TAP Vol 3 Issue 8 by Harborside Press LLC

Managing Fever and Neutropenia

3 |

Understanding Triple-negative Breast Tumors

14 |

Adjuvant Therapy for NSCLC

VOLUME 3, ISSUE 8

MAY 15, 2012

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

Practice Guidelines

ASCO Issues New Guideline on Chemotherapy Dosing for Obese Patients

ASCOPost.com

Maintenance of Certification in Medical Oncology

By Jo Cavallo

n April, ASCO released a new clinical practice guideline on the appropriate dosing of chemotherapy drugs given to obese adult patients with cancer. The result of an analysis by a panel of experts assembled by ASCO, the guideline calls for the use of a patient’s actual Gary H. Lyman, MD, MPH body weight when calculating chemotherapy dosing, rather than limiting the dose or using an adjusted ideal body weight, as is commonly done. The panel looked at 56 studies on cytotoxic chemotherapy dosing strategies for overweight and obese patients with cancer. The review excluded leukemia studies and did not address dosing of novel targeted agents. According to the resulting analysis and recommendations, which were See Page 89 published online in the Journal of Clini-

cal Oncology (JCO),1 clinical practice patterns show that up to 40% of obese patients are receiving chemotherapy doses that are lower than what would be optimal in the curative setting when calculated according to actual body weight. Limiting chemotherapy in overweight and obese patients may lead to poorer outcomes in terms of survival and cancer recurrence, according to the report.

Heightened Risks “If you dose-reduce patients just based on their weight, it may contribute to what we have seen in multiple settings, which is poorer survival in obese patients with cancer,” said Gary H. Lyman, MD, MPH, Professor of Medicine in the Division of Medical Oncology, Department of Internal Medicine at Duke University School of Medicine and the Duke Cancer Institute and Co-Chair of ASCO’s Clinical Practice Guideline for Appropriate Chemotherapy Dosing for Obese Adult Patients with Cancer. “The data are very clear that obesity not only puts people at greater risk of getting cancer, but continued on page 15

Advances in Prostate Cancer Accompanied by Ongoing Debates

Issues in Oncology

cientific advances have markedly improved prostate cancer survival, but this clinical success story is not without its share of controversy. From screening through treatment, a growing array of options offer an admixture of promise and confusion for clinicians and patients. Moreover, today’s heated debate over health-care costs brings another element of turmoil to prostate cancer management, which can involve among the highest-priced therapies in oncol-

t is said that time is perhaps the most treasured asset we have. If you are a practicing oncologist, everyone wants more and more of your time, and I’m not referring to patients. Rather, there is an increasing proliferation of folks who want to make sure we’re doing a good job, and they are imposing external oversight and mandatory training. External groups are measuring and requiring a great many things, and expanding “regulatory” tasks consume more of our time than ever before. Training required by institutional review boards, hospital-based infection control and safety modules, continuing medical education (CME) requirements from the state, and more are layered on our workday seemingly without anyone counting the hours necessary to do these things.

Meaningful Education What I really want is continued meaningful education that will make me a better oncology continued on page 26

Dr. Stewart is a medical oncologist at Baystate Medical Center in Springfield, Massachusetts.

By Ronald Piana

By James A. Stewart, MD, FACP

ogy. To clarify some of the new directions and existing challenges associated with this disease, The ASCO Post recently spoke with several experts in the field.

New Study Compares Three Modalities

Determining which modality has the best outcome with the least toxicity and morbidity has long been a source of debate in the treatment of prostate cancer. A new study has shed light on this important issue.1 The study's lead author, Jay Ciezki, MD, Cleveland Clinic, Ohio, We feel the principal reason said, “Using billing codes brachytherapy is rarely used stems from associated with toxicityrelated treatments, we its inception in the 1990s, when it was looked at three major motargeted specifically for low-risk patients, dalities: external-beam radiation therapy, prostateca rather small cancer population. tomy, and brachytherapy. — Jay Ciezki, MD We then obtained infor-

MORE IN THIS ISSUE Oncology Meetings Coverage American Association for Cancer Research �� 7, 8 Society of Surgical Oncology �� 10, 14 European Lung Cancer Conference �� 38, 39, 42 FDA Update �� 2, 54–58 Kanti R. Rai, MD, on Leukemia �� 27 Direct from ASCO �� 47 Alfred L. Goldberg, PhD, on Cachexia �� 62

continued on page 18

Visit The ASCO Post at ASCO’s Annual Meeting, booth 6068

A Harborside Press® Publication

The ASCO Post | MAY 15, 2012

PAGE 2

FDA Update

FDA Approves Pazopanib for Advanced Soft-tissue Sarcoma

Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

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

ASSOCIATE EDITORS

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

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

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

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute 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 E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 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

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 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 INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada 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

Wendy McGullam, Director of Production Wendy@harborsidepress.com

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

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

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

Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Anthony Cutrone, President Anthony@harborsidepress.com

Michael Buckley, Graphic Designer Michael@harborsidepress.com

John A. Gentile, Jr., Chairman Jack@harborsidepress.com

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.

he FDA has approved pazopanib (Votrient) to treat patients with advanced soft-tissue sarcoma who have previously received chemotherapy. Pazopanib is an oral agent that works by interfering with angiogenesis. Soft-tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval. Pazopanib is not approved for patients with adipocytic soft-tissue sarcoma and gastrointestinal stromal tumors. “Soft-tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Pivotal Trial The safety and effectiveness of pazopanib was evaluated in a single

clinical study in 369 patients with advanced soft-tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive pazopanib or a placebo. The study was designed to measure progression-free survival. The disease did not progress for a median of 4.6 months for patients receiving pazopanib, compared with 1.6 months for those receiving placebo. The most common side effects in pazopanib-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration. Pazopanib carries a boxed warning alerting patients and health-care professionals to the potential risk of hepatotoxicity, which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.

■

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 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 ©2012 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 26,000 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: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com. Correspondence: Address general inquiries to Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

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

ASCOPost.com | MAY 15, 2012

PAGE 3

Symptom Management Infection

Managing Febrile Neutropenia: What Are the Best Antibiotic Regimens? By Susan London

anagement of patients with cancer who have fever and a low neutrophil count is one of the most common scenarios oncologists face today. “Physicians have to be keenly aware of the infection risks, diagnostic methods, and microbial therapies required for managing febrile neutropenic patients because they’re highly vulnerable to rapidly progressive, severe infections in the absence of neutrophils,” said Alison G. Freifeld, MD, Professor in the Department of Medicine, Division of Infectious Diseases, at the University of Nebraska Medical Center in Omaha, in an interview with The ASCO Post.

