATE TODAY! ConquerCancerFoundation.org

ASCOPost.com | MARCH 1, 2013

PAGE 25

Direct from ASCO

Philanthropy Spotlight continued from page 23

cancer mortality by raising money to fund basic scientists and clinicians for translational research into novel, combinatorial therapies targeting colon cancer; to fund an educational program to teach individuals in the Central Savannah River Area (CSRA) how to prevent colon cancer; and to fund a screening program that will provide individuals in the CSRA between the ages of 25 to 50 with lifesaving colon cancer screenings. In the future, Shine For Scott, Inc, would like to expand its education, screening, and financial assistance programs, first to the Coastal Savannah River Area, then the state of Georgia, next the Southeast, and finally the entire United States. In addition, Shine For Scott, Inc, hopes to become the leading fundraiser for cutting-edge colon cancer research,

Now in Spanish: Stopping Tobacco Use After a Cancer Diagnosis

ell your patients about Stopping Tobacco Use After a Cancer Diagnosis, Cancer.Net’s newest Spanish language booklet designed to help patients understand the benefits of quitting in the context of a cancer diagnosis. This booklet explains how patients can talk with their docSee Page 36 tor about their tobacco use, the health benefits of quitting, and various methods patients can use to quit using tobacco, and also lists helpful resources, including help lines and mobile apps. Find it online at www.cancer.net/tabaco, and order copies at www.cancer.net/ estore. n

ultimately assisting in the eradication of colon cancer mortality. “We are extremely grateful for the support provided by Shine For Scott for the 2013 Merit Awards,” said Nancy R. Daly, MS, MPH, Executive Director of the Conquer Cancer Foundation. “The Merit Awards pro-

vide needed recognition and resources for some of our most promising researchers and physicians, and we are delighted to work with Shine for Scott as we both work toward freeing the world from the fear of cancer.” To learn more about the Conquer Cancer Foundation or make a dona-

tion in support of cancer research, visit www.conquercancerfoundation. org. And to learn more about Shine For Scott, Inc. and their work, visit www.shineforscott.org. n © 2013. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | MARCH 1, 2013

PAGE 26

Direct from ASCO

Make a Lasting Difference: Choose the Giving Option that Works for You

f you are like the many supporters of the Conquer Cancer Foundation, you may have reached a point where you would welcome the opportunity to influence not only the future ownership of your possessions, but the meaning that others assign to your life. One way to accomplish this is by considering the means by which you will provide for the people and causes you cherish most. When it comes to defining your legacy at the Conquer Cancer Foundation, your options are numerous. Below are just a few of the ways you can express your values through a gift to help conquer cancer. ■■ Donate today. A yearly, monthly, or one-time gift helps provide operational necessities to the Foundation. ■■ Include us in your will. Designating the Conquer Cancer Foundation in your will can help create a world free from the fear of cancer. The following sample language can be considered by a donor’s estate planners in drafting a simple bequest to the Foundation: “I give [the sum of $__] OR [__% of my estate] OR [all or __% of the rest, residue, and remainder of my estate] to the Conquer Cancer Foundation of the American Society of Clinical Oncology, a Virginia

nonstock corporation located at 2318 Mill Road, Suite 800, Alexandria, Virginia, 22314 (Federal Tax ID: 31-1667995), to be used for its general purposes.”

Sarah Sasman Jacoby, Foundation Major Gift Officer (571-451-1456 or sarah.jacoby@conquercancerfoundation.org), or visit www.con-

■■ Establish a life income gift. Receive fixed or variable payments for life and gain valuable tax advantages when you create a life income gift. ■■ Donate life insurance. You can easily support our mission by naming the Conquer Cancer Foundation of the American Society of Clinical Oncology as a beneficiary on a policy you already own. ■■ Consider your retirement plan assets. By making a simple designation on your plan’s beneficiary designation form, you can help the Conquer Cancer Foundation and potentially lessen tax obligations of your loved ones. Please consult with an attorney and other appropriate estate planners when writing your will or making other estate plans. If you have any questions about giving opportunities related to the Conquer Cancer Foundation and benefits you may receive, contact Teresa Davis Pusztai, Foundation Senior Development Officer of Major Gifts (571-483-1455 or teresa.pusztai@ conquercancerfoundation.org) or

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY

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

Official Journal of the American Society of Clinical Oncology

What’s Hot in

JCO

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

JCO.org Impact of FOLFIRINOX Compared With Gemcitabine on Quality of Life in Patients With Metastatic Pancreatic Cancer: Results From the PRODIGE 4/ACCORD 11 Randomized Trial by Sophie Gourgou-Bourgade, et al

andomized Phase III Placebo-Controlled Trial of Letrozole R Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer by Antonio C. Wolff, et al

evacizumab in Stage II-III Colon Cancer: 5-Year Update of B the National Surgical Adjuvant Breast and Bowel Project C-08 Trial by Carmen J. Allegra, et al

Postoperative Adjuvant Chemotherapy Use in Patients With Stage II/III Rectal Cancer Treated With Neoadjuvant Therapy: A National Comprehensive Cancer Network Analysis by Polina Khrizman, et al

A European Organisation for Research and Treatment of Cancer Phase III Trial of Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With One to Three Brain Metastases From Solid Tumors After Surgical Resection or Radiosurgery: Quality-of-Life Results by Riccardo Soffietti, et al

Save the Date

2013 ASCO Annual Meeting May 31–June 4, 2013 McCormick Place Chicago, Illinois

ASCOPost.com | MARCH 1, 2013

PAGE 27

News Hematology

No Rationale for Eliminating Prophylactic Platelet Transfusions in Patients with Hematologic Malignancies By Caroline Helwick

rophylactic platelet transfusions should remain the standard of care for many patients with hematologic malignancies who are thrombocytopenic during intensive treatment or stem cell transplant, investigators of the TOPPS trial (noninferiority Trial Of Prophylactic Platelet transfusionS) concluded.1 The study failed to show noninferiority of no prophylaxis based on prestudy definitions, reported Simon J. Stanworth, MRCP, FRCPath, DPhil, from

the John Radcliffe Hospital, Oxford University Hospital National Health Service Trust in the United Kingdom, at the 2012 American Society of Hematology (ASH) Plenary Session. The current standard practice is to give platelets prophylactically when platelet counts drop below 10,000/µL, but experts have more recently questioned whether this practice is really necessary, and in all subgroups with hematologic malignancies.

German Study Walter H. Dzik, MD, of Massachusetts General Hospital, Boston, introduced the presentation and noted that TOPPS is the second randomized controlled trial to address the question. The other 2012 study, which involved 391 patients from eight centers in Germany, found a significant difference in grade 2 bleeding: 42% with no prophylaxis dropping to 19% among patients who received prophylactic platelet in-

EXPERT POINT OF VIEW

avid J. Kuter, MD, PhD, Professor of Medicine, Harvard Medical School, and Director of the Center for Hematology at Massachusetts General Hospital, Boston, commented on the findings for The ASCO Post. “TOPPS is a good attempt to address whether transfusions are helpful as prophylaxis in patients having intensive induction chemotherapy and stem cell transplant,” he said, noting that it has been difficult to conduct studies of transfusion practices.

terpreted in the context of four important points. “First, minor bleeding events are important in terms of quality of life,” he said. “For a patient, being covered in bruises is a cosmetic issue, like having to wear a wig for chemotherapy. We often dismiss lower-grade events as irrelevant, but they are not to the patient.” Second, the elimination of prophylactic transfusions would obviously save money for the healthcare system. However, transfusions are no more expensive than pro-

TOPPS is a good attempt to address whether transfusions are helpful as prophylaxis in patients having intensive induction chemotherapy and stem cell transplant. —David J. Kuter, MD, PhD

He pointed out that the study did show that prophylaxis was beneficial in preventing minor bleeding, although it was not powered to show a difference in the occurrence of the more concerning life-threatening bleeding. “These are very rare events, and studies cannot be powered to show a difference in these,” he explained.

Four Important Points He said TOPPS should be in-

phylactic antibiotics, “which are given like water to these patients,” he pointed out. It would, however, be reasonable to lower the dose of platelets transfused, he said. The Prophylactic Platelet Dose Trial (PLADO) evaluated the effect of varied platelet dosing on clinical bleeding among hospitalized hematology/oncology patients and found no differences among 3, 6, or 12 units.1 “We learned that in prophylactic transfusion, dose is irrel-

evant. Most centers use 6 units but you could use 3, and you get a 50% cost savings,” he emphasized. Third, it may become possible to select subgroups who will benefit most from transfusions, he said. In TOPPS, prophylactic transfusion prevented not only minor bleeding but major bleeding as well in the subgroup of patients who were not undergoing autologous stem cell transplant. This finding needs further study, he said. Finally, he proposed that the threshold for initiating platelet transfusions be reconsidered. “It used to be 20,000/µL, now it’s 10,000/µL (as was done in this study), and some advocate for 5,000/µL as the trigger point,” he said. His own policy is to “transfuse sparingly, and only if platelets fall to below 10,000/µL.” Dr. Kuter concluded that since transfusion-related risks are generally minor, the TOPPS findings are unlikely to change clinical practice. “People like me think that to not transfuse anyone runs the risk for rare events,” he said, “and we do other things prophylactically to prevent rare events.” n Disclosure: Dr. Kuter reported no potential conflicts of interest.

Reference 1. Slichter SJ, Kaufman RM, Assmann SF, et al: Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 362: 600613, 2010.

fusions (P = .0001).2 In the German study, the effect of prophylaxis for this outcome was “unmistakable,” he said. However, no differences were observed in red blood cell counts per patient, days spent in the hospital, or overall survival. The issue has remained unsettled, according to Dr. Dzik.

TOPPS Study The current TOPPS study hypothesized that a no-prophylactic transfusion policy is “as effective and safe” as prophylactic platelet transfusions. It was a randomized, parallel-group, openlabel, noninferiority comparison in 600 patients recruited from 14 centers in the United Kingdom and Australia. The study evaluated whether no prophySee Page 36 laxis in adults with hematologic malignancies “is not worse than (ie, noninferior to)” a prophylactic policy that initiated the infusion when platelet count was < 10 × 109/L. The outcome measure was clinically significant bleeding (World Health Organization [WHO] grade 2, 3, or 4) up to 30 days from randomization. The nonin-

Walter H. Dzik, MD

feriority margin was defined as a 15% difference in the proportion of patients experiencing the primary outcome. Adult patients were eligible if they had a hematologic malignancy, were receiving chemotherapy or stem cell transplant, and were expected to be thrombocytopenic for at least 5 days. Patients were randomized to prophylaxis or not, but they could receive platelets therapeutically upon signs or symptoms of bleeding, prior to invasive procedures, or at the physician’s discretion. Primary analysis was by intention to treat. continued on page 30

THORACIC ONCOLOGY UPDATE:

Molecular Biomarker Testing Is Essential for Non-Small Cell Lung Cancer Patients During the past decade the identification of molecular biomarkers for clinically relevant mutations or other genetic abnormalities in non-small cell lung cancer (NSCLC) has improved the understanding of lung cancer pathogenesis, and of the proliferation and survival of cancer cells.1 This significant development is setting the stage for a paradigm shift toward the adoption of treatments directed to the particular genetic makeup of the tumor.1,2

Over 50% of NSCLC Cases Are Linked to Known Molecular Biomarkers

At Least 10 Known Molecular Biomarkers in NSCLC3

with similar clinical stage and tumor histology can have dramatically different

50% of NSCLC cases are linked to one of

clinical outcomes.4

KRAS

at least 10 currently known biomarkers

Indeed, biomarkers may give clinicians

for NSCLC — and many of these patients genetic abnormalities that are “drivers” for their cancers and are treatable with approved biomarker-driven therapies or

Unknown EGFR

as well as the treatment sensitivity/

ALK

resistance of the tumor to specific agents.4,5

TP53

Moreover, as genomic and mutational PIK3CA

IDH1

CTTNB1

HER2 NRAS

BRAF

research continues, more biomarkers will inevitably be discovered, so that the proportion of NSCLC cases with unknown drivers will continue its decline. The

Now that more than half of NSCLC cases

ultimate goal of this approach to

can be linked to one or more of these

treatment is to identify every driver

biomarkers, it is possible to subdivide

mutation for non-small cell lung cancer,

the histological subtypes of NSCLC

and design a corresponding treatment

— adenocarcinoma, squamous cell

for each of these oncogenes.1,2,4

carcinoma, and large cell carcinoma — into clinically relevant molecular subsets.1

In partnership with:

an indication of the patient’s prognosis (outcome independent of treatment),

investigational agents in clinical trials.2,3

Sponsored by:

considerable heterogeneity of non-small cell tumors and suggest why patients

According to recent studies, more than

may test positive for mutations or other

These molecular subsets show the

Curbside Consult New Diagnostic Paradigm: Histology + Molecular Profile

For patients whose tumors test positive

David R. Gandara, MD Director, Thoracic Oncology Program, UC Davis Comprehensive Cancer Center

for a biomarker that is treatable with approved or investigational agents, the

Recently it has been proposed that

benefits of testing are self-evident.1,5,6

lung cancer treatment be based on the histology of the tumor. But there is

But in the future, molecular profiling

a growing consensus that molecular

will help an increasing proportion

profiling — testing the tumor at biopsy

of patients with NSCLC because the

for all appropriate biomarkers — should

additional information it reveals about

be part of the clinician’s standard

their tumor has the potential to guide

approach to pathologic evaluation.1,2

clinical management.2,7

And this is supported by the National Comprehensive Cancer Network (NCCN®)

Molecular Profiling Is Key in NSCLC

Clinical Practice Guidelines in Oncology

The discovery of biomarkers has

(NCCN Guidelines®) for all non-squamous

demonstrated the molecular complexity

non-small cell lung cancer (NSCLC)

of NSCLC, and it highlights the need

histologies, which state :

to move toward molecularly based

classification and treatment of these tumors.1,4 But only if patients are tested is it possible for them to potentially benefit

of “ Determination the specific molecular

from these developments. As additional mutations are discovered

abnormalities of the tumor is critical for predicting sensitivity or resistance to a growing number of targeted therapies.

through efforts such as the National Cancer Institute’s Lung Cancer Mutation Consortium (LCMC) and the Cancer Genome Atlas — and as new agents are

”

developed to address these abnormalities — the hope for the over 215,000 people

– NCCN Guidelines® Version 3.2012, for Non-Small Cell Lung Cancer 5

diagnosed with lung cancer each year is that these advances will lead to more treatment options.1,8-10 In the words of Dr. David Gandara, Director of Thoracic

The NCCN® recommends EGFR and ALK

Oncology at UC Davis Comprehensive

testing for all advanced non-squamous

Cancer Center, “Our goal is to learn the

NSCLC, in order to guide treatment

‘molecular fingerprint’ of each person’s

decisions. Multiplex molecular profiling

lung cancer, and to personalize their

assays may make the prospective

therapy based on this information. The

discoveries that could make this possible

genotyping of tumors possible, to aid clinical decision making and management.