Alison G. Freifeld, MD

Eric J. Bow, MD, Professor in the Departments of Medical Microbiology and Internal Medicine, and Director of the Infection Control Services, CancerCare Manitoba, Winnipeg, agreed, noting, “Patients with a neutropenic fever syndrome who are untreated or improperly treated have a high risk of dying, with a median survival on the order of 72 hours.” Yet, treatment— starting with appropriate antibiotic

selection—is not always straightforward, given factors such as patient diversity, an array of antibiotic options, and emergence of antimicrobial resistance.

Practice Guidelines Evidence-based practice guidelines, such as those of the Infectious Diseases Society of America (IDSA)1 and the National Comprehensive Cancer Network (NCCN),2 offer helpful information and algorithms when it comes to antibiotic therapy for febrile neutropenic patients. (ASCO guidelines for managing febrile neutropenia in the outpatient with cancer are currently being written, and publication is anticipated this year.) “An algorithmic approach to febrile neutropenia, infection prophylaxis, diagnosis, and treatment helps to guide clinical management,” Dr. Freifeld noted. “It’s not intended to replace clinical judgment, but in an era of increasing antimicrobial resistance and an everwidening array of pathogens, we need some structure in our initial management approaches.” It is also noteworthy that guidelines have become less dogmatic and more flexible over time, according to Dr. Bow. “They allow physicians to use their judgment a little bit more and also to be confident that in so doing, they will be complying with standards of practice,” he explained. This approach not only accommodates local circumstances, such as antibiotic availability and prevailing resistance patterns, but

Table 1: Multinational Association for Supportive Care in Cancer (MASCC) Risk Index Scoring System for Febrile Neutropenic Patients with Cancera Risk Characteristic

Points

Burden of febrile neutropenia

■■ No or mild symptoms

■■ Moderate symptoms

No hypotension

No chronic obstructive pulmonary disease

Solid tumor or hematologic malignancy with no previous fungal infection

Outpatient status

No dehydration requiring parenteral fluids

Age < 60 years

Cumulative point score of 21 or more defines a low-risk patient. The maximum theoretical score is 26. Adapted with permission from Klastersky J, et al.4 Copyright © 2000 by the American Society of Clinical Oncology. All rights reserved. a

Recommendations for Managing Febrile Neutropenia ■■ Within 1 hour of presentation, patients with febrile neutropenia should

be started on a broad-spectrum, antipseudomonal, bactericidal antibiotic regimen as initial empiric therapy.

■■ Key factors determining the choice of regimen include the bacterial

pathogen likely to be associated with the presenting clinical syndrome, the resistance profile in the environment of the clinic/institution, the site of infection, comorbid medical conditions, the presence of tissue hypoperfusion (hypotension, oliguria, or altered mental state), and antibiotic allergies.

■■ Monotherapy with cefepime, ceftazidime, meropenem, imipenem, or

piperacillin-tazobactam are options for empiric coverage for most patients. Additional agents, like aminoglycosides or vancomycin, are not advocated unless there are specific indications.

■■ Risk stratification at presentation according to high or low risk of serious

complications during neutropenia is the major determinant of the treatment setting (inpatient vs outpatient) of initial therapy, and may also help determine the regimen and route (intravenous vs oral). The MASCC Risk Index is a recommended, validated risk-stratification method.

■■ Modification of initial antibiotic therapy during the course of treatment

is not necessary in a stable patient who is persistently febrile and neutropenic. Antimicrobial modifications or additions are based on specific culture, radiograph, or clinical evidence of infection; the absolute neutrophil count; antimicrobial resistance patterns; and prevailing outbreaks (ie, influenza).

also addresses liability concerns. The guidelines concur that speed is of the essence when treating febrile neutropenia: Patients should be started on initial empiric antibacterial therapy within 1 hour of presentation to a triage facility. As Dr. Bow noted, using the standardized emergency department triage assessment system,3 febrile neutropenic patients with cancer can be recognized and classified in a manner similar to that for patients with acute ST-wave myocardial infarction or acute stroke for timely management. During those first few minutes, “full clinical assessments, blood cultures, and appropriate blood work all need to be done. That’s difficult but achievable,” he said. Over the past 2 decades, the initial empiric antibacterial approach for fever and neutropenia have actually been simplified. In the 1970s and 1980s, multidrug antibiotic regimens were often prescribed, including an antipseudomonal cephalosporin or penicillin plus an aminoglycoside and vancomycin. Current guidelines recommend monotherapy with a potent broadspectrum antipseudomonal agent such as intravenous cefepime, meropenem, or piperacillin-tazobactam.1,2 Universal coverage with vancomycin (or similar anti–gram-positive agents) and

aminoglycosides has been found to be generally unnecessary in clinical trials, but these agents may be reserved for specific situations (see below).

Eric J. Bow, MD

Patient Risk and Initial Therapy A patient’s risk of serious medical complications during the course of neutropenia is an important determinant of the route (intravenous vs oral) and treatment setting (inpatient vs outpatient) of empiric antibiotic therapy at the outset. Risk can be assessed from individual factors, such as age, underlying cancer, treatment regimen intensity, medical comorbidities (including dehydration or hypotension), and evidence of sepsis, or using the Multinational Association for Supportive Care in Cancer (MASCC) Risk Index, on which a score of less continued on page 22

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

Mechanism of action

Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) 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 hypertension, hypokalemia, and 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 because these patients were excluded from the randomized clinical trial. 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 has been reported in clinical trials 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—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. 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. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. 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 AUC 0-∞ (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.

KAPLAN-MEIER SURVIVAL CURVES OF PATIENTS TREATED WITH EITHER ZYTIGA® + PREDNISONE OR PLACEBO + PREDNISONE (INTERIM ANALYSIS) 100

P < 0.0001; HR = 0.646; 95% CI: 0.543, 0.768

% Survival

ZYTIGA®: 14.8 months (median) (95% CI: 14.1, 15.4)

60 Placebo: 10.9 months (median) (95% CI: 10.2, 12.0)

40 20 0 0

736 355

657 306

68 30

2 3

0 0

Time to Death (Months) ZYTIGA® 797 Placebo 398

520 210

282 105

The median duration of treatment with ZYTIGA® was 8 months.