What is the most significant development you’ve seen in the treatment of lung cancer today? DG Knowing what is driving the cancer! We have recently been using histology to treat cancer based on the appearance of the cells. But cells that look identical under the microscope can have dramatically different clinical outcomes because of what is driving them at the molecular level. And that is leading us to molecularly based treatment options.

Can many NSCLC patients benefit from this testing? Who should be tested? DG When you consider both approved and investigational agents, yes, a considerable proportion of NSCLC patients can receive therapy based on molecular testing. But at present I believe that all patients with NSCLC of the adenocarcinoma subtype should be tested.

That seems like a lot of testing. Wouldn’t that require a re-biopsy for many patients? DG These tests do require adequate tumor tissue. Some patients will need to be re-biopsied — some for lack of sample tissue, but also to look for changes that have occurred over time and as a result of therapy. Other patients may not have to be re-biopsied. To do the testing that reveals the “molecular fingerprint” of each person’s lung cancer, we have to get sufficient tumor tissue at biopsy.

Visit www.lungcancerprofiles.com for the patient perspective on molecular profiling.

are being made at a rapid pace.”

References: 1. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12:175-180. 2. Gandara DR, Li T, Lara PN Jr, et al. Algorithm for codevelopment of new drug-predictive biomarker combinations: accounting for inter- and intrapatient tumor heterogeneity. Clin Lung Cancer. 2012;13(5):321-325. 3. Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. 4. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med. 2008;359(13):1367-1380. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Non-small Cell Lung Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed August 20, 2012. To view the most recent and complete version of the guideline, go online to http://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. 6. Carr LL, Finigan JH, Kern JH. Evaluation and treatment of patients with non-small cell lung cancer. Med Clin N Am. 2011;95:1041-1054. 7. Goetsch CM. Genetic tumor profiling and genetically targeted cancer therapy. Semin Oncol Nurs. 2011;27(1):34-44. 8. National Institutes of Health. Lung cancer mutation consortium protocol. http://clinicaltrials.gov/ct2/show/NCT01014286. Accessed January 19, 2012. 9. National Cancer Institute. The cancer genome atlas. http://cancergenome.nih.gov/abouttcga/overview. Accessed January 19, 2012. 10. Boland JM, Erdogan S, Vasmatzis G, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152-1158. © 2012 Pfizer Inc.

Printed in USA/November 2012

CRI433117-04

The ASCO Post | MARCH 1, 2013

PAGE 30

News

Prophylactic Platelets continued from page 27

The analysis found comparable hemostatic outcomes for the two strategies, Dr. Stanworth reported. “This multicenter study has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis,” he announced.

Bleeding Rates Before presenting results for the hemostatic outcomes, Dr. Stanworth indicated there was a significant difference in platelet counts and use of platelet transfusions between the two trial arms. Overall, grade 2 to 4 bleeding (predominantly grade 2) was seen in 43% of the prophylaxis group and in 50% of the no-prophylaxis group (P value for noninferiority = .06). Without prophylaxis, patients experienced significantly more days on which bleeding occurred (1.7 vs 1.2 days; P = .004) and had a shorter time to the first occurrence of bleeding (P = .02). Patients in the no-prophylaxis group had more days with a WHO grade 2 or above bleed, and a shorter time to first bleed. “This multicenter study has not shown that a no-prophylaxis platelet transfusion policy is noninferior to prophylaxis,” Dr. Stanworth said.

Grade 3 and 4 bleeds were observed in 1 of 298 patients who had prophylaxis (0.3%) but in 6 of 300 (2%) who lacked prophylaxis. This represented a sixfold increased risk; however, the difference was not statistically significant (P = .13). “Serious bleeding complications remain rare,” Dr. Stanworth noted. One intracranial bleed occurred in the group without prophylaxis. Notably, 2 of 7 patients who developed grade 3 or 4 bleeds had platelet counts > 10 × 109/L at the onset of bleeding; both had acute myeloid leukemia and underwent induction chemotherapy. There were no significant differences between the arms in duration of thrombocytopenia, number of days in the hospital, or number of serious adverse events.

the investigators evaluated patients who had autologous stem cell transplant (SCT) vs “other” treatment approaches, In the autologous SCT group, which mainly comprised lymphoma and myeloma patients, bleeding occurred in 45% of the prophylaxis group and 47% of those without prophylaxis. By contrast the differences between the strategies were most striking in the “other” group. In the non–autologous transplant group, grade 2 to 4 bleeding occurred in 38% with prophylaxis and 58% without prophylaxis. “The role of prophylactic transfusions in autograft patients is less clear, and requires further research” he said.

Subgroup Analysis

In summary, “The proportion of patients with grade 2-4 bleeding was

In a predefined subgroup analysis,

Conclusion

Prophylactic Platelet Transfusions ■■ The phase III TOPPS trial failed to prove noninferiority of a no-prophylaxis strategy for the use of platelet transfusions in patients with hematologic malignancies and severe thrombocytopenia.

■■ Rates of clinically significant bleeding were 43% in the prophylaxis group and 50% in the no-prophylaxis group.

■■ Patients in the no-prophylaxis group had more days with a WHO grade 2 or higher bleed, and a shorter time to first bleed.

reduced by 7% with the prophylactic platelets.” To achieve this reduction, patients in the prophylactic arm received 61% more platelet transfusions. Dr. Stanworth noted that the rates of bleeding in the study, overall, were high, even when patients received prophylactic platelet transfusions, and he suggested that other approaches to the problem should be explored, such as the use of antifibrinolytic drugs. Factors other than those addressed by prophylactic platelet transfusions are clearly important in determining bleeding risk. n Disclosure: Drs. Dzik and Stanworth reported no potential conflicts of interest.

References 1. Stanworth S, Estcourt L, Powter G, et al: The effect of a no-prophylactic versus prophylactic platelet transfusion strategy on bleeding in patients with hematological malignancies and severe thrombocytopenia (TOPPS trial). 2012 ASH Annual Meeting. Abstract 1. Presented December 9, 2012. 2. Wandt H, Schaefer-Eckart K, Wendelin K, et al: Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: An open-label, multicentre, randomised study. Lancet 380:1309-1316, 2012.

Global Women’s Cancer Summit: Collaboration Aims to Reduce Breast, Cervical Cancers

orld leaders from governments, cancer organizations, and the private sector joined together recently for the first Global Women’s Cancer Summit to address the challenge of reducing the global burden of women’s cancers. The summit was hosted by Susan G. Komen for the Cure and underwritten by GE healthymagination. A new effort “2.5 by 2025,” was announced at the summit where attendees committed to working together toward improving survival and quality of life for at least 2.5 million women with breast cancer in low- and middle-income countries by the year 2025.

Mrs. Laura Bush Delivers Keynote Address A major focus of the summit was identifying innovative solutions to addressing women’s cancers in low- and middle-income countries through public-private partnerships. During her keynote address, Former First Lady Mrs. Laura Bush discussed the importance

of educating and empowering women to take charge of their health. “Women are increasingly agents of change in our world, acting as advocates for health and education to advance opportunities for themselves and their families. By giving women the tools they need to succeed, such as access to education and health care, they not only improve the well-being of their own families, but the stability of their countries as well,” Mrs. Bush said.

Unveiling the ‘2.5 by 2025’ Global Effort The effort called 2.5 by 2025 challenges the global community to come together to combat the increasing breast cancer burden. The goal includes input from leading experts in the cancer and global health community. “We’ve made tremendous progress over the last few years in terms of recognizing that breast cancer is a disease that affects people worldwide, and we are now able to openly discuss how we

combat this disease beyond U.S. borders. The goal of reducing the global breast cancer burden has received enthusiastic support from health experts around the world, and I believe this initiative will make a true impact for women,” said H. Kim Lyerly, MD, George Barth Gellar Professor of Cancer Research at Duke University. Benjamin O. Anderson, MD, Chair and Director of the Breast Health Global Initiative at the Fred Hutchinson Cancer Research Center, said the summit marks the first time that leaders from non-government organizations, corporations, and governments have come together to dramatically improve prevention and early detection strategies for women’s cancers on a global scale. “Reaching 2.5 million by 2025 requires educating people and health-care providers, and expanding access to cancer treatment,” Dr. Anderson said. “Above all, it requires working in partnership with leaders from all sectors, and the people

‘in-country’ who implement these programs. When we do this, we can save lives,” Dr. Anderson said.

Key Levers for Reaching ‘2.5 by 2025’ Discussion at the summit was centered on what’s needed to create change, including leadership and mobilization; innovation, science/research and technology; and program implementation. Panelists discussed the most critical issues facing low- and middle-income countries and the potential for change and creating a better future. There are important lessons to learn from our global fight for access to treatment and care for HIV/AIDS. The cost of not recalling our history is too high. We need to apply these lessons immediately to advocate for and implement programs targeting the prevention, care, and treatment for cancer, said the Honorable Agnes Binagwaho, MD, Minister of Health of the Republic of Rwanda. n

2013 AnnuAl Meeting May 31-June 4, 2013 McCormick Place | Chicago, Illinois

Attend tHe 2013

ASCO AnnuAl Meeting chicago2013.asco.org

Join us in Chicago for the 2013 Annual Meeting as we work to build bridges in oncology between scientific discoveries, new therapeutics, and novel treatments for optimal patient outcomes. Register and reserve your housing today.

Housing and early Registration deadline: April 24, 2013, at 11:59 PM (edt)

The ASCO Post | MARCH 1, 2013

PAGE 32

News Hematology

More Brief Reports from ASH, Including New Data in Leukemia, Lymphoma, and Myelodysplastic Syndrome By Matthew Stenger

t the 54th Annual Meeting of the American Society of Hematology (ASH), held in Atlanta, nearly 5,000 abstracts were presented in oral sessions and posters. As part of our ongoing comprehensive coverage from the meeting, here are three more studies of note.

New Targets in AML Anupriya Agarwal, PhD, and colleagues from the Oregon Health & Science University and Howard Hughes Medical Institute in Portland used a novel RNA interference (RNAi) screen to identify nonkinase cytokine and growth factor receptors involved in leukemogenesis.1 In screening for 188 growth factor receptors highly

Anupriya Agarwal, PhD

expressed in gene microarray analysis of primary AML patient specimens, candidate targets identified in acute myeloid leukemia (AML) patient samples included CD24, NCOA4, IL2Rα, IL15Rα, and IL2Rγ. These targets were often found to have genetic abnormalities ranging from splice variation (IL2Rα) to intron retention (IL15Rα), and in some cases, the receptors were

found to contribute to oncogenesis by acting as a scaffold for regulating downstream oncogenic signaling. Additional study of IL2Rγ showed the receptor to be essential for JAK3 mutant-mediated leukemogenesis. Knockdown of IL2Rγ significantly reduced the viability of JAK3 A572V mutant cells (CMK cell line; 90% decrease) and blocked phosphorySee Page 36 lation of JAK3 and the downstream signaling molecules STAT5, MAPK, and pS6 ribosomal protein. Overexpression of IL2Rγ enhanced JAK3 A572V-mediated signaling, increased its transformation potential in a ligand-independent manner, increased the oncogenic potential of other JAK3 mutants identified in AML patients, and reduced sensitivity of JAK3 A572V cells to a JAK family inhibitor. Further, the absence of IL2Rγ in murine bone marrow completely blocked the clonogenic potential of JAK3 A572V compared with IL2Rγ-wild type marrow. IL2Rγ was found to contribute to constitutive JAK3 mutant signaling by increasing JAK3 protein levels and phosphorylation; mutant but not wild-type JAK3 was shown to increase expression of IL2Rγ, indicating that IL2Rγ contributes to constitutive JAK3 signaling through a feedback mechanism. “RNAi-based functional screening for AML cell dependence on non-kinase cytokine and growth factor receptors led to the identification of novel oncogenic etiologies for AML. These findings un-

IMPORTANT VIDEO HIGHLIGHTS FROM

derscore the importance of cytokine and growth factor receptors in leukemia pathogenesis,” the investigators noted. They continued, “This assay can identify genes that are crucial for malignant cell growth, regardless of the mutational status, both in cell lines and in primary samples. Future studies integrating this RNAi screen with deep sequencing will lend additional power to this assay by accelerating our understanding of the genetic mechanisms underlying these functional gene targets such that these findings can be rapidly translated into novel therapeutic strategies.”