Proven survival benefit At the interim analysis of the phase 3 study,*† ZYTIGA® in combination with prednisone showed a statistically significant improvement in overall survival compared with placebo plus prednisone and resulted in a 35% reduction in the risk of death (hazard ratio [HR] = 0.646; P < 0.0001; 95% confidence interval [CI]: 0.543, 0.768; median survival: 14.8 months vs 10.9 months, respectively) In an updated survival analysis,‡ results were consistent with those from the interim analysis (HR = 0.74; 95% CI: 0.638, 0.859; median survival: 15.8 months vs 11.2 months)

*Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12066B

study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events. 08Z11121R3

Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration 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. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®.

Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

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

www.zytiga.com

ASCOPost.com | MAY 15, 2012

PAGE 7

AACR Annual Meeting 2012 Immunotherapy Clinical Trials Show Benefits for Patients with Advanced Cancers By Charlotte Bath

mmunotherapeutic approaches, including vaccines, a monoclonal antibody, and a combination of low-dose interleukin (IL)-2 (Proleukin) and retinoic acid, are showing some success in clinical trials investigating the prevention of breast cancer recurrence in women at high risk, the treatment of gliomas in children, and the treatment of several advanced cancers in adults. The results of the trials were presented at the recent American Association for Cancer Research Annual Meeting in Chicago.1-4 At a press conference during the meeting, Olivera Finn, PhD, Director of the Immunology Program at the University of Pittsburgh Cancer Institute and Chair and Professor in the Department of Immunology at the University of Pittsburgh School of Medicine, cautioned, “Don’t be discouraged when you hear about ‘moderate success.’ Moderate success in the setting of advanced cancer is great news, and it also allows us to learn something so that we can move the therapy closer and closer to the early stages of the tumor or the disease, where the successes are probably going to be much greater.” Dr. Finn noted that a common theme of the four trials discussed is to “provoke the attack on the tumor by the immune system” late in disease, “when the immune system has already met the cancer and they have had this interplay where they have changed one another. The immune system changes the cancer and the cancer changes the immune system, and then we immunotherapists come at the end and try to reverse that dance in favor of the host and against the tumor.”

Breast Cancer Vaccine Targets HER2

The breast cancer trial used a peptide vaccine, known as AE37, to target HER2.1 “The goal of the vaccine is to prime the immune system to recognize and attack the HER2 protein that is found in some breast

Diane F. Hale, MD

cancers. Thus, if or when the patient has a recurrence, their immune system will recognize it and take action against it,” stated Diane F. Hale, MD, a research resident in general surgery at Brooke Army Medical Center in Fort Sam Houston, Texas. “HER2 is also the target of Herceptin [trastuzumab],” but trastuzumab “is currently used in the adjuvant setting only for the approximately 20% of patients who are found to be HER2-positive, defined as having overexpression of the protein as detected by immunohistochemistry or having amplification of the HER2 gene,” Dr. Hale said. “This vaccine will be available for breast cancer patients expressing any degree of HER2 including low expression, which accounts for an additional 50% to 60% of breast cancer patients.” A phase I trial demonstrated AE37 to be “safe and capable of stimulating a CD4-positive helper T-cell response with HER2-specific antitumor activity.” Following that study, a prospective, randomized, single-blinded phase II trial is comparing AE37 paired with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GMCSF, Leukine) to GM-CSF alone in the prevention of breast cancer recurrence.

Learning from Advanced Disease

urrent testing of immunotherapy approaches against cancer involves patients in whom standard therapies have failed. “That really puts us at a great disadvantage because a lot of the standard therapies are immunosuppressive, as is the tumor itself as it grows,” Olivera Finn, PhD, said at a press conference on immunotherapy at the American Association for Cancer Research Annual Meeting. “But many of us have run clinical trials of immunotherapy in advancedstage cancer, and everything that we know about the Olivera Finn, PhD immunosuppressive tumor microenvironment has been derived from those trials.” Cellular and molecular analyses to find out why patients don’t respond have revealed information about T-regulatory and T-suppressor cells. “We can now give you a perfect picture of the tumor microenvironment because we discovered it by looking at the failures of our late-stage disease immunotherapy trials,” Dr. Finn stated. At least some of the immunosuppressive factors that compromise success in treating advanced disease may not exist in early-stage disease. “We are working on this,” Dr. Finn said, and if this work can be integrated with work of other scientists looking for biomarkers of disease and indicators of risk for recurrence, then vaccines or other immunotherapy approaches could be applied earlier or used to prevent disease. “We think the successes are going to be much greater,” Dr. Finn said.

■

40% reduction of recurrence in those patients,” she added. The phase II study is continuing and has nearly completed enrollment.

Highest-risk Patients “We currently have 217 patients enrolled—109 patients randomly assigned to AE37 and 108 to GM-CSF,” Dr. Hale reported. All patients completed standard-of-care therapy for breast cancer and were disease-free at the start of the trial. “We wanted the patients who are at the highest risk for recurrence, so we included those who were node-positive or who were node-negative but had poor prognostic factors, such as estrogen/progesterone receptor negativity,” Dr. Hale noted. Patients were inoculated with the vaccine monthly for the first 6 months, then had a booster inoculation once every 6 months. Delayed hypersensitivity reactions were evaluated by injecting a small, nontherapeutic dose of the vaccine beneath the patient’s skin and looking for a physical reaction of greater than 5 mm. Results at 24 months revealed that 86% of patients in the vaccine group had a significant response compared with 27% of patients in the control group. In addition, researchers evaluated in vitro proliferation responses and found that the vaccine group had

Responses Observed in Glioma Trial

Ian F. Pollack, MD

more responders than the control group. Researchers also measured T-regulatory cells at baseline and after vaccination in a subset of patients. “A large number of vaccinated patients had decreased levels of these cells from baseline, leaving us to think they have an improved immune response to the vaccine,” Dr. Hale commented. “Other studies had previously found that higher levels of T-regulatory cells are associated with invasive tumors vs ductal carcinoma in situ, and more importantly, that the number of T-regulatory cells correlates with clinical outcomes,” she said. “There is a trend toward survival benefit in the vaccinated patients,” she said, and subset analysis of the low HER2-expressing patients showed “an even greater benefit—approximately

Building on extensive experience with immunotherapy in adults “that involved a cocktail of novel glioma-associated antigen peptides,” researchers at the University of Pittsburgh Cancer Institute and the Children’s Hospital in Pittsburgh tested a peptide vaccine among children with gliomas.2 The vaccine includes three gliomaassociated antigens—IL13Rα2, EphA2, and survivin, which are overexpressed in pediatric gliomas—emulsified in the immune modulator Montanide-ISA-51. The vaccine was administered every 3 weeks subcutaneously for eight courses. “Immunologic and clinical evidence of activity, in some cases very dramatic, has been obtained,” reported Ian F. Pollack, MD, Co-Director of the Brain Tumor Program at the University of Pittsburgh Cancer Institute and Chief of Pediatric Neurosurgery at the Children’s Hospital in Pittsburgh. “Our continued on page 8

The ASCO Post | MAY 15, 2012

PAGE 8

AACR Annual Meeting 2012 Immunotherapy Clinical Trials continued from page 7

vaccine-based approach has been welltolerated in terms of systemic toxicity,” he added, but “pseudoprogression— transient enlargement of the tumor and neurologic worsening—is a concern that warrants close monitoring and, in some cases, intervention.” Cases of pseudoprogression responded well to corticosteroids, Dr. Pollack said. “The prognosis for children with diffuse brain stem gliomas and other highgrade gliomas is really awful with current therapy,” Dr. Pollack noted. “The only treatment modality that has shown any sort of efficacy for diffuse brain stem gliomas is radiation. Numerous chemotherapy and radiation intensification approaches have been used, but the 1-year event-free survival is still in the range of only 15% to 20% with overall survival in the range of about 35% to 50%. So there is a strong rationale for novel treatment approaches such as immunotherapy,” he explained.

Eligibility Criteria The key eligibility criteria were that patients had to have newly diagnosed diffuse brain stem gliomas or malignant non–brain stem gliomas, very poor-risk tumors, or gliomas that recurred after standard therapy. Diffuse brain stem gliomas “are not amenable to surgical resection because the tumor infiltrates the brain stem,” Dr. Pollack said. “So these patients had all of their tumor still intact but were newly diagnosed.” Some other tumors could be only partially removed. According to results reported at the AACR meeting, 19 of 22 evaluable had stable disease or responses through at least two vaccine cycles. “This is quite good in this poor-risk population,” Dr. Pollack noted. “We’ve had 7 cases of pseudoprogression, 3 partial responses, 1 minor response, and 1 case of prolonged disease-free status after resection. We also had 2 patients who had responses immediately after going off the vaccine and starting on corticosteroids.” He continued, “8 of 11 of our brain stem glioma patients have survived beyond the historical median for these tumors, which is about 10½ months, and many remain on therapy. From an immunologic standpoint, 11 of 13 patients have had positive responses on ELISPOT assay, which is a functional measure of T-cell response, mostly commonly to IL13Rα2. We’ve looked at five of these tumors with immunohistochemistry so far, and they all overexpress at least one of the glioma-associated antigens,” Dr. Pollock noted.

Disease Control Rate of 75% in Liver Cancer Study Treatment with tremelimumab (CP 675,206), a fully humanized IgG2 monoclonal antibody that antagonizes binding of CTLA-4 to B7 ligands, stabilized patients with advanced hepatocellular carcinoma due to chronic hepatitis C infection for more than 12 months, according to data presented by Ignacio Melero, MD, PhD.3 A consultant in the Department of Oncology at Clinica Universidad de Navarra and Senior Investigator in El Centro de Investigación Médica Aplicada at Universidad de Navarra in Pamplona, Spain, Dr. Me-

precludes drawing definitive conclusions.” For the current study, 21 patients were treated with tremelimumab intravenously at a dose of 15 mg/kg every 90 days until disease progression. To enroll, patients had to have hepatitis C virus, the major cause of hepatocellular carcinoma in Western countries, and untreatable liver cancer. Of 17 patients evaluated for response, “we observed 3 patients who had shrinkage of the tumor beyond 20%,” Dr. Melero said, “and 10 patients with disease stabilization, for a 76.4% disease control rate.” Researchers also observed a reduction of hepatitis C virus in the patients’

Recent Research on Immunotherapy in Advanced Cancer ■■ After completing standard therapy, patients with HER2-expressing breast

cancer who received the peptide vaccine AE37 plus GM-CSF had significant immunologic responses compared to those who received GM-CSF alone, in 6-monthly inoculations. A trend toward survival benefit and reduction of recurrence was seen in vaccinated patients, and the study is ongoing.

■■ Peptide vaccination in children with gliomas was generally well tolerated

and showed evidence of immunologic and clinical activity, although several cases of transient pseudoprogression warranted close monitoring and aggressive management.

■■ In a preliminary analysis, the monoclonal antibody tremelimumab showed

promising antitumor efficacy against hepatocellular carcinoma and intense antiviral activity against hepatitis C virus, with a good safety profile.

■■ In patients with advanced cancer who showed clinical benefit from

chemotherapy, maintenance therapy with interleukin-2 and retinoic acid improved long-term disease-free and overall survival.

lero reported that in a three-center trial, tremelimumab showed an intense and persistent antiviral effect in more than half of the patients. The disease control rate was 75%, and time to progression was longer than 4 months. Sorafenib (Nexavar) is the only currently approved systemic agent that prolongs survival in hepatocellular carcinoma, Dr. Melero noted, and thus, there exists an unmet need for new systemic agents. “Anti-CTLA-4 monoclonal antibodies had previously shown activity in a variety of mouse tumor models, and tremelimumab has been reported to have clinical activity against metastatic melanoma,” he stated. “The limited number of patients in this first trial, nevertheless,

Ignacio Melero, MD, PhD

blood, “and this clearly correlates with an immune response against hepatitis C virus antigens,” Dr. Melero said. While tremelimumab was considered well tolerated, about 80% of patients had treatment-related adverse events. “About 40% showed some signs of dermatitis, some of them with quite a lot of itching,” Dr. Melero reported, and “10% had episodes of diarrhea related to inflammatory bowel disease.” The study was supported by Pfizer, and tremelimumab has been licensed by MedImmune. Dr. Melero is a consultant for Bristol-Myers Squibb.