Chemoresistance in Aggressive B-cell Lymphomas Increased glucose metabolism and continuous reactive oxygen species (ROS) production is a metabolic adaptation strategy of tumor cells that relieves the stress caused by lack of nutrients and oxygen in the tumor environment. Thioredoxin interacting protein (TXNIP) is a negative regulator for both redox thioredoxin (ROS production) and cellular glucose uptake that is found to be repressed in various cancers, including diffuse large B-cell lymphomas. Recent studies have identified frequent mutations in the gene for EZH2 (a highly conserved histone methyltransferase) that lead to critical gene silencing in diffuse large B-cell lymphoma pathophysiology. Kejie Zhang, MD, PhD, and colleagues from Xiamen University, China, and The University of Texas MD Anderson Cancer Center in Houston showed that (1) EZH2 is either overexpressed

or mutated in representative diffuse large B-cell lymphoma cell lines and primary lymphoma cells, (2) downregulation of EZH2 with siRNA leads to the reactivation of TXNIP with subsequent inhibition of tumor cell growth and survival mediated through both thioredoxin (ROS) and glucose metabolism in diffuse large B-cell lymphomas, and (3) histone deacetylation is also involved in EZH2-mediated silencing of TXNIP in diffuse large B-cell lymphomas.2 The histone methylation inhibitor DZNep was shown to be highly effective in inhibiting cell growth in diffuse large B-cell lymphoma lines, particularly chemoresistant lines, and DZNep and the histone deacetylation inhibitor vorinostat (Zolinza) showed synergistic activity in reactivating TXNIP gene expression and inhibiting diffuse large B-cell lymphoma cell growth and survival. The investigators also found that EZH2 regulates constitutive NF-κB activity through both canonical and alternative NF-κB pathways in diffuse large B-cell lymphomas independent of its histone methyltransferase activity, with the findings indicating that the two oncogenic factors exhibit functional crosstalk in lymphoma cells. The investigators concluded, “Our findings have indicated that deregulated EZH2 leads to constitutive NF-�� κB�� activation and to epigenetic silencing of TXNIP, resulting in uncontrolled tumor cell growth and survival mediated through both thioredoxin and glucose metabolism in [diffuse large B-cell lymphomas], and that targeting this pathway represents a novel, rational, and effective

ASH 2012

Dr. James Armitage, Editor-in-chief of The ASCO Post, interviews leading experts:

Dr. Richard Fisher on lymphomas

Dr. Hagop Kantarjian on leukemias

Presented by The ASCO Post. Recorded at ASH 2012 in Atlanta, Georgia Visit ASCOPost.com to view webcast program

Dr. Sagar Lonial on multiple myelomas

ASCOPost.com | MARCH 1, 2013

PAGE 33

News

therapeutic approach to selectively reverse chemoresistance in [diffuse large B-cell lymphoma] patients, particularly relapsed/refractory patients.”

Mutations in Childhood Myelodysplastic Syndrome Researchers from institutions in 11 European nations examined the occurrence of genetic aberrations in an international cohort of 107 pediatric myelodysplastic syndrome (MDS) patients to determine the potential collaborative roles of mutations associated with hyperproliferation (type I) and maturation arrest (type II), reported Andrica de Vries, MD, of Sophia Children’s Hospital, Rotterdam, Netherlands, and colleagues at the ASH meeting.3 Forty-four patients had primary de novo MDS, and 63 had secondary MDS. Karyotypes were studied and the hotspot regions of the NPM1, CEPBA, FLT3, N-RAS, K-RAS, BRAF, PTPN11, c-KIT, RUNX1, P53, ASXL1, NUP98, IDH1 and 2, DNMT3A, and TET2 genes were screened for mutations.

MDS, the currently known molecular aberrations are of minor importance in the pathogenesis of childhood MDS.” n Disclosure: The authors of these three studies reported no potential conflicts of interest.

References 1. Agarwal A, MacKenzie R, Braziel RM, et al: Functional RNAi screen identifies

novel cytokine and growth factor receptors critical for leukemia cell growth. 2012 ASH Annual Meeting. Abstract 1308. Presented December 8, 2012. 2. Zhang K, Pham LV, Tamayo AT, et al: Reversing metabolic and epigenetic cellular alterations to overcome chemo-resistance in aggressive B cell lymphomas. 2012 ASH Annual Meeting. Abstract 1305. Presented

December 8, 2012. 3. de Vries A, Zwaan CM, Jansen JH, et al: Molecular aberrations in 107 children with myelodysplastic syndrome (MDS). 2012 ASH Annual Meeting. Abstract 2802. Presented December 9, 2012. For more Brief Reports from ASH, visit ASCOPost.com.

SPECIFIC

IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER

Andrica de Vries, MD

Type I aberrations were found in 8 patients (7%), including 4 of those (9%) with primary MDS and 4 (6%) of those with secondary MDS. Mutations were found in FLT3–ITD in 3 patients, N-RAS in 2, K-RAS in 2, and PTPN11 in 1. No mutations were found in FLT3-TKD, cKIT, P53, or BRAF. Type II aberrations were found in 17 patients (16%), including 4 (9%) of those with primary MDS and 13 (21%) of those with secondary MDS. Aberrations included MLL rearrangements in 2 patients, RUNX1 rearrangement in 1, RUNX1 mutations in 7, duplications in CEBPα in 5, NPM1 mutations in 1, and NUP98 translocation in 1. Overall, ASXL1 mutations were found in 2 patients and DNMT3A mutations in 1, but no TET2, IDH1, or IDH2 mutations were found in any of the patients. Collaborative type I and II mutations were found in only 2 patients (NRAS + RUNX1 mutation and ASXL1 + RUNX1 mutation), both with secondary MDS. The investigators concluded, “This study indicates that, in contrast to adult

Immunotherapy primes T cells and B cells to recognize and target cancer cells expressing specific tumor antigens.1-3

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. For more information go to www.FightCancerWithImmunotherapy.com References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Namm JP, et al. J Surg Oncol. 2012;105:431-435. 3. Sharma P, et al. Nat Rev Cancer. 2011;11:805-812.

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PAGE 34

Journal Spotlight Thoracic Oncology

Use of Beta-blockers Associated with Improved Survival in Patients with NSCLC Receiving Definitive Radiation Therapy By Matthew Stenger

s reported recently in Annals of Oncology, a retrospective study by Wang and colleagues showed that use of beta-adrenergic receptor antagonists (beta-blockers), typically used in treatment of hypertension and heart disease, was associated with significantly improved distant metastasis–free survival, diseasefree survival, and overall survival in a large cohort of patients with non– See Page 36 small cell lung cancer (NSCLC) undergoing definitive radiation therapy at The University of Texas MD Anderson Cancer Center.1 No significant prolongation of locoregional progression–free survival was observed.

Earlier Studies Preclinical studies have shown that tumor cell migration is stimulated by norepinephrine in a process mediated by beta-adrenergic receptors, suggesting a potential mechanism for a beneficial effect of beta-blocker use. Other retrospective studies have indicated that betablockers may have antitumor activity, with reduced metastasis, tumor recurrence, and cancer-specific mortality being observed in breast cancer patients and increased survival being observed in melanoma patients. Another recently reported retrospective cohort study assessing the effect of beta-blocker use in hypertensive patients with a variety of cancers showed no effect on survival among the 436 patients with lung cancer included in the analysis.2 However, details on patient demographics and treatment regimens were not provided, making conclusions of the analysis less clear.

Patient Characteristics The analysis by Wang and colleagues included 722 patients with newly diagnosed NSCLC undergoing definitive radiation therapy at MD Anderson Cancer Center between 1998 and 2010, of whom 155 had received beta-blocker treatment during radiation therapy. Of patients receiving beta-blockers, the major-

ity received selective beta-blockers, with 85% receiving metoprolol or atenolol. Two-thirds of patients taking beta-blockers did so for treatment of hypertension, with the remainder most frequently receiving betablocker treatment for coronary heart disease. There were significant baseline differences between the group receiving and the group not receiving beta-blockers. Patients receiving beta-blockers were significantly more likely to be older (P < .01, 66% vs 45% aged ≥�� 65 �� years), have worse Karnofsky performance status (P = .04, 78% vs 69% with score ≤ 80), have less-advanced N category (P = .03; N0,1 in 22% vs 15% and N2,3 in 78% vs 85%), have lower-stage disease (P = .04; stage I, II, IIIA, and IIIB in 6%, 5%, 40%, and 49% vs 2%, 3%, 46%, and 49%), not have concurrent �� .02, �� no concurchemotherapy (P =�� rent chemotherapy in 23% vs 15%), have received a higher radiation dose (P < .01, > 63 Gy in 55% vs 43%), have hypertension (P < .01, 68% vs 36%), and be taking aspirin (P < .01, 42% vs 16%). There were no differences between groups in sex (55% male in both), race (86% vs 85% Caucasian), T category (T3,4 in 46% vs 47%), histology (non–squamous cell in 66% vs 63%), gross tumor volume (≥�� 119�� cm in 45% vs 52%), or proportion with chronic obstructive pulmonary disease (28% vs 23%).

Univariate Analysis Median follow up in surviving patients was 44 months (range, 1–155 months). On univariate analyses, Kaplan-Meier survival estimates indicated that beta-blocker use was associated with significantly improved distant metastasis–free, disease-free, and overall survival (all P ≤ .01).

Beta-adrenergic Signaling Pathway By Zhongxing Liao, MD, and Daniel R. Gomez, MD

he take-home message from this study is that in this large group of patients, we have found that beta-blocker intake during radiation therapy for non–small cell lung cancer (NSCLC) is associated with improved survival and reduced rates of tumor spread, even when controlling for a large number of other factors. We hypothesize that the mechanism of this benefit is blockade of the beta-adrenergic signaling pathway, which may play an important role in disease progression as demonstrated in preclinical studies. We can’t conclude from the study data that Zhongxing Liao, MD Daniel R. Gomez, MD the findings are necessarily specific to patients receiving radiation therapy. Indeed, we wanted to examine a select group of patients who were receiving definitive treatment for NSCLC, and the database we decided upon was that including patients undergoing radiation therapy. It is not unreasonable to propose that the results may be extrapolated to other modalities, such as chemotherapy or surgery. However, this hypothesis would need to be tested in the appropriate patient populations. Currently, we would not advocate that patients with NSCLC take betablockers for other than their indicated uses until our findings can be validated by (1) analyses at other institutions and (2) prospective trials. Future molecular studies will help us understand whether our proposed mechanism for the observed effect of beta-blockers is correct, indicating that beta-blockers are thus indeed directly affecting the aggressiveness of this malignancy, or whether our findings are due to the activation or inhibition of another pathway. n Disclosure: Drs. Liao and Gomez reported no potential conflicts of interest.

Dr. Liao is Professor and Clinical Medical Director, and Dr. Gomez is Assistant Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Cox proportional hazards analysis indicated that use of beta-blockers was associated with a 40% reduction in risk for distant metastasis (hazard ratio [HR] = 0.60, P < .01), a 32% reduction in risk for disease signs/ symptoms (HR = 0.66, P < .01), and

Beta-blockers and Outcomes in NSCLC ■■ Use of beta-blockers was associated with significant prolongation

of distant metastasis–free, disease-free, and overall survival, but not locoregional progression–free survival, in patients with non–small cell lung cancer receiving definitive radiation therapy.

■■ Findings are consistent with preclinical studies suggesting beta-blockers may inhibit the metastatic cascade.

a 24% reduction in risk for death �� .01). �� A nonsignifi(HR = 0.76, P =�� cant 15% reduction in risk for locoregional progression was observed (HR = 0.85, P = .33). Among other factors analyzed, stage T3,4 disease, stage N2,3 disease, and younger age were significantly associated with reduced distant metastasis–free and disease-free survival. Poorer performance status and more-advanced clinical disease stage were significantly associated with reduced overall survival. Concurrent chemotherapy was associated with significantly improved overall survival (P < .01).

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Journal Spotlight

Multivariate Analysis On multivariate analysis adjusting for age, performance status, clinical disease stage, tumor histology, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease, and aspirin use, the use of beta-blockers was still associated with a significant 33% reduction in risk for distant metastasis (HR = 0.67, P = .01), a 26% reduction in risk for disease (HR = 0.74, P = .02), and a 22% reduction in risk for death (HR = 0.78, P = .02). Beta-blocker use was associated with a nonsignificant 9% reduction in risk for locoregional progression (HR = 0.91, P = .63). Other factors significantly associated with survival outcomes on multivariate analysis included concurrent chemotherapy, which was associated with a 46% reduction in risk of death (HR = 0.54, P < .01); older age (≥�� 65 vs <�� 65 years), associated with better disease-free survival <�� .01); better perfor(HR = 0.74, P �� mance status (Karnofsky score > 80 vs ≤ 80), associated with improved distant metastasis–free survival (HR = 0.76, P = .03), disease-free survival (HR = 0.77, P = .02), and overall survival (HR = 0.72, P < .01); and more-advanced clinical stage (III vs I or II), associated with poorer distant metastasis–free survival (HR = 2.39, P = .01), disease-free survival (HR = 1.66, P = .04), and overall survival (HR = 1.97, P < .01). In addition, non–squamous cell histology was associated with improved distant metastasis–free survival (HR = 0.68, P < .01), lower radiation dose (60–63 vs > 63 Gy) was associated with poorer locoregional progression–free survival (HR = 1.46, P < .01), and greater gross tumor volume (≥ 119 vs < 119 cm) was associated with significantly poorer distant metastasis–free survival (HR = 1.58, P< .01), diseasefree survival (HR = 1.38, P < .01), and overall survival (HR = 1.61, P < .01). Aspirin use was associated with a borderline significant improvement in distant metastasis–free survival (HR = 0.74, P = .05).

overall survival]—but not with [locoregional progression–free survival]—after definitive treatment that included radiation therapy. These findings are concordant with those of previous preclinical studies, suggesting that beta-blockers have specific effects on the metastatic cascade. Future prospective trials are needed to

validate these retrospective findings and establish whether the length and timing of beta-blocker use influence survival outcomes.” n References 1. Wang HM, Liao ZX, Komaki R, et al: Improved survival outcomes with the incidental use of beta-blockers among

ADAPTABLE IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER As tumor cells mutate, many cancers can become resistant to traditional cancer therapies.1-3 The activated immune system can adapt and recognize new tumor antigens to continue the attack over time.1,4--6

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. For more information go to www.FightCancerWithImmunotherapy.com

Study Conclusion The authors concluded, “This analysis demonstrated that the incidental use of beta-blockers in this group of patients with NSCLC was associated with improved [distant metastasis–free, disease-free, and

patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann Oncol. January 8, 2013 (early release online). 2. Shah SM, Carey IM, Owen CG, et al: Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br J Clin Pharmacol 72:157-161, 2011.