IL-2/Retinoic Acid May Prolong Survival in Advanced Cancers Maintenance therapy with IL-2 and 13-cis retinoic acid may be an inexpensive method for increasing survival in patients with a wide range of stage IV cancers, according to findings from a 500-patient study.4 The results were reported by Francesco Recchia, MD, Director of Oncology at the Civilian Hospital in Avezzano, Italy, who started evaluating the maintenance therapy in patients with advanced disease in

Francesco Recchia, MD

1995, after one patient with metastatic melanoma did not tolerate the usual 18 international megaunits (IMU)/m2 high-dose IL-2 therapy. “The patient was treated with lower doses, and he had a wonderful, long-lasting response,” Dr. Recchia said. “We demonstrated in this phase I study that using low doses of IL-2, we had exactly the same results as [have been obtained with] higher doses, at least from a biologic point of view.” After this observation, he conducted several other studies of IL-2, with or without retinoic acid, and was encouraged by the results. For the current study, his research team evaluated 500 patients with a wide range of advanced cancers that had a clinical benefit from chemotherapy. Patients were assigned to selfadministered subcutaneous IL-2 (1.8 IMU/m2) and oral retinoic acid (0.5 mg/kg) 5 days a week for two consecutive cycles of 3 weeks, followed by a 1-week rest, for 1 year.

Survival Rates Comparing 5-year survival rates of trial participants with data from the NCI’s Surveillance, Epidemiology and End Results (SEER) program, Dr. Recchia pointed out significant improvements with immunotherapy. “In breast cancer, we had almost double the 5-year survival [for IL-2/retinoic acid vs standard chemotherapy] (42.7% vs 23.3%),” he said. “In colorectal cancer, we showed improvement from 11.7%, which is the 5-year survival rate you expect after chemotherapy, to 43.6% with IL-2. Patients with lung cancer showed a dramatic improvement, from 3.6% [in SEER data] to 26.4%. And in renal cell carcinoma, we found 5-year survival doubled, from 11% to 23%.” At 15 years, the disease-free survival rate in immunotherapy recipients was 32.6%, and the overall survival rate was 36.8%. After a median follow-up of 90 months, researchers reported increased numbers of natural killer cells and a decrease of vascular endothelial growth continued on page 10

platinum + taxane

platinum + non-taxane

The ASCO Post | MAY 15, 2012

PAGE 10

Society of Surgical Oncology Plenary Presentation

Regional Infusion of Designer T Cells to Treat Intrahepatic Metastases By Matthew Stenger

esigner T cells are modified from normal T cells to express specific immune receptors that allow them, via antibody-directed recognition or other mechanisms, to kill malignant cells bearing particular antigens. The Surgical Immunotherapy Lab at the Roger Williams Medical Center, Providence, Rhode Is-

the suppressive effect could be mitigated with regional infusion of anti-CEA designer T cells. The experimental model is designed to parallel the researchers’ ongoing Hepatic Immunotherapy for Metastases (HITM) phase I trial for patients with CEA-positive liver metastases (NCT01373047), in which patients receive percutaneous hepatic artery designer T-cell infusions. Steven C. Katz, MD, FACS, the principal investigator for the laboratory project and phase I trial, presented results of the research at a plenary session of the Society of Surgical Oncology Annual Symposium.

Study Design In the study, Katz and colleagues transduced murine splenocytes with a chimeric immune receptor containing an anti-CEA immunoglobulin moiety, the CD3ζ chain, and the CD28 costimulatory molecule. In vitro, designer Tcell proliferation was measured by flow cytometry, and myeloid-derived suppressor cells were added to assess their

Steven C. Katz, MD, FACS

land, is focused on enhancing designer T-cell therapy for liver metastases. In a recent experimental study, investigators there identified a factor that suppressed the designer T-cell response to CEApositive liver metastases and showed that

100%

P = .045 Regional control T cells

Survival

80%

Regional designer T cells Systemic designer T cells

60% 40% 20% 0%

100

Days Fig. 1: Survival in mice with liver metastasis receiving tail vein infusion of anti-CEA (systemic) designer T cells, portal vein infusion of regional control T cells, or portal vein infusion of (regional) designer T cells. Adapted with permission from Naheed S, et al.1

Immunotherapy Clinical Trials continued from page 8

factor levels. “Another important aspect of this therapy is the cost,” Dr. Recchia commented. The immunotherapy strategy represented an 82% cost reduction compared to other cancer treatments. The AACR press release on the study concluded, “Although [these]

results appear promising, a blinded, controlled, randomized trial would be needed before clinicians could begin using this maintenance regimen.”

■

Disclosure: Drs. Finn, Hale, Pollack, Melero, and Recchia reported no potential conflicts of interest.

References 1. Hale DF, Vreeland TJ, Dabney RS,

Immunotherapeutic Strategy for Treating Liver Metastasis ■■ Designer T cells are engineered to kill malignant cancer cells bearing particular antigens.

■■ The immune suppressive milieu induced by liver metastasis growth may inhibit proliferation and efficacy of designer T cells.

■■ The antitumor effect of anti-CEA designer T cells in a liver metastasis model is enhanced by regional infusion and by depletion of myeloid-derived suppressor cells.

capacity to inhibit designer T-cell proliferation. CEA-positive colorectal liver metastases were established in mice via splenic injection, and designer T cells were infused via either the tail vein or the portal vein, with or without myeloidderived suppressor cell depletion. After injection of murine colorectal cancer cells, myeloid-derived suppressor cells expanded 2.4-fold compared with levels in normal mouse livers. Following 7 days of tumor growth, myeloid-derived suppressor cells accounted for 72.2% of liver CD45-positive cells, compared with 30.1% of cells in normal livers (P = .007). The addition of myeloid-derived suppressor cells to designer T cells resulted in a significantly decreased percentage of CD3-positive designer T cells that were undergoing division (53.1 vs 94.1%, P < .001). The suppressive effect of myeloid-derived suppressor cells was also significant for both CD4-positive and CD8-positive designer T cells (P < .001). Portal vein infusion of designer T cells was performed to increase delivery to the liver and to determine whether such regional administration could reduce the suppressive effect of myeloid-derived suppressor cells in the liver. Portal vein injection was associated with a 6.7-fold increase in designer T-cell delivery to the liver compared with tail vein injection (P = .05). In mice with liver metastases, portal vein infusion of anti-CEA designer T cells was associated with a significant prolongation of survival compared with tail vein infusion (P = .045; Fig. 1). Animals received et al: Immune response assessment in a phase II trial of AE37 HER2 peptide vaccine. AACR Annual Meeting. Abstract LB218. Presented April 3, 2012. 2. Pollack IF, Jakacki RI, Butterfield LH, et al: Peptide vaccine therapy for childhood gliomas: Interim results of a pilot study. AACR Annual Meeting. Abstract LB-131. Presented April 2, 2012. 3. Melero I, Sangro B, Riezu-Boj JI, et al: Antiviral and antitumoral effects of

intraperitoneal anti-Gr1 antibody injections for in vivo myeloid-derived suppressor cell depletion. When myeloid-derived suppressor cell depletion was added to portal vein designer T-cell infusion, a significant increase in tumor cell death was noted by flow cytometry (P < .05).

Conclusions As stated by Dr. Katz, “Growth of liver metastases results in a significant expansion of [myeloid-derived suppressor cells] that suppresses anti-CEA [designer T-cell] division. Regional infusion of [designer T cells] represents a potential strategy to overcome the suppressive intrahepatic milieu induced by liver metastasis growth, which we hope will be further enSee Page 89 hanced through modulation of [myeloidderived suppressor cells]. A multifaceted immunotherapeutic approach that targets both the tumor and host suppressive factors will be critical in order to achieve meaningful results for our patients with incurable metastatic disease.”

■

Disclosure: This work was supported by the Society of Surgical Oncology Clinical Investigator Award (supported by an educational donation provided by Genentech) and the Rhode Island Foundation.

Reference 1. Naheed S, Ahmed N, Nguyen C, et al: Society of Surgical Oncology 65th Annual Cancer Symposium. Abstract 2. Presented March 23, 2012.

the anti-CTLA4 agent tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection: Results from a phase II clinical trial. AACR Annual Meeting. Absract 4387. Presented April 3, 2012. 4. Recchia F, Candeloro G, Desideri G, et al: Extended phase II study of maintenance immunotherapy in advanced cancer. AACR Annual Meeting. Abstract 5366. Presented April 4, 2012.

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

The first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

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) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, 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. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation, then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur 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 with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.

EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9 mo) for ZELBORAF patients vs 4.5 months (95% CI, <0.1-11.7 mo) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of analysis.

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 months vs 1.6-1.7 months) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%)3 There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

0.294 inrash, alopecia, fatigue, photosensitivity The most common adverse reactions of any grade (≥30%) reported were arthralgia, reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

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, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. 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 ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) 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 Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. http://f1000.com/reports/m/3/8. Published April 1, 2011. Accessed July 14, 2011. 3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

zelboraf.com

The ASCO Post | MAY 15, 2012

PAGE 14

Society of Surgical Oncology Plenary Presentation

Inhibition of SFRP2 Found to Inhibit Growth of Triple-negative Breast Tumors By Matthew Stenger

ecreted frizzled related protein 2 (SFRP2), a protein that modulates the Wnt signaling pathway and is involved in embryonic development, has been thought to exert a tumor-suppres-

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.

scription factor that stimulates angiogenesis and tumor growth. On the hypothesis that SFRP2 is an oncoprotein rather than a tumor suppressor, these investigators assessed the effects of the protein

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

on the Wnt pathway in breast tumor and endothelial cells and the effects of SFRP2 antagonism on breast See Page 89 tumor growth in vivo. Lead author Emily M. Fontenot, MD, presented the team’s findings at a plenary session of the Society of Surgical Oncology Annual Cancer Symposium, in Orlando, Florida.1

Study Design To test effects on the Wnt pathway, human triple-negative (estrogen-, progesterone-, and HER2 receptor–negative) breast cancer cells (MDA-MB-231) and murine endothelial cells (2H11) were incubated with recombinant SFRP2 or control medium and nuclear samples were probed by Western blotting for NFATc3 and β-catenin. It was found that SFRP2 increased nuclear β-catenin and nuclear NFATc3 in endothelial cells and β-catenin in breast cancer cells. To assess effects of SFRP2 inhibition in vivo, human triple-negative breast cancer xenografts (MDA-MB-231) were established in mice. Treatment with buffer control, the antiangiogenic agent bevacizumab (Avastin), or an anti-SFRP2 monoclonal antibody was started when average tumor size was 200 mm3, and tumors were harvested when tumor diameter reached 2 cm or at 28 days. Treatment with anti-SFRP2 monoclonal antibody resulted in a significant 54% reduction in tumor volume compared with control Safety:10"

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

sive effect via inhibition of β-catenin activation. However, researchers at the University of North Carolina at Chapel Hill have found that SFRP2 promotes angiogenesisSafety:7" by activating NFAT, a tran-

continued on page 21

SFRP2 and Breast Cancer ■■ SFRP2 has been considered

to be a tumor-suppressive protein that exerts its effect via inhibition of β-catenin activation.

■■ In a recent study, SFRP2 was

found to increase nuclear β-catenin and NFATc3 in endothelial cells and β-catenin in triple-negative breast cancer cells in vitro, suggesting that it does not exert a tumorsuppressive effect.

■■ Further, an anti-SFRP2

monoclonal antibody was shown to significantly inhibit growth of triple-negative breast cancer xenografts, suggesting that SFRP2 may be a therapeutic target in breast cancer.

ASCOPost.com | MAY 15, 2012

PAGE 15

Practice Guidelines

Chemotherapy in Obese Patients continued from page 1

if you are being treated for cancer, obesity puts you at a greater risk of disease recurrence or death from cancer. Part of the reason for that appears to be that obese patients with cancer are often undertreated.” Dr. Lyman wrote a commentary on the ASCO guideline in the Journal of Oncology Practice.2

Fear of Treatment Toxicities Up to 60% of patients are underdosed, according to unpublished data from Jennifer J. Griggs, MD, MPH, Associate Professor in the Departments of Internal Medicine and Health Management and Policy at the University of Michigan in Ann Arbor, Co-Chair of ASCO’s Guideline Expert Panel, and lead author of the current JCO paper. The reason that so many obese patients are underdosed is that physicians may be concerned about the increased risk of adverse side effects from treatment, but those concerns are unfounded, according to data showing no increase in short- or long-term toxicity in obese patients receiving full weight–based doses. In fact, most data suggest that myelosuppression is the same or less pronounced in obese patients vs healthy-weight patients receiving full weight–based chemotherapy doses, according to the study

report. “We may actually be underdosing when we use actual body weight, although there is no evidence supporting dose escalation,” said Dr. Griggs. “The reason I’m not recommending dose escalation is because when fully dosed, obese patients have the same outcome [as fully dosed nonobese patients].” However, the panel did recommend

is crucial to ensure that the care of obese patients with cancer not be compromised because of limited-dose chemotherapeutic treatment simply because of the patient’s obesity, said Dr. Lyman. “All we are saying is don’t use obesity [and the fear of increased toxicities] as the reason for dose reduction. If oncologists have other reasons for dose

The reason I’m not recommending dose escalation is because when fully dosed, obese patients have the same outcome [as fully dosed nonobese patients]. —Jennifer J. Griggs, MD, MPH

fixed dosing for certain chemotherapy agents, including vincristine, due to the risk of neuropathy; bleomycin, due to the potential for lung scarring; and carboplatin, which should be dosed based on kidney function. The recommendations also call for modified dosing in patients with comorbidities (such as heart, kidney, or lung disease), whether they are obese or not. With two-thirds of Americans either overweight or obese, and increasing prevalence of the problem worldwide, it

reduction—for example, the patient’s overall health, the stage of disease, or comorbidities—that’s fine. But obesity alone shouldn’t be the reason,” he said.