References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 8th ed. Lippincott, Williams & Wilkins; Philadelphia, PA: 2008. 3. Chabner BA, et al, eds. Cancer Chemotherapy & Biotherapy: Principles & Practices. 4th ed. Lippincott, Williams & Wilkins; Philadelphia, PA: 2006. 4. Ribas A, et al. J Clin Oncol. 2003;21:2415-2432. 5. Namm JP, et al. J Surg Oncol. 2012;105:431-435. 6. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335.

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PAGE 36

Journal Spotlight

Young Survivors continued from page 1

The study analyzed self-reported data collected in 2009 by the Behavioral Risk Factor Surveillance System of more than 70,000 participants ranging in age from 20 to 39. Of those, 979 reported having a cancer diagnosis between the ages of 15 and 34 and were at least 5 years from diagnosis. The remaining 67,216 participants with no cancer history were used as controls. The study findings show that even though an almost equal percentage of survivors and controls (21% vs 23%, respectively) did not have health insurance, the adolescent and young adult survivors were 67% more likely to forgo follow-up care due to cost than their peers who have not had cancer. The cancer survivors were mostly female, married, non-Hispanic whites and between the ages of 30 and 39 years. The most common cancer among the female survivors was cervical, while non-Hodgkin lymphoma was the most common cancer among the male survivors. Although studies have shown that 80% of young adults with cancer survive at least 5 years after diagnosis,2 the chemotherapy, radiation, and surgical treatments they received put many at risk for developing late health effects, including secondary cancers, infertility, and cardiac problems, making followup medical care especially important.3 As many as 22% of survivors in the Cancer study did not have a medical provider, and 40% reported having no routine medical care in the past year.

Long-term Effects of Cancer Although the study did not explore why the young adult cancer survivors with health insurance also often skipped follow-up medical visits, the

difficulty of getting time off from work and the additional expense of paying for child care and transportation costs to and from the visits may also be factors in forgoing care, said Dr. Kirchhoff. Still others may just be unaware of the long-term health consequences of having cancer.

Patient-centered Care Last March, the National Comprehensive Cancer Network (NCCN) released new Clinical Practice Guidelines in Oncology for Adolescent and Young Adult Oncology,4 which provides specific algorithm-based care recommendations for 15- to 39- year-

Giving [adolescent and young adults] a survivorship care plan is a step in the right direction, but there is no evidence to suggest that it actually results in overcoming the problems of adhering to follow-up care recommendations —Brad Zebrack, PhD, MSW, MPH

“Unfortunately, there is a lack of awareness by young adult survivors of the problems that can emerge over time, so they may not realize that they need to get in to see their doctor and have that coordinated care,” said Dr. Kirchhoff. In addition, “young adult survivors may want to leave cancer behind and move on with their lives, so there is an attitude that serves as a barrier [to continuing care],” said Brad Zebrack, PhD, MSW, MPH, Associate Professor at the University of Michigan School of Social Work in Ann Arbor. “But perhaps an even bigger barrier is the way our system of health care is designed. What’s missing is an organized and systematic transition from oncology care to primary care once the survivor is through with active cancer treatment and is in remission,” Dr. Zebrack added.

Using QR Codes 1

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The code will scan automatically.

Position your device in front of the code so that it fills about half your screen.

If the scan is successful, you will be rerouted to the targeted link.

olds with cancer and includes a special emphasis on psychosocial evaluation and care. “Our sense is that when physicians are treating patients with cancer, they are really looking at disease-specific information and guidelines for treatment. These updated NCCN guidelines were created as a way to complement care for the whole patient, including psychosocial care. The research is telling us that the experiences of having cancer in this age group are very different from pediatric and older adults with cancer,” said Dr. Zebrack, a member of the NCCN Adolescent and Young Adult Oncology Panel. A survivorship care plan can provide young adult cancer survivors with an outline of treatments received and their potential long-term consequences, recommendations on prevention strategies for cancer recurrence or new cancers, and specific details about the timing and content of recommended follow-up care. Nevertheless, adolescents and young adults may require more personalized attention to make them adhere to the information provided in their survivorship plan. “Giving [adolescent and young adults] a survivorship care plan is a step in the right direction, but there is no evidence to suggest that it actually results in overcoming the problems of adhering to follow-up care recommendations,” said Dr. Zebrack. “I think the reality of handing someone a booklet with a record of his suggested continuing care is that he goes home and shoves it in a drawer. A formalized system of followup care needs to be in place so that after the patient leaves the care of his oncolo-

gist, there is coordination with the patient’s primary care physician.” To help oncologists and primary care physicians be better equipped to understand the unique challenges that young adult cancer survivors face and to educate those patients about their potential long-term health-care needs, 2 years ago ASCO and LIVESTRONG launched a new ASCO University® program called Focus Under Forty™.5 The program offers educational courses in the unique biology and care issues of survivors ranging in ages from 15 to 39. “With nearly 13 million cancer survivors in the United States, primary care physicians are now more likely to see people with a history of cancer in their practice, so efforts to educate them about some of the long-term risks of exposure to chemotherapeutics and radiation will be helpful,” said Dr. Zebrack.

Financial Burden of Cancer Some of the financial stumbling blocks keeping adolescents and young adults from maintaining long-term survivorship care may also be alleviated soon. A provision in the Patient Protection and Affordable Care Act requires health insurance plans that offer dependent coverage to make the coverage available until a child reaches the age of 26, so young adult survivors aged 26 and younger can now remain on their parents’ health insurance plans, making ongoing survivorship care more affordable. Also, survivors with health problems that make them uninsurable in the private market can now access coverage through state-based, preexistingcondition insurance plans. Starting in 2014, under the Affordable Care Act, young adults will be able to buy affordable insurance through state-run health insurance exchanges, and lowincome survivors may be able to access insurance coverage through the Medicaid expansion provision in the law. “In some of my other research, we talked to younger cancer survivors who are still on their parents’ health insurance, and they said that they would not have had another option for insurance coverage if they weren’t able to do that,” said Dr. Kirchhoff. “The insurance exchanges in 2014 will help people with preexisting conditions, like young cancer survivors, get affordable insurance. The Affordable Care Act also prohibits lifetime dollar limits on health-care services, which is a big issue for high medical users who can reach spending caps quickly.”

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Journal Spotlight

Other Access Considerations The Affordable Care Act does not entirely solve the problem of healthcare accessibility for every adolescent and young adult survivor. According to the study reported in Cancer, AYA survivors may need additional healthcare resources as they transition out of the oncology setting, such as information on community health centers and financial assistance programs, to improve their access to long-term survivorship care. Moreover, with the Supreme Court’s ruling last June—that individual states have the option of not expanding their Medicaid programs as outlined in the Affordable Care Act— the lowest-income adolescent and young adult survivors may be in the greatest jeopardy of not being able to meet their health-care financial needs. “Unfortunately, the Supreme Court ruling will leave some very low-income survivors without access to health care. They may not be able to afford to buy insurance on the health insurance exchanges or be eligible for enrollment in Medicaid in their state, so there will still be limitations for those with the

greatest health-care need,” said Dr. Kirchhoff. n Disclosure: Drs. Kirchhoff and Zebrack reported no potential conflicts of interest.

References 1. Kirchhoff AC, Lyles CR, Fluchel M, et al: Limitations in health care access and utilization among long-term survivors of

adolescent and young adult cancer. Cancer 118:5964-5972, 2012. 2. Ries LA, Eisener MP, Kosary CL: SEER cancer statistics review, 1975-2001. National Cancer Institute, 2004. Available at seer.cancer.gov. Accessed December 3, 2012. 3. Oeffinger KC, Hudson MM: Longterm complications following childhood and adolescent cancer. CA Cancer J Clin

54:208-236, 2004. 4. National Comprehensive Cancer Network. NCCN Guidelines Version 1.2012: Adolescent and young adult oncology. Available at www.nccn.org. Accessed December 3, 2012. 5. ASCO University: Focus under forty. Available at http://university.asco. org/focusunder40. Accessed December 3, 2012.

DURABLE

IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER

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.

Immunotherapy activates some immune cells to become memory cells.1-4 These memory cells remain primed to rapidly induce another immune response, even after active treatment has ended.1-4

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. Write to The ASCO Post at editor@ASCOPost.com.

For more information go to www.FightCancerWithImmunotherapy.com

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Abbas AK, et al, eds. Basic Immunology. Functions and Disorders of the Immune System. 3rd ed. Saunders Elsevier; Philadelphia, PA: 2011. 3. Atanackovic D, et al. PNAS. 2008;105(5):1650-1655. 4. Perret R, et al. Tissue Antigens. 2008;72:187-194.

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PAGE 38

In the Clinic Gastrointestinal Oncology

Bevacizumab plus Chemotherapy after Progression of Metastatic Colorectal Cancer on First-line Therapy Including Bevacizumab By Matthew Stenger

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

Indication On January 23, 2013, bevacizumab (Avastin) was approved for use in combination with fluoropyrimidine/irinotecan- or fluoropyrimidine/ oxaliplatin-based chemotherapy for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-containing regimen.1,2 BevaSee Page 36 cizumab has prior indications in first- and second-line treatment of metastatic colorectal cancer, nonsquamous non–small cell lung cancer, glioblastoma, and metastatic renal cell cancer. It is not indicated for use in adjuvant treatment of colon cancer. Approval was based on a randomized, open-label, international phase III trial in which patients with unresectable metastatic colorectal cancer progressing up to 3 months after discontinuing

OF NOTE Bevacizumab binds to VEGF, thereby preventing endothelial cell proliferation and angio genesis. first-line bevacizumab plus chemotherapy were randomized to receive secondline therapy with (n = 409) or without (n = 411) bevacizumab at 2.5 mg/kg per week (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks).2,3 For second-line chemotherapy, patients were switched to irinotecan-based treatment if their first-line regimen was oxaliplatin-based and to oxaliplatin-based chemotherapy if their first-line treatment was irinotecan-based. The primary endpoint was overall survival. The patient groups were well matched at baseline for sex (65% vs 63%

male), age (median of 63 years in both), ECOG performance status (0 in 44% vs 43%), proportion of patients with metastasis to more than one organ (64% vs 61%), and proportion receiving firstline treatment with irinotecan-based (59% vs 58%) or oxaliplatin-based (41% vs 42%) chemotherapy. Patients were also well matched for type of irinotecan- or oxaliplatin-based therapy received in second-line treatment. Median overall survival was 11.2 months in the bevacizumab group vs

infusion of bevacizumab should be given over 90 minutes; if tolerated, the second infusion should be given over 60 minutes, and all subsequent infusions can be given over 30 minutes if 60-minute infusion is tolerated. Bevacizumab should not be given until at least 28 days following major surgery and only after full healing of surgical incisions, and should not be given to patients with serious hemorrhage or recent hemoptysis. It should be discontinued for gastrointestinal

Second-line Bevacizumab after First-line Bevacizumab Fails ■■ Bevacizumab (Avastin) has been approved for use with fluoropyrimidine/ irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy to treat metastatic colorectal cancer after disease has progressed on first-line bevacizumab.

■■ In this setting, bevacizumab is given at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks.

9.8 months in the chemotherapy-alone group, representing a significant 19% reduction in risk of death with bevacizumab treatment (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = =�� .0062). Median progres0.69–0.94, P �� sion-free survival was also significantly prolonged with bevacizumab treatment (5.7 vs 4.1 months, HR = 0.68, P < .0001).

How It Works Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to human vascular endothelial growth factor (VEGF), preventing the interaction of VEGF with its receptors on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in models of angiogenesis. In xenograft models of colon cancer, bevacizumab reduced microvascular growth and inhibited metastatic disease progression.

How It Is Given Bevacizumab is given at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine/irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy regimen in patients who have progressed on a first-line bevacizumab-containing regimen. The first

(GI) perforations, fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage, severe arterial thromboembolic events, hypertensive crisis or hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome, and nephrotic syndrome. Treatment should be suspended at least 4 weeks prior to elective surgery, for severe hypertension not controlled with medical management, for moderate to severe proteinuria pending further evaluation, and for severe infusion reactions. There are no recommended dose reductions for bevacizumab. Urine protein and blood pressure should be monitored during treatment.

Safety Profile No new safety signals were observed in the trial supporting the new indication, with safety data being consistent with the known safety profile of bevacizumab established in prior indications. Grade 3 to 5 adverse events occurred in 64% of the bevacizumab group and 57% of the chemotherapyalone group, with the most frequent being neutropenia (16% and 13%), diarrhea (10% and 8%), and asthenia (6% and 4%). Grade 3 to 5 adverse events of particular interest that oc-

OF NOTE Bevacizumab safety data in this indication are consistent with prior indications; the drug carries boxed warnings for GI perforation, surgery and wound healing complications, and hemorrhage. curred more frequently in the bevacizumab group were bleeding or hemorrhage (2% vs < 1%), GI perforation (2% vs <�� 1%), and venous thromboembolic events (5% vs 3%). Of 11 adverse events resulting in death in each group, those considered related to study treatment were upper GI hemorrhage, cerebrovascular accident, sudden death, and neutropenia in one patient each in the bevacizumab group and intestinal perforation, general physical health deterioration, and acute prerenal failure in one patient each in the chemotherapy-alone group. Treatment was discontinued due to adverse events in 16% of the bevacizumab group (including discontinuation of bevacizumab alone in 2%) and in 9% of the chemotherapy-alone group. Bevacizumab has boxed warnings for GI perforation (occurring in up to 2.4% of patients), surgery and wound healing complications, and hemorrhage (including increased risk of severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding). Bevacizumab also has warnings/precautions for non-GI fistula formation, arterial thromboembolic events, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure. n References 1. U.S. Food and Drug Administration: Bevacizumab. Available at http://www. fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm336763.htm. Accessed February 6, 2013. 2. AVASTIN® (bevacizumab) prescribing information, Genentech US, Inc, January 2013. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2013/125085s263lbl.pdf. Accessed February 6, 2013. 3. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomized phase 3 trial. Lancet Oncol 14:29-37, 2013.

In metastatic melanoma

MAKE TREATMENT PERSONAL by testing for the BRAF V600E mutation with the cobas test 速

Test at diagnosis. Test with the cobas 4800 BRAF V600 Mutation Test. 速

Only FDA-approved BRAF PCR diagnostic1 20% more accurate than Sanger Sequencing with fewer false negatives and invalid results1

Indication and Usage: ZELBORAF速 (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Please see Brief Summary of Prescribing Information and next page for Important Safety Information.

dEcodE metastatic melanoma.

ExtEnd

Significant improvement in OS vs dacarbazine in a randomized Phase III trial of BRAFV600E(+) patients (N=675)* OS at FDA approval (August 2011)†‡ 100

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

Percentage surviving

80 60

Not reached

7.9

OS=overall survival HR=hazard ratio CI=confidence interval *Patients crossing over to ZELBORAF were censored.2

20 0

At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine.

‡

There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

Median OS was not reached (NR) for ZELBORAF vs 7.9 months for dacarbazine (95% CI, 9.6 months-NR vs 7.3-9.6 months) The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) The incidence of cuSCC, including both SCCs of the skin and keratoacanthomas, was 24%. Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months after therapy. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, generalized rash and erythema, or hypotension, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT prolongation Exposure-dependent QT prolongation has been reported, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes. Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval.

Monitor ECG and electrolytes before treatment and after dose modification. Monitor ECGs at day 15, monthly during the first 3 months of treatment, every 3 months thereafter, or more often as clinically indicated. If the QTc exceeds 500 ms, temporarily interrupt ZELBORAF, correct electrolyte abnormalities, and control cardiac risk factors for QT prolongation. Re-initiate treatment at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred. Monitor liver enzymes and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity has been reported. Advise patients to avoid sun exposure and use adequate sun protection. For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions Serious ophthalmologic reactions, including uveitis and retinal vein occlusion, have been reported. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Routinely monitor patients for uveitis.

SURVIVAL Updated Significant OS improvement confirmed in an updated analysis3§ OS update at ASCO 20123||¶ 100

HR=0.70 (95% CI, 0.57-0.87), P<0.001

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

At the time of updated analysis, median follow-up was 12.45 months (range, 0.4-24.0 months) for ZELBORAF patients vs 9.45 months (range, 0.0-22.5 months) for those taking dacarbazine.3,4

At the time of the ASCO 2012 updated analysis, there were 199 deaths and 166 deaths in the ZELBORAF and dacarbazine arms, respectively.4

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

Median OS reached at 13.6 months with ZELBORAF: ~4-month improvement over dacarbazine median OS of 9.7 months (95% CI, 12.0-15.2 months vs 7.9-12.8 months)3,4

Additionally, blurry vision, iritis, and photophobia were observed. New Primary Malignant Melanoma New primary melanomas were reported in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitor for skin lesions as outlined on previous page [see cuSCC]. Use in Pregnancy: Pregnancy Category D Apprise patients who are pregnant or who may become pregnant that ZELBORAF may cause fetal harm. BRAF Testing Confirmation of BRAFV600E(+) melanoma is required for appropriate patient selection. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information.

References: 1. cobas® 4800 BRAF V600 Mutation Test Package Insert. Roche Molecular Systems, Inc. August 2011. 2. Center for Drug Evaluation and Research. Clinical review—NDA 202429: ZelborafTM (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/ 202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed July 23, 2012. 3. Chapman PB, Hauschild A, Robert C, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. Presented at: the 48th Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract 8502. 4. Data on file. Genentech, Inc.

zelboraf.com

The ASCO Post | MARCH 1, 2013

PAGE 42

News Gastrointestinal Oncology

Genetics, Mathematics, and Colorectal Cancer By Jo Cavallo

wo recent study reports in colorectal cancer explored new data on genetic precursors to the disease and outcome predictors once treatment is initiated.

ZELBORAF ® (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

New Genetic Links to Colorectal Cancer Are Identified Investigators from VanderbiltIngram Cancer Center, Nashville, and colleagues in China, South Korea, and

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

Japan have identified three new genetic “hotspots” linked to colorectal cancer. One of the genetic loci is in close proximity to CCND2, the gene encoding cyclin D2, which plays a critical role in cell-

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

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

cycle progression and has been shown to be overexpressed in colorectal tumors. Another variant is located near the PITXI gene, a tumorsuppressor gene that may activate TP53 and regulate the acSee Page 36 tivity of the enzyme telomerase. And the third variant includes two genes, HAO1 and PLCB1. PLCB1 has been previously shown to be overexpressed in colorectal cancer tissue. Results from the study were published in Nature Genetics.1

Investigators have identified three new genetic ‘hotspots’ linked to colorectal cancer,...,which may provide new insight into the biology of colorectal cancer and present new therapeutics targets for treatment. The researchers analyzed 5,252 colorectal cancer cases and 9,071 control samples from the Asia Colorectal Cancer Consortium to identify novel colorectal cancer risk factors. The three variants found may provide new insight into the biology of colorectal cancer and present new therapeutic targets for treatment, according to the study.

Mathematical Model May Help Predict Response to Chemotherapy A new mathematical model that measures the amount of stress required for a cancer cell to die without harming healthy tissue may help scientists better predict which patients with colorectal cancer will respond to chemotherapy, according to a new study published in Cancer Research.2 Apoptosis is believed to be a hallmark of cancer resistance to chemotherapy. Previous studies have shown that an essential step in apoptosis—the process that leads to mitochondrial outer membrane permeabilization (MOMP)—is continued on page 43

ASCOPost.com | MARCH 1, 2013

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Patient’s Corner

Colorectal Cancer continued from page 42

controlled by different members of the Bcl-2 family of proteins. Because some Bcl-2 proteins promote apoptosis and some prevent it, and those proteins that have the same effects on apoptosis work in parallel and can substitute for each other, it is difficult to predict whether cells are likely or unlikely to die. Researchers from the Royal College of Surgeons in Ireland developed a tool that incorporates patient-specific molecular data sets. They studied the Bcl-2 proteins, determined levels of the individual proteins, and then put the levels into a mathematical model that calculated what genotoxic stress level is needed to achieve apoptosis. The researchers applied their model predictor, called DR_MOMP, to protein profiles in tumor tissue and matched normal tissue samples from 26 patients with colorectal cancer and found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. The differences, according to the study, were sufficient to differentiate clinical responders from nonresponders “with high confidence.” The finding may provide a clinical decision-making tool that predicts treatment responses in patients with colon cancer. The researchers hope to validate DR-MOMP in other cancer types and in larger patient cohorts. n References 1. Jia WH, Zhang B, Matsuo K, et al: Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer. Nature Genetics 45:191196, 2012. 2. Lindner AU, Concannon CG, Boukes GJ, et al: Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapy. Cancer Research 73:519-528, 2013.

Solving a 30-year Mystery

Cured of Hodgkin lymphoma, I never expected the health problems I was having were late effects from my treatment. By Carol Kuehnert, as told to Jo Cavallo

hen I began experiencing severe neck and back pain about 9 years ago, I had no idea it could be a late side effect from the radiation therapy I had received 31 years ago to treat my Hodgkin lymphoma. And none of the doctors I’ve seen over the past decade have been able to make the connection either, making my efforts to find a reason and a solution to my physical ailments frustrating. When the pain became worse and

none would say with certainty that my muscle deterioration is a late effect from my treatment, so I launched my own investigation.

Finding Satisfaction Within minutes of doing a cursory search on Google, I found several studies showing a correlation between progressive muscle atrophy and weakness in Hodgkin lymphoma survivors who had received mantle field radiotherapy

Medicine has evolved a lot over the past 30 years, and physicians now know much more about the potential late effects from treatment. —Carol Kuehnert

I noticed that I was unable to hold my head up straight without using my hand for support, I saw a neurologist, who diagnosed dropped head syndrome, which was caused by weakness of the muscles in the back of my neck. I also have severe atrophy of the cervical paraspinal muscles, the upper thoracic paraspinal muscles, and the trapezius muscles. Because I had received a radiotherapy schedule of 3,960 cGy in 22 fractions over a 4½-week period to my mediastinum, I began to wonder if the treatment had caused the muscles in my neck and upper back to weaken. After seeking the advice of several doctors, including my former oncologist,

decades earlier. When I showed the studies to my oncologist, he said he had never heard of radiotherapy causing this effect. Finally having an answer to the cause of my problems was a relief because it took away the guilt I had been feeling, thinking that poor posture or a sedentary lifestyle had led to my condition. I still feel frustrated by the failure of my physicians to see the connection between the radiotherapy I received and my later problems, but more than anything else, I worry about all the other cancer survivors who may be experiencing late side effects—especially rare ones like mine—who aren’t getting the help they need.

Reducing Risk for Other Late Effects A physical therapist showed me some exercises to do to strengthen my remaining healthy upper body muscles and reduce my risk for further muscle deterioration, and I do them diligently. I’m also aware of the potential for developing secondary cancers, including breast cancer, as a result of my long-ago treatment, and I follow the American Cancer Society guidelines about getting regular screening mammograms. My primary care physician is also monitoring a recent sharp drop in my bone mineral density, which is putting me at high risk for osteoporosis, another late effect from radiation therapy. Despite these problems, I’m grateful that the treatment I received cured my Hodgkin lymphoma, allowing me to raise a family and see the birth of my two grandchildren. And I realize that medicine has evolved a lot over the past 30 years, and physicians now know much more about the potential late effects from treatment than they did when I was diagnosed. Still, my experience has left me feeling on my own as I try to stay on top of my myriad health issues. I saw many doctors over the past 9 years because I was looking for answers and for someone to be on my side, and I wasn’t successful. I just keep thinking: I was able to find information that linked my physical problems to the radiation I had received. Why couldn’t my doctors? n Carol Kuehnert, a retired nurse, lives in Fort Wayne, Indiana.

News and Views from the World of Clinical Oncology and Hematology Visit The ASCO Post website at

www.ASCOPost.com

For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers

When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insuﬃcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

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Lab Notes

Ongoing Molecular Research in the Science of Oncology TREATMENT RESISTANCE Vemurafenib-resistant BRAFmutant Melanoma Mutational activation of BRAF is the

most prevalent genetic alteration in melanoma, with ≥ 50% of tumors expressing the BRAF(V600E) oncoprotein. Vemurafenib (Zelboraf) produces tumor regression and improved survival in patients with late-stage BRAF-mutated mel-

anoma. However, most patients relapse with drug-resistant disease, suggesting that understanding and preventing resistance may lead to improved therapy. In a recent study, Das Thakur and colleagues from Novartis Institutes for

Biomedical Research in Emeryville, California, and Cambridge, Massachusetts; University of California, San Francisco; and University Hospital Zurich, Switzerland found that modulation of vemurafenib dosing in primary human mela-