ASCO’s Recommendations The ASCO Clinical Practice Guideline on Appropriate Chemotherapy Dosing for Obese Adult Patients with Cancer recommends the following: ■■ Actual body weight should be used when choosing cytotoxic chemotherapy doses—intravenous or

oral—for all patients, regardless of obesity status, especially if the goal of treatment is cure. ■■ Full weight–based dosing should be used for morbidly obese patients, and treatment-related toxicities in obese patients with cancer should be monitored and responded to similarly in obese and nonobese patients. ■■ Dose reduction for side effects should be made consistently for all patients. Full dosing should resume once the cause of the toxicity has been resolved. ■■ Established dosing limits on certain chemotherapies, such as vincristine, bleomycin, and carboplatin, should be used for all patients. The complete guideline recommendations, as well as clinical tools and other resources, can be accessed at www.asco.org/guidelines/wbd.

■

Disclosure: Drs. Lyman and Griggs reported no potential conflicts of interest.

References 1. Griggs JJ, Mangu PB, Anderson H, et al: Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. April 2, 2012 (early release online). 2. Lyman GH: Weight-based chemotherapy dosing in obese patients with cancer: Back to the future. J Oncol Pract. April 3, 2012 (early release online).

Obese Children with Cancer May Be at Greater Risk for Cancer Recurrence

study published in the Journal of Clinical Oncology in 2008 found that obesity is an important contributing factor to chemotherapy resistance and rising relapse rates in children with leukemia.1 According to the study, obese children diagnosed with leukemia have a 50% higher chance of relapsing compared to lean children with the cancer. Investigating the mechanisms underlying this relationship between obesity and leukemia relapse, subsequent authors from the University of Southern California developed a mouse model, culturing fat and leukemia cells together, and then treating the leukemia cells with standard chemotherapy agents used in treating children, including vincristine, nilotinib (Tasigna), daunorubicin, and dexamethasone.2 The obese mice had higher relapse rates than the lean mice, and the researchers suggested that the leukemia cells in the relapsed mice were “hiding out” in the fat tissue during chemotherapy, effectively blocking the

drugs from reaching the malignant cells. Obesity is also generally linked with higher cancer incidences in both adults and children. “Obesity puts people in a chronic inflammatory state, and inflammation appears to promote cancer development,” said Jennifer J. Griggs, MD, MPH, Associate Professor in the Departments of Internal Medicine and Health Management and Policy at the University of Michigan in Ann Arbor, and Co-Chair of ASCO’s Guideline Expert Panel on Appropriate Chemotherapy Dosing for Obese Adult Patients with Cancer (see article).

Need for Additional Research Because pediatric oncologists calculate chemotherapy doses in children based on their weight rather than on body surface area, as is used to measure dosing in adults with cancer, limited dosing does not appear to be as much of a concern in children. However, more research is needed to more accurately

pinpoint why cancer incidence and recurrence is more common in obese children and adults with cancer. “Our final recommendation in ASCO’s clinical practice guideline on chemotherapy dosing for obese adults is the need for more research in pharmacokinetics, and that’s true in obese children with cancer as well—maybe even more so in children because of the wide range of weight variation as they go from toddlers to teenagers,” said Gary H. Lyman, MD, MPH, Professor of Medicine in the Division of Medical Oncology, Department of Internal Medicine at Duke University School of Medicine and the Duke Cancer Institute, and Co-Chair of ASCO’s Guideline Expert Panel. “As we point out, and studies show,” he continued, “obese patients who get dosed based on their actual weight have no greater toxicity and perhaps less than the healthy-weight patient getting full weight–based dosing, and it may be that even with the full cal-

culated dose, they’re still getting underdosed pharmacologically. The only way we’re going to sort this out is with pharmacokinetics, by looking at the level of drugs in the body, and with pharmacodynamics, by looking at how much of the drug is actually getting to the tumor site.” The recommendations in the new clinical practice guideline, said Dr. Lyman, represent just the first step in providing oncologists with information to help them in their dosing decisions for obese patients.

■

Disclosure: Drs. Lyman and Griggs reported no potential conflicts of interest.

References 1. Butturini AM, Dorey FJ, Lange BJ, et al: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25:2063-2069, 2007. 2. Behan JW, Yun JP, Proektor MP, et al: Adipocytes impair leukemia treatment in mice. Cancer Res 69:7867-7874, 2009.

All lung cancers are tough to treat. Why are some even tougher?

We ask why. Although outcomes in certain subtypes of lung cancer have improved, many patients have complex pathology and progress rapidly. We at Celgene believe there should be more options for these patientsâ&#x20AC;&#x201D;and we are working to find them.

For more information on our research and development, visit celgene.com

The ASCO Post | MAY 15, 2012

PAGE 18

Issues in Oncology

Prostate Cancer Debates continued from page 1

mation on the initial treatment and any toxicity-related treatments.” Using billing code data, the researchers computed cost per patientyear relative to each of the three modalities. “The cost per patient-year is determined by averaging the cost of initial treatment and the cost of treating side effects. External-beam radiation therapy was about $6,400 per year, radical prostatectomy about $3,200, and brachytherapy was the least expensive at around $2,500,” said Dr. Ciezki. He added that cure rates for the three modalities are about the same. Considering that brachytherapy had the lowest cost per patient-year and the lowest percentage of treatment-associated toxic effects, it begged the question: Why is brachytherapy the least used therapy in prostate cancer? Dr. Ciezki responded, “One thought is that newer modalities are simply perceived to be better than older ones. However, we feel the principal reason brachytherapy is rarely used stems from its inception in the 1990s, when it was targeted specifically for low-risk patients, a rather small cancer population. We know now that brachytherapy is effective in a much broader clinical setting, but some of that earlier perception might still dissuade its use. Hopefully, this and other studies will add needed clarity to the choice issue.”