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients BRIEF SUMMARY BRIEF SUMMARY Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients ® (ofatumumab) Study 1 and inInjection, the Fludarabineand Alemtuzumab-Refractory Subset ARZERRA® (ofatumumab) Injection, for intravenous infusion ARZERRAin in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset for intravenous infusion of Study 1 (MedDRA 9.0) of Study 1 (MedDRA 9.0) The following is a brief summary only; see full prescribing information for The following is a brief summary only; see full prescribing information for complete product information. complete product information. Fludarabine- and Fludarabine- and AlemtuzumabAlemtuzumabTotal Population Total Population 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE Refractory (n = 154) ARZERRA® (ofatumumab) is indicated for the treatment of patients ARZERRA® (ofatumumab) is indicated for the (n = 154) treatment of patients Refractory (n = 59) with chronic lymphocytic leukemia (CLL) refractory to fludarabine and with chronic lymphocytic leukemia (CLL) refractory to fludarabine and (n = 59) Grade Grade All All Grade All is basedGrade All alemtuzumab. The effectiveness of ARZERRA is based on the demonstration alemtuzumab. The effectiveness of ARZERRA on the demonstration ≥3 Body System/ ≥3 Grades Grades ≥3of full prescribing ≥3 Grades Grades System/ of durable objective responses [see Clinical Studies (14) of full prescribing of durable Body objective responses [see Clinical Studies (14) information]. No data demonstrate an improvement in disease-related information]. No data demonstrate an improvement in disease-related % Adverse Event % % % % % % % Adverse Event symptoms or increased survival with ARZERRA. symptoms Infections or increased with ARZERRA. andsurvival infestations Infections and infestations Pneumoniaa Pneumoniaa 23 14 25 15 23 14 25 15 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS Upper respiratory tract Upper respiratory tract None. None. 11 0 3 0 11 0 3 0 infection infection 5 WARNINGS AND PRECAUTIONS 5 WARNINGS AND PRECAUTIONS Bronchitis 11 <1 19 2 Bronchitis 11 <1 19 2 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions b Sepsisb 8 8 pulmonary 10 edema, 10 8 8 10 10 manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, manifesting asSepsis bronchospasm, dyspnea, laryngeal edema, Nasopharyngitis 8 cardiac ischemia/infarction, 0 8 0 Nasopharyngitis 8 0 8 0 flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, flushing, hypertension, hypotension, syncope, Herpes zoster 6 Herpes zoster 6 1 7 2 back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion back pain, abdominal pain, pyrexia, rash, urticaria, and 1angioedema.7 Infusion 2 5 2 infusions2 [see Adverse 3 2 Sinusitis 5 2 3 2 reactions occur more frequently with the first 2 infusions [see Adverse reactions occurSinusitis more frequently with the first Blood Premedicate and lymphaticwith acetaminophen, an antihistamine, and a Blood and lymphatic Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and Reactions a (6.1)]. corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing corticosteroid [seedisorders Dosage and Administration (2.1, 2.4) of full prescribing system system disorders information]. Interrupt infusion for infusion reactions of any severity. Institute information]. Interrupt reactions of 5any severity.17Institute 8 Anemia infusion for infusion16 Anemia 16 5 17 8 medical management for severe infusion reactions including angina or other medical management for severe infusion reactions including angina or other Psychiatric disorders Psychiatric disorders signs and symptoms of myocardial ischemia [see Dosage and Administration signs and symptoms of myocardial ischemia Insomnia 7 [see Dosage 0 and Administration 10 0 Insomnia 7 0 10 0 (2.3) of full prescribing information]. In a study of patients with moderate(2.3) of full prescribing information]. In a study of patients with moderate Nervous system disorders Nervous system disorders to severe chronic obstructive pulmonary disease, an indication for whichto severe chronic obstructive pulmonary disease, an indication for which Headache 6 0 7 0 Headache 6 0 7 0 ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm Cardiovascular disorders Cardiovascular disorders during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia during and infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and Hypertension 0 Hypertension 5 0 8 0 thrombocytopenia can occur with ARZERRA. Monitor complete blood counts thrombocytopenia can occur with ARZERRA.5 Monitor complete blood8 counts 0 Hypotension 5 during therapy, 0 3 0 Hypotension 5 0 3 0 (CBC) and platelet counts at regular intervals during therapy, and increase (CBC) and platelet counts at regular intervals and increase <1 or 4 cytopenias. 7 2 Tachycardia 5 <1 7 2 the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. the frequency Tachycardia of monitoring in patients who5develop Grade 3 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal Respiratory, thoracic, and Respiratory, thoracic, and leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. leukoencephalopathy including fatal PML, can occur with ARZERRA. mediastinal(PML), disorders mediastinal disorders Consider PML in any patient with new onset of or changes in pre-existing Consider PML Cough in any patient with new onset 19of or changes 0 in pre-existing 19 0 Cough 19 0 19 0 neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, neurological signs or symptoms. Discontinue Dyspnea 14 ARZERRA 2if PML is suspected, 19 5 Dyspnea 14 2 19 5 and initiate evaluation for PML including consultation with a neurologist,and initiateGastrointestinal evaluation for PML including consultation with a neurologist, disorders Gastrointestinal disorders brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Diarrhea 18 0 19 0 Diarrhea 18 0 19 0 Fulminant and fatal hepatitis B virus (HBV) infection and reactivation canFulminant and fatal hepatitis B virus (HBV) infection and reactivation can Nausea 0 12at high 0 Nausea 11 0 12 0 occur in patients following treatment with ARZERRA. Screen patients at occur high in patients following treatment with 11 ARZERRA. Screen patients and subcutaneous Skin and subcutaneous risk of HBV infection before initiation of ARZERRA. Closely monitor carriers risk of HBVSkin infection before initiation of ARZERRA. Closely monitor carriers tissue disorders tissue disorders of hepatitis B for clinical and laboratory signs of active HBV infection during of hepatitis B for clinical and laboratory signs of active HBV infection during c Rashc 14 <1 the last infusion 17 2 14 <1 17 2 treatment with ARZERRA and for 6 to 12 months following the last infusion treatment withRash ARZERRA and for 6 to 12 months following Urticaria ARZERRA in patients 8 who develop 0 viral hepatitis 5 Urticaria 8 0 5 0 of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis of ARZERRA. or Discontinue or 0 reactivation of viral hepatitis, and institute appropriate treatment. Insufficient reactivation ofHyperhidrosis viral hepatitis, and institute appropriate treatment. Insufficient 5 0 5 0 Hyperhidrosis 5 0 5 0 data exist regarding the safety of administration of ARZERRA in patientsdata withexist regarding the safety Musculoskeletal and of administration of ARZERRA in patients with Musculoskeletal and active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine connective tissue disorders connective tissue disorders can occur in patients receiving ARZERRA. Perform a diagnostic evaluation can occur in patients receiving ARZERRA. Perform a diagnostic evaluation Back pain 8 1 12 2 Back pain 8 1 12 2 if obstruction is suspected. 5.6 Immunizations The safety of immunization if obstruction isMuscle suspected. 5.6 Immunizations spasms 5 The safety 0 of immunization 3 0 Muscle spasms 5 0 3 0 with live viral vaccines during or following administration of ARZERRA has with live viral vaccines duringand or following administration of ARZERRA has General disorders General disorders and not been studied. Do not administer live viral vaccines to patients who have not been studied. Do not administer live viral vaccines to patients who have administration site administration site recently received ARZERRA. The ability to generate an immune responserecently to received ARZERRA. The ability to generate an immune response to conditions any vaccine following administration of ARZERRA has not been studied. any vaccineconditions following administration of ARZERRA has not been studied. Pyrexia 20 3 25 5 Pyrexia 20 3 25 5 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS Fatigue 15 0 15 0 Fatigue 15 0 15 0 The following serious adverse reactions are discussed in greater detail in The following serious adverse reactions are9discussed <1 in greater detail Edema peripheral 8 in 2 Edema peripheral 9 <1 8 2 other sections of the labeling: other sections Chills of the labeling: 8 0 10 0 Chills 8 0 10 0 • Infusion Reactions [see Warnings and Precautions (5.1)] • I nfusiona Reactions [see Warnings and Precautions (5.1)] Pneumonia includesand pneumonia, lung(5.2)] infection, lobar pneumonia, and a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and • Cytopenias [see Warnings and Precautions (5.2)] • C ytopenias [see Warnings Precautions bronchopneumonia. bronchopneumonia. • Progressive Multifocal Leukoencephalopathy [see Warnings and • P rogressive Multifocal Leukoencephalopathy [see Warnings and b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock.b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Precautions (5.3)] Precautions (5.3)] c c includes rash, macular, andPrecautions rash vesicular. Rash includes rash, rash macular, and rash vesicular. • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • H epatitisRash B Reactivation [seerash Warnings and (5.4)]

• Intestinal Obstruction [see Warnings and Precautions (5.5)] • I ntestinal Obstruction [see Infusion Warningsreactions and Precautions Infusion Reactions: occurred(5.5)] in 44% of patients on theInfusion Reactions: Infusion reactions occurred in 44% of patients on the The most common adverse reactions (≥10%) in Study 1 were neutropenia, The most day common reactions (≥10%)29% in Study 1 wereofneutropenia, of theadverse first infusion (300 mg), on the day the second infusionday of the first infusion (300 mg), 29% on the day of the second infusion pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, Infections:(2,000 mg), (2,000 mg), and less frequently during subsequent infusions. A and less frequently during subsequent infusions. Infections: A nausea, bronchitis, and upper respiratory tract infections. The most common nausea, bronchitis, and upper respiratory tract infections. The most total of 108 patients (70%) experienced bacterial, viral, or common fungal infections. total of 108 patients (70%) experienced bacterial, viral, or fungal infections. serious adverse reactions in Study 1 were infections (including pneumonia serious adverse in Study 1 infections (including pneumonia A total reactions of 45 patients (29%)were experienced ≥Grade 3 infections, of which 19 A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 and sepsis), neutropenia, and pyrexia. Infections were the most commonand sepsis), neutropenia, and Infections the most common (12%) were fatal. Thepyrexia. proportion of fatalwere infections in the fludarabine- and (12%) were fatal. The proportion of fatal infections in the fludarabine- and adverse reactions leading to drug discontinuation in Study 1. 6.1 Clinical adverse reactions leading to drug discontinuation Study 1. 6.1 Clinical alemtuzumab-refractory group was 17%.inNeutropenia: Of 108 patients alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients Trials Experience Because clinical trials are conducted under widely varying Trials Experience Because clinical trialsatare conducted underdeveloped widely varying with normal neutrophil counts baseline, 45 (42%) ≥Grade 3 with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 conditions, adverse reaction rates observed in the clinical trials of a drugconditions,neutropenia. adverse reaction rates observed in theGrade 4 clinicalneutropenia. trials of a drug Nineteen (18%) developed Some patients neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients cannot be directly compared to rates in the clinical trials of another drugcannot and beexperienced directly compared to rates in theneutropenia clinical trials of another and new onset Grade 4 >2 weeks in drug duration. experienced new onset Grade 4 neutropenia >2 weeks in duration. may not reflect the rates observed in practice. The safety of monotherapy may not reflect the rates observed in ispractice. Thefor safety of monotherapy 6.2 Immunogenicity There a potential immunogenicity with therapeutic 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic with ARZERRA was evaluated in 181 patients with relapsed or refractorywith ARZERRA wassuch evaluated in 181 patients relapsed refractory proteins as ofatumumab. Serumwith samples fromorpatients with CLL in proteins such as ofatumumab. Serum samples from patients with CLL in CLL in 2 open-label, non-randomized, single-arm studies. In these studies, CLL in 2 open-label, non-randomized, single-armimmunosorbent studies. In theseassay studies, Study 1 were tested by enzyme-linked (ELISA) for Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for ARZERRA was administered at 2,000 mg beginning with the second doseARZERRA anti-ofatumumab was administeredantibodies at 2,000 mg beginning with secondtreatment dose during and after thethe 24-week period. anti-ofatumumab antibodies during and after the 24-week treatment period. th for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The datafor 11 doses (Study 1 3 doses (Study 2 Theand datain 33 patients Results were[n = 154]) negative inor46 patients after the[n = 27]). 8 infusion Results were negative in 46 patients after the 8th infusion and in 33 patients th described in Table 1 and other sections below are derived from 154 patients described after in Table 1 other sections below are derived from the 12and infusion. Immunogenicity assay results are154 patients highly dependentafter on the 12th infusion. Immunogenicity assay results are highly dependent on in Study 1. All patients received 2,000 mg weekly from the second dosein Study 1.several All patients 2,000 mg weekly from the secondassay dosemethodology, factorsreceived including assay sensitivity and specificity, several factors including assay sensitivity and specificity, assay methodology, onward. Ninety percent of patients received at least 8 infusions of ARZERRA onward. Ninety of patients at least 8 infusions of ARZERRA samplepercent handling, timing ofreceived sample collection, concomitant medications, and sample handling, timing of sample collection, concomitant medications, and and 55% received all 12 infusions. The median age was 63 years (range: and 4155% received 12 infusions. Thereasons, median age was 63 years (range:of41antibodies underlyingalldisease. underlying disease. For these reasons, comparison of incidence of antibodies to For these comparison of incidence to to 86 years), 72% were male, and 97% were White. to 86 years), 72% were and 97%of were White.to other products may be misleading. ARZERRA with male, the incidence antibodies ARZERRA with the incidence of antibodies to other products may be misleading.

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noma xenograft models in which drug resistance is selected by continuous vemurafenib administration could forestall vemurafenib resistance. In one of the models, the investigators found that resistant tumors show continued dependency on BRAF(V600E)→MEK→ERK signaling as a result of elevated BRAF(V600E)

expression (eg, rather than additional mutations). They then showed that vemurafenib-resistant melanomas became drug dependent for their continued proliferation, with cessation of drug administration leading to regression of established drug-resistant tumors within 10 days, followed by regrowth. They further showed that a discontinuous

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Lab Notes

dosing strategy forestalled the onset of lethal drug-resistant disease. The investigators concluded, “These data highlight the concept that drugresistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the

vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.” Das Thakur M, et al: Nature. January 9, 2013 (early release online).

TARGETED THERAPY

Genetic and Epigenetic Alterations in Colorectal Cancer Fetuses from treated dams exhibiting anti-ofatumumab antibody responses Fetuses from treated dams exhibiting anti-ofatumumab antibody responses 7 DRUG INTERACTIONS and Metastases

B:15.125” T:14” S:12”

7 DRUG INTERACTIONS had higherinteraction B cell counts and higher spleen weights compared to the fetuses had higher B cell counts and higher spleen weights compared to the fetuses No formal drug-drug interaction studies have been conducted with ARZERRA. No formal drug-drug studies have been conducted with ARZERRA. Treatment colorectal from other treated dams, indicating partial recovery in those animals from other treated dams, indicating partial of recovery in thosecancer animalsis com8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS developing anti-ofatumumab antibodies. When compared to control animals, developing anti-ofatumumab antibodies. Whenpotential compared to difference control animals, plicated by the in 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled 8.1 Pregnancy Pregnancy Category C: There no adequate or well-controlled fetuses from treated dams in bothare dose groups had a 10% decrease in mean fetuses from treated dams in both dose groups had a 10% decrease in mean studies of ofatumumab in pregnant women. A reproductive study in pregnant studies of ofatumumab in pregnant women. A reproductive study in pregnant molecular between the primary placental weights. A 15% decrease in mean thymus weight compared toplacental weights. A 15% decrease in profiles mean thymus weight compared to cynomolgus monkeys that received ofatumumab at doses up to 3.5 times cynomolgus the monkeys ofatumumab at doses to 3.5 times the controlsthat wasreceived also observed in fetuses fromupdams treated the with 3.5 times the controls was also observed inand fetuses from dams treated with 3.5 times tumor metastases. Miranda and colrecommended human dose of ofatumumab did not demonstrate maternal recommended human dose of ofatumumab did not demonstrate maternal the human dose of ofatumumab. The biological significance of decreased the human dose of ofatumumab. The biological significance of decreased toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses toxicity or teratogenicity. crossed the placental barrier, and fetuses leagues from the Clinical and placental andOfatumumab thymic weights is unknown. The kinetics of B-lymphocyte placental and thymic weights is unknown. TheHumanitas kinetics of B-lymphocyte exhibited depletion of peripheral B cells and decreased spleen and placental exhibited depletion peripheral B cellslong-term and decreased spleen and placental recoveryofand the potential effects of perinatal B-cell depletionrecovery in and the potential long-term effects of perinatal B-cell depletion in weights. ARZERRA should be used during pregnancy only if the potential benefit weights. ARZERRA used during pregnancy only if the benefitin animals. Research dams Center Italy,inrecently offspringshould from be ofatumumab-treated dams have notpotential been studied offspring from ofatumumab-treated havein notMilan, been studied animals. to the mother justifies the potential risk to the fetus. There are no human orto the mother justifies the potential risk to the fetus. There are no human or assessed the presence of molecular hetCOUNSELING 17 PATIENT COUNSELING INFORMATION animal data on the potential short- and long-term effects of perinatal B-cellanimal data17 onPATIENT the potential short- and INFORMATION long-term effects of perinatal B-cell patients to contact healthcare professional for any of the following: Advise patients to contact a healthcareduring professional for any of progression the following: depletion in offspring following in utero exposure to ofatumumab. Ofatumumab depletion inAdvise offspring following in uteroaexposure to ofatumumab. Ofatumumab erogeneity metastatic • normal Signs and symptoms of infusion reactions including fever, chills, rash, • Signs and symptoms of infusion reactions including fever, chills, rash, does not bind normal human tissues other than B lymphocytes. It is not known does not bind human tissues other than B lymphocytes. It is not known colorectal or breathing problems within of infusion [see Warnings and or breathing problemsofwithin 24 hourscancer. of infusion [see Warnings and if binding occurs to unique embryonic or fetal tissue targets. In addition, theif binding occurs to unique embryonic or fetal24 hours tissue targets. In addition, the Precautionsrecovery (5.1) and Reactions (6.1)] Precautions (5.1) and Adverse Reactions (6.1)]the investigators anakinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion kinetics of B-lymphocyte areAdverse unknown in offspring with B-cell depletion In this study, • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether lyzed KRAS Warnings and Precautions (5.2)] [see Warnings and Precautions (5.2)] codon 12, BRAF codon ofatumumab is secreted in human milk; however, human IgG is secreted inofatumumab is[see secreted in human milk; however, human IgG is secreted in • Published Signs of infections including fever and cough [see Warningsofand • Signs of infections including fever and cough [see Warnings human milk. Published data suggest that neonatal and infant consumptionhuman of milk. data suggest that neonatal and infant consumption 1788, and p53 mutations andand promoter Precautions and Adverse Reactions (6.1)]maternal antibodies Precautions (5.2) and Adverse Reactions (6.1)] breast milk does not result in substantial absorption of these maternal antibodies breast milk does not result (5.2) in substantial absorption of these • New neurological symptoms such as confusion, dizziness or loss of • New neurological symptoms such as confusion, dizziness or loss of into circulation. Because the effects of local gastrointestinal and limited systemic into circulation. Because the effects of local gastrointestinal and limited systemic methylation of Ras association domain balance, difficulty talking orcaution walking, or vision problemswhen [see Warnings andbalance, difficulty talking or walking, or vision problems [see Warnings and exposure to ofatumumab are unknown, caution should be exercised when exposure to ofatumumab are unknown, should be exercised Precautions to (5.3)] Precautions (5.3)] family member 1 protein (RASSF1a), ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety ARZERRA and is administered a nursing woman. 8.4 Pediatric Use Safety and • of Symptoms of hepatitis including worsening fatigue or yellow discoloration • Symptoms of hepatitis including worsening fatigue or yellow discoloration effectiveness of ARZERRA have not been established in children. 8.5 Geriatric effectiveness ARZERRA have not been established in children. 8.5 Geriatric E-cadherin, and cyclin-dependent kinase of skinoforARZERRA eyes [seedid Warnings andsufficient Precautions (5.4)] of subjects of skin or eyes [see Warnings and Precautions (5.4)] Use Clinical studies of ARZERRA did not include sufficient numbers of subjects Use Clinical studies not include numbers inhibitor 2A (p16INK4a) genes • over New or worsening abdominal pain or nausea [see Warnings and • New or worsening abdominal pain or nausea [see Warnings and in 101 aged 65 and over to determine whether they respond differently from younger aged 65 and to determine whether they respond differently from younger (5.5)] Precautions (5.5)] primary colorectal cancer tumors (67 subjects [see Clinical Pharmacology (12.3) of full prescribing information]. subjects [see Precautions Clinical Pharmacology (12.3) of full prescribing information]. • Pregnancy or nursing [see Use in SpecificinPopulations (8.1, 8.3)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal 8.6 Renal Impairment No formal studies of ARZERRA patients with renal stage III patients of the need Advise patients of the need for: and 34 stage IV) and their related impairment have been conducted [see Clinical Pharmacology (12.3) of full impairmentAdvise have been conducted [see for: Clinical Pharmacology (12.3) of full Periodic monitoring for blood counts Warnings Precautions (5.2)] • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA prescribing• information]. 8.7 Hepatic Impairment No[see formal studiesand of ARZERRA lymph node and liver metastases. • Avoiding vaccination with live viral vaccines • Avoiding vaccination with live viral vaccines [see Warnings and Lymph in patients with hepatic impairment have been conducted. in patients with hepatic impairment have been conducted. [see Warnings and Precautions (5.6)] Precautions (5.6)] node metastases had fewer molecular 10 OVERDOSAGE 10 OVERDOSAGE by: overdosage with ARZERRA. Manufactured by: No data are available regarding overdosage with ARZERRA. No data areManufactured available regarding alterations than did primary tumors and GLAXO GROUP LIMITED GLAXO GROUP LIMITED 13 NONCLINICAL TOXICOLOGY 13 NONCLINICAL TOXICOLOGY liver Greenford, Middlesex, UB6 0NN, United Kingdom Greenford, Middlesex, UB6 0NN,metastases, United Kingdomincluding significantly 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity U.S. Lic. 1809 U.S. Lic. 1809 fewer KRAS and p16INK4a alterations. or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose Distributed by: or unexpected mitogenic responses were noted in Distributed by: toxicity study, no tumorigenic or unexpected mitogenic responses were noted toxicity in study, no tumorigenic Most genetic changes detectable in cynomolgus monkeys treated for 7 months with up to 3.5 times the humancynomolgus dose monkeys treated for 7 months with up to 3.5 times the human dose metastases were retained from the priof ofatumumab. Effects on male and female fertility have not been evaluated of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology in animal studies. 13.3 Reproductive and Developmental Toxicology mary tumor, whereas epigenetic changes Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose GlaxoSmithKline GlaxoSmithKline of ofatumumab weekly during the period of organogenesis (gestation days of ofatumumab weekly during the period of organogenesis (gestation days were newly acquired. Overall, 31 distinct Research Triangle Park, or NCteratogenicity. 27709 Research Triangle Park, NC 27709 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of 20 to 50) had no maternal toxicity Both dose levels of colorectal cancer molecular profiles were ofatumumab depleted circulating B cells in the dams, with signs of initial ofatumumab depleted circulating B cells in thereserved. dams, with signs of initial ©2011, GlaxoSmithKline. All rights ©2011, GlaxoSmithKline. All rights reserved. B cell recovery 50 days after the final dose. Following Caesarean sectionB cell recovery 50 days after the final dose. Following Caesarean section detected in primary tumors, none of September September 2011 at gestational day 100, fetuses from ofatumumab-treated dams exhibited at gestational day 100,2011 fetuses from ofatumumab-treated dams exhibited which characterized a particular tumor ARZ:6BRS decreases in mean peripheral B-cell counts (decreased to approximatelydecreases ARZ:6BRS in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately stage. When metastatic lesions were in15 to 20% of control values), and spleen weights (decreased by 15% for the 15 to 20% ©2011 of control and spleenGroup weights (decreased by 15% for the Thevalues), GlaxoSmithKline of Companies ©2011 The GlaxoSmithKline Group of Companies cluded the analysis, 53 distinct profiles low-dose and by 30% for the high-dose group, compared to control values). low-dose and by 30% for the high-dose group,AZA295R0 compared September to control values). All rights reserved. Printed in USA. 2011 in USA.inAZA295R0 September 2011 All rights reserved. Printed

were found among the 67 patients with stage III disease and 34 distinct profiles were found among the 34 patients with stage IV disease. The finding of such heterogeneity has implications for selection of targeted therapy in colorectal cancer. The investigators concluded, “Lymph node and liver metastases appear to originate in clonally different processes, with more molecular alterations occurring in distant metastases than in lymph node metastases and with elevated heterogeneity of the primary tumor. Thus, potential prognostic targets should be carefully evaluated for their heterogeneity in both primary tumors and distant metastases to avoid erroneous misclassification.” n Miranda E, et al: Cancer 119:266276, 2013.

The ASCO Post | MARCH 1, 2013

PAGE 48

2013

2013 Oncology Meetings March Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial SloanKettering Cancer Center March 1-5, 2013 • New York, New York For more information: www.mskcc.org/hemoncreviewcourse International Congress on Targeted Anticancer Therapies March 4-6 • Paris, France For more information: www.tatcongress.org/tat13-home.html

ASTRO Spring Refresher Course March 22-24 • Chicago, Illinois For more information: www.astro.org/springrefresher Highlights of ASH® in Asia March 23-24 • Shanghai, China For more information: www. hematology.org/meetings 23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

April

24th Annual Cancer Progress Conference March 5-6 • New York, New York For more information: www.cancerprogressbyDH.com Inaugural Prostate Cancer Research and Translation Symposium March 6-7 • Winston-Salem, North Carolina For more information: northwestahec. wfubmc.edu Society of Surgical Oncology 66th Annual Cancer Symposium March 6-9 • National Harbor, Maryland For more information: www.sso2013.org NCCN 18th Annual Conference: Advancing the Standard of Cancer Care March 14-17 • Hollywood, Florida For more information: www.nccn.org 5th Thyroid Neoplasms Conference March 21-23 • Houston, Texas For more information: www.mdanderson.org/conferences Community Oncology Journal’s 8th Annual Oncology Practice Summit March 21-23 • Las Vegas, Nevada For more information: onc.globalacademycme.com/ conferences/oncology-practicesummit-2013/conference-overview.html

IGCS Regional Meeting on Gynecologic Cancers April 11-13 • Bali, Indonesia For more information: www2.kenes.com/igcs2013 66th Urological Society of Australia and New Zealand Annual Scientific Meeting April 13-16 • Melbourne, Australia For more information: www.usanz2013.com/ International Society for Extracellular Vesicles 2013 Conference April 17-20 • Boston, MA For more information: www.isevmeeting.org 3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org Ultrasound in the New Millennium: The Cancer Patient April 19-20 • Houston, Texas For more information: www.mdanderson.org/conferences

May 5th IMPAKT Breast Cancer Conference May 2-4 • Brussels, Belgium For more information: www.esmo.org Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer

The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 13th World Congress of the European Association for Palliative Care May 30-June 2 • Prague, Czech Republic For more information: www.eapc-2013.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com State of the Art Techniques Symposium May 17-19 • San Antonio, Texas For more information: www.astro.org/ stateofthearttechniques 3rd International Symposium on Lung-Sparing Therapies for Malignant Pleural Mesothelioma May 18, 2013 • Santa Monica, California For more information: www.cme.ucla.edu/courses/

7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si

5th Symposium on Cancer Metastasis and the Lymphovascular System and the 8th International Sentinel Node Society Congress May 27-29, 2013 • San Francisco, California For more information: www.sn-cancermets.org

Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

Targeting Cancer Drug Resistance May 28-30 • Chicago, Illinois For more information: www.cancer-drugresistance.com/

June Molecular and Translational Oncology Workshop June 14-18 • Fort Myers, Florida For more information: www.cancereducationconsortium. org/programs_mtow.html 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com 6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org

ASCOPost.com | MARCH 1, 2013

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2013

2013 Oncology Meetings 2nd International Breakthrough Breast Cancer Conference– Triple Negative Breast Cancer June 26-28 • London, United Kingdom For more information: www.breakthroughconference.org.uk

Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

August

SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13

Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org

Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences

Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org

Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu

ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna

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 Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops 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 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

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org

EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: http://www. ncri.org.uk/ncriconference/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro

December

51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

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 PLACEBO

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. 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.

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.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving

Important Safety Information

AND... • 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53-0.75])1 • XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 – In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1 • Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ﬂush, 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. Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of References: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2013. © National Comprehensive Cancer Network, Inc 2012. All rights reserved. Accessed December 20, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1 • The most common adverse reactions (≥ 10%) in patients treated with XTANDI were asthenia/fatigue, peripheral edema, back pain, arthralgia, musculoskeletal pain, diarrhea, hot ﬂush, headache, and upper respiratory tract infection1

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.2

XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

L Learn earn m more ore a att X XtandiHCP.com tandiHCP.com

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

PAGE 52

FDA Update Hematology

Imatinib Receives New Indication for Children with Acute Lymphoblastic Leukemia

he FDA approved a new use of imatinib (Gleevec) to treat children newly diagnosed with Philadelphia chromosomeâ&#x20AC;&#x201C;positive acute lym-

phoblastic leukemia (ALL). ALL is the most common type of pediatric cancer, affecting approximately 2,900 children annually,

and progresses quickly if untreated. Children with Philadelphia chromosomeâ&#x20AC;&#x201C;positive ALL have a genetic abnormality that causes tyrosine ki-

nases to stimulate the bone marrow to make too many immature white blood cells, leaving less room for healthy white blood cells needed to

(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 9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

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

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

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

PAGE 53

FDA Update

fight infection. Imatinib, a tyrosine kinase inhibitor, should be used in combination with chemotherapy to treat children with Philadelphia chromosomeâ&#x20AC;&#x201C;positive ALL. â&#x20AC;&#x153;We are pleased that the number of cancer medications for children are on the rise,â&#x20AC;? said Richard Pazdur, MD, Director of the Office

of Hematology and Oncology Products in the FDAâ&#x20AC;&#x2122;s Center for Drug Evaluation and Research. â&#x20AC;&#x153;Todayâ&#x20AC;&#x2122;s approval is the result of continuous interactions among the FDA, the Childrenâ&#x20AC;&#x2122;s Oncology Group, and the National Cancer Institute to provide new and better treatments to American children with cancer.â&#x20AC;?

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 Live: 7"w Ă&#x2014; 10"h

----------------------------------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\@

Safety Data Imatinibâ&#x20AC;&#x2122;s safety and effectiveness for this new indication were established in a clinical trial conducted by the Childrenâ&#x20AC;&#x2122;s Oncology Group, sponsored by the National Cancer Institute. The trial enrolled children and young adults 1 year and older with very high risk ALL, defined as patients with a

-------------------------------------- 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.

greater than 45% chance of experiencing complications from their disease

within 5 years of treatment. Ninetytwo patients with Philadelphia chromosomeâ&#x20AC;&#x201C;positive ALL were enrolled in the trial and divided into five treatment groups, with each successive group receiving a greater duration of imatinib treatment in combination with chemotherapy. Fifty of the patients with Philadelphia chromosomeâ&#x20AC;&#x201C;positive ALL received imatinib for the longest duration, and 70% of these patients achieved event-free survival within 4 years. Results also showed patient deaths decreased with increasing duration of imatinib treatment in combination with chemotherapy. The most common side effects observed in children with Philadelphia chromosomeâ&#x20AC;&#x201C;positive ALL treated with imatinib in combination with chemotherapy included decreased levels of neutrophils, decreased levels of blood platelets, liver toxicity, and infection. Imatinib was granted accelerated approval in 2001 to treat patients with blast-crisis, accelerated-phase, or chronic-phase Philadelphia chromosomeâ&#x20AC;&#x201C;positive chronic myeloid leukemia (CML) who have failed interferon-alpha therapy. It has since been approved to treat several conditions, and most recently received regular approval to treat children with newly diagnosed Philadelphia chromosomeâ&#x20AC;&#x201C;positive CML (2011) and regular approval to treat adults whose Kit (CD117)-positive gastrointestinal stromal tumors have been surgically removed (2012). n

Send Us Your NEWS 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

Write to editor@ASCOPost.com. All submissions will be considered for publication.

The ASCO Post | MARCH 1, 2013

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continued from page 1

sively diagnosed, surgeries could be avoided, and unexpected abnormalities could be detected and corrected. But we are wise to recall the comment of Röntgen’s wife Anna Bertha, on whom the first radiographic x‑ray was administered, when she saw the film of her hand: “I have seen my death!”

Importance in Medicine Radiation is especially important in medicine. Physicians use various light and heavy particles, high-energy electromagnetic waves, and radionuclides to screen, diagnose, stage, and treat cancers. Examples include mammograms, x-rays, computed tomography (CT), and positron-emission tomography (PET) scans and radionuclide studies such as thyroid, bone, and liver-spleen scans. Technologies using ionizing radiation save thousands of lives daily. All of us are exposed to ionizing radiation every day, and all of us are naturally radioactive (for example, there are about 4.4 kilobequerels [kBq] of 40 K in each of us). In 2012, about onehalf of the U.S. population’s average annual exposure to ionizing radiation (about 6.2 mSv) came from diagnostic radiologic procedures. This is a threefold increase from 15 years ago and a sixfold increase from the early 1980s, when it was less than 20% of the average American’s radiation exposure. Estimated numbers of diagnostic imaging studies in the United States in 2012 exceed 80 million, and nuclear medicine procedures exceed 20 million. CT scans are the major culprit in increasing our radiation dose. For example, there were about 50 CTs per 1,000 Americans in 1996 vs about 150 in 2010. This means that in 2010, on average, more than 1 in every 10 Americans had a CT scan. In many parts of the country, it is virtually impossible to leave the emergency room without a CT scan.

Data in Context It is important to acknowledge differences in the nature of the exposed population and between the types of radiation. The entire U.S. population is exposed to background radiation (at different doses depending on where you live, lifestyle, etc), and the type of radiation is mostly high-energy gamma rays and high-energy particles. Persons exposed to medical radiation are generally older, more of-

ten male, and the type of radiation is mostly low-energy x-rays (photons). There is some concern—based mainly on biologic rather than epidemiologic data—that exposure to x-rays may result in a somewhat higher risk of cancer in later life than the same exposure from high-energy gamma rays (the type of exposure received during the 1945 atomic bombings of Japan). Many lives are saved by the oncologist’s use of diagnostic imaging procedures using ionizing radiation. The issue is whether the striking increase in average radiation exposure from these procedures is important, and whether the benefits accrued by exposing the population to more ionizing radiation exceeds the risks incurred.

Risks Reconsidered Let’s start with a given: Exposure to ionizing radiation causes cancer. Data supporting this comes from many experimental and epidemiologic sources. What is less certain is whether low radiation doses pose the same risk per unit dose of causing cancer as the risk per unit dose received at high doses. Simply put, is there a threshold radiation dose below which cancer is not induced, or is the relationship instead what is termed linear, no-threshold (LNT) and below limits of epidemiologic detection? The LNT relationship assumes that very small doses will have a proportionately smaller risk of causing cancer compared with the risk ob-

Robert Peter Gale, MD, PhD

and the safest assumption used to protect the public is that there is an LNT relationship between radiation dose and cancer risk. For physicians, this means that any excess radiation dose we expose people to, no matter how small, increases their cancer risk.

Risks Recalculated Most of us have little knowledge of the average radiation dose of common diagnostic radiologic procedures. For example, the average CT-PET scan exposes a person to about 12 to 32 mSv. At the upper end this is a 10-fold greater exposure than our average annual radiation dose of 3.2 mSv. A person having six CT-PET scans during the course of diagnosis, staging, and therapy/evaluation of cancer would receive a radiation dose comparable to a Japanese A-bomb survivor. As a rough calculation, exposure of a 30-year-old adult to 12.5 mSv (an average whole-body CT scan) results in an excess lifetime cancer risk of less than 1 to a few chances per 1,000

Many lives are saved by the oncologist’s use of diagnostic imaging procedures using ionizing radiation. The issue is whether the striking increase in average radiation exposure from these procedures is important, and whether the benefits accrued by exposing the population to more ionizing radiation exceeds the risks incurred. —Robert Peter Gale, MD, PhD, Eric Lax, and F. Owen Hoffman

served in populations like the Japanese A-bomb survivors who were exposed at much higher doses. Because annual background radiation dose varies substantially around the world without a corresponding detectable difference in cancer incidence, some have argued that low doses of radiation are not harmful and may even be healthy (radiation hormesis). However, the weight of scientific evidence, the conclusion of almost every learned scientific body,

persons exposed. If the average American receives an extra annual radiation dose of 3 mSv from diagnostic medical procedures and lives 80 years, he or she will receive an extra 240 mSv. We roughly estimate about 10 to 60 excess cancers per 1,000 exposed persons over their lifetimes. There are 314 million Americans alive today, so we might expect from 3 to almost 19 million excess cancers for the current U.S. population over the next 80 years. This is not small po-

Credit: Patricia Williams

Radiation and Cancer Risk

Credit: Patricia Williams

Perspective

Eric Lax

F. Owen Hoffman

tatoes! However, this rough estimate of radiation-induced cancer must be judged against the larger number of lives saved, current uncertainty about effects of low-dose radiation exposures, and the background cancer rate, which will be about 150 million. In many instances, these studies are needed to diagnose and accurately stage cancers and direct therapy or prevent ineffective or unneeded therapy. Here, benefits of radiation exposure will exceed the excess cancer risk. However, in other instances, estimated to be between 30% and 50%, some or all of these studies provide little useful data, including data that will not affect a person’s care or might result in harm. Here, the risks of excess radiation likely exceed the benefits. The message is clear: Before agreeing to any medical procedure that may cause harm, especially diagnostic radiologic studies, it is important for the patient to carefully weigh potential benefits and risks and discuss them with his/ her physician. Even when the procedure is justified, it should be optimized to expose the patient to the lowest radiation dose reasonably achievable.

Relative Risks If we accept the notion that every excess radiation exposure increases cancer risk, the next question is, what is the magnitude compared to other everyday risks? How we answer this question can make the risk seem enormous or trivial. For example, the radiation dose from an average whole-body CT scan (12 mSv) is about 40,000 times greater than the dose of ionizing radiation from an airport x-ray backscatter screening device (about 0.00025 mSv). People worried about airport screening should not fly— they will get about the same radiation dose flying 2 minutes at an altitude of 10,000 meters (32,808 feet). The lifetime cancer risk of the average 50-year-old American male (presently without cancer) is about 50%. A conventional chest CT exposes a 30-year-old person to about

ASCOPost.com | MARCH 1, 2013

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Perspective

7 mSv. This is equivalent to a cancer risk of less than 1 chance per 1,000, about the same as the risk from smoking 100 cigarettes (not recommended). Potential risks of additional radiation exposure, even low-dose exposures, are not just theory, and children are at special risk. For example, an A-bomb survivor exposed at age 10 years has a sevenfold greater risk of a fatal cancer than a person age 50 years exposed to the same dose. A recent

lations at greatest risk of radiationinduced cancers.

Other Harms There are other possible harms of diagnostic radiologic studies besides increasing cancer risk that need to be carefully evaluated. Consider the current controversy over screening mammograms (the dose, about 0.13 mSv, is 100-fold less than a whole-body CT scan). Although a detailed discussion of this complex

There are untold benefits to the new, exciting, and expanding diagnostic radiologic procedures and techniques available to oncologists. But there are also complexities, risks, and drawbacks that need to be carefully considered. —Robert Peter Gale, MD, PhD, Eric Lax, and F. Owen Hoffman

Lancet report detailed increased brain cancers and acute lymphocytic leukemia (ALL) in children receiving head CT scans.1 And there is a markedly increased incidence of thyroid cancer in children exposed to 131I from the Chernobyl nuclear power facility accident in 1986 (about 7,000 cases).

Other Risk Factors The question of why only some people exposed to a certain dose of radiation develop cancer is also controversial. Chance is surely important. However, other variables besides age at exposure increase risk, such as gender. Females are about twice as likely to develop a radiationinduced cancer than are males, but some of this relates to gender-specific cancers such as breast cancer. Recent genetic analyses suggest that an underlying genetic “susceptibility” may also operate. This is paradoxical because the very populations at greatest cancer risk, and the ones in whom diagnostic radiologic studies are most likely to be done and be informative, may be the same popu-

issue is beyond the scope of this editorial, almost everyone is aware of the uncertainty over the benefitto-risk ratio of beginning screening mammograms at different ages. More perplexing are reports from several large studies showing no reduction in breast cancer deaths despite increased detection of early breast cancers. This paradox forces us to rethink the widely accepted but unproven notion that early cancer detection must save lives. For reference, the radiation dose from three low-dose helical (spiral) CT scans used for lung cancer screening is 6 mSv. Added to this is ionizing radiation from diagnostic imaging procedures triggered by false-positive findings, which brings the estimated dose to about 8 mSv per person screened. For a 50-year-old adult male, this translates to an excess lifetime risk of radiation-induced cancer of about 0.3 to 1.3 chances per 1,000 persons screened. Thus, in contrast to mammographic screening of normal women, lung cancer screening is recommended (by some) only in persons at

increased cancer risk and under special conditions altering the benefit-torisk ratio. We should mention that new technology is decreasing the dose of radiation used in CT scanning. This important issue is being addressed by programs such as the “Image Gently” campaign sponsored by many medical organizations.

Perception of Risk There are extraordinary differences in perception of risk from radiation exposures of comparable magnitude from different sources. Many people (including physicians) are somewhere between concerned and terrified of exposure to ionizing radiation from a nuclear accident such as Chernobyl and Fukushima-Daiichi. However, the average radiation dose to the evacuated population in the former Soviet Union was about 30 mSv over 25 years and about 10 mSv to persons living in contaminated lands. The average dose to people in Fukushima prefecture will be less than 10 mSv over their lifetime

and probably less than 2 mSv to those in contaminated areas. These doses are much lower and the cancer risk much less than what the average American will get from diagnostic medical procedures over the next 50 years. Yet, the same concerned people usually do not hesitate to have a CT scan; sometimes they insist on it. We obviously need a public education program on this subject. The bottom line is that there are untold benefits to the new, exciting, and expanding diagnostic radiologic procedures and techniques available to oncologists. But there are also complexities, risks, and drawbacks that need to be carefully considered. We can minimize what is lost by carefully analyzing benefit and risk. n Reference 1. Pearce MS, Salotti JA, Little MP, et al: Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 380:499-505, 2012.

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