Medical Arms Race The phrase “trust but verify,” became the mantra in the waning years of the Cold War; some health-care experts contend we are trusting expensive new therapies before verifying their clinical worth. None exemplifies that pattern more than a proton beam center, which houses some of the most

expensive machinery ever built, costing about $200 million. Despite theoretical advantages of proton beam therapy, no data have shown any benefit over less expensive radiation therapies, such as intensitymodulated radiotherapy. Even so, there are currently 10 proton centers operating in the United States, with 7 new centers in development. “We are moving ahead with proton therapy in a way that won’t allow us to gather the critical information needed to guide proper decision-making,” said Steven Pearson, MD, MSc, FRCP, Director of the Institute for Clinical and Economic Review.

before services are geared up for clinical practice. “There are ways that payers, such as Medicare, could adapt recently developed approaches, either by linking initial coverage with a requirement for further evidence or by not paying for new services until they demonstrate better effectiveness than existing services,” said Dr. Pearson.

Photon vs Proton The debate as to whether proton therapy’s benefit justifies its use over less expensive therapies such as intensity-modulated radiotherapy remains ongoing in lieu of definitive data. “We have more work to do to understand

With the advent of new, extremely costly technologies like proton therapy, in essence, we’ve entered into a medical arms race. —Steven Pearson, MD, MSc, FRCP

Dr. Pearson commented that although proton beam services are much more expensive than other treatments, our system is not geared to incentivize comparative data collection. “With the advent of new, extremely costly technologies like proton therapy, in essence, we’ve entered into a medical arms race. This is a recurring theme in health care, and it may be too late in the proton beam story to step back and reassess the true value of this technology,” said Dr. Pearson. To prevent the continuation of employing technologies before they are fully vetted, Dr. Pearson suggests creating better dialogue with the clinical research and manufacturing community about the need for evidence

Continuing Controversies in Prostate Cancer ■■ In a comparison of external-beam radiation therapy, prostatectomy, and

brachytherapy, brachytherapy had the lowest cost per patient-year and the lowest percentage of treatment-associated toxic effects, yet it is the least used therapy in prostate cancer.

■■ No data have shown a benefit for proton-beam therapy over less

expensive radiation therapies, but new proton centers continue to be developed without allowing for research that could appropriately guide decisions about the technology.

■■ Recent trials raise questions about the potential for some placebo-

controlled designs to blunt survival benefits, the need for surrogate endpoints other than survival, and the problem of misleading “pseudoprogression” on bone scans.

the differences between proton therapy and intensity-modulated radiotherapy. A limited amount of proton therapy trials are being developed. It will be challenging, but I’m supportive of any effort—including a registry to look at prospective data—to answer this question,” said Howard M. Sandler, MD, MS, Professor and Chair of the Department of Radiation Oncology at Cedars Sinai Medical Center, Los Angeles. A chief draw for men with prostate cancer is proton therapy’s purported side-effect advantage, particularly with regard to incontinence and erectile dysfunction. “Whatever evidence exists is not level 1 quality, and in my opinion the toxicity profile between proton therapy and intensity-modulated radiotherapy is very similar,” said Dr. Sandler. He added, “In general, proton beam is an excellent form of radiation therapy. My concern is that, in prostate cancer, I don’t think superiority over other therapies has been demonstrated.” Asked whether the growing number of sophisticated technologies poses a quandary for doctor-patient conversations about less expensive treatment options, especially active surveillance, Dr. Sandler responded, “Over the past year, we’ve seen momentum that suggests an increase in thoughtful conversations between physicians and selected men regarding active surveillance. This

Howard I. Scher, MD

discussion should take place with all men with localized prostate cancer, but especially for men with lower-risk disease, for whom other treatments might well be overtreatment.”

Recent Study Yields Interesting Results At the 2012 Genitourinary Cancers Symposium in San Francisco, Howard I. Scher, MD, Chief, Genitourinary Oncology Service, Memorial SloanKettering Cancer Center, presented data from the phase III study, AFFIRM, which looked at the androgen receptor signaling inhibitor MDV3100 in advanced prostate cancer.2 The results showed a median improvement in survival of 4.8 months along with a 37% reduction in the risk of dying. Moreover, the proportions of patients reporting adverse events with MDV3100 and placebo were very similar. Fatigue was the most common adverse event seen more frequently with MDV3100 than with placebo treatment,” said Dr. Scher. During the time the study was conducted, cabazitaxel ( Jevtana) and abiraterone (Zytiga) were shown to prolong life and were FDA-approved for this population. A review of the therapies received by AFFIRM study patients after discontinuing the study drug was performed. Even though a higher percentage of placebo patients than MDV3100 patients received cabazitaxel and/or abiraterone, the survival benefit of MDV3100 was still seen. “When patients are enrolled on a placebo-controlled trial of an experimental drug and their disease progresses (on either arm of the study), they typically go on to receive additional treatment. If the additional treatment is in itself active—ie, it has been shown previously to prolong life—it is possible that its relative benefit will be greater for placebo-treated patients vs experimental drug–treated patients, such that the survival benefit of the experimental drug on the original study is lessened,” said Dr. Scher. “That was not seen with the MDV3100 trial.” He continued, “The AFFIRM trial

ASCOPost.com | MAY 15, 2012

PAGE 19

Issues in Oncology

also provided further evidence that these tumors are not hormone refractory, a finding we have seen clinically for over a decade. This is not simply a semantic argument, because if you consider the disease to be refractory to hormones, you may be depriving a patient of a safe, life prolonging treatment,” stressed Dr. Scher.

specific antigen] for several months, which are followed by slow increases. Should we stop treatment because of these small rises even though the patient feels well and there are no other signs that the treatment is not working? I would argue no.”

■

Disclosure: Drs. Ciezki and Pearson

reported no potential conflicts of interest. Dr. Sandler receives research support from RTOG. Dr. Scher is an uncompensated consultant to Medivation.

References 1. Ciezki J, Reddy CA, Angermeier K, et al: A SEER/Medicare database study. 2012 Genitourinary Cancers Symposium.

Abstract 4. Presented February 2, 2012. 2. Scher HI, Fizazi K, Saad F, et al: Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI) on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. 2012 Genitourinary Cancers Symposium. Abstract LBA1. Presented February 2, 2012.

Researchers as Doctors Another key issue is that the trial included the evaluation of several biomarkers, in particular those that might be used as clinical trial endpoints in place of overall survival. Dr. Scher explained that a current focus of the research is to qualify a surrogate biomarker that could be used to accelerate drug approvals. As a member of the Prostate Cancer Clinical Trials Working Group, Dr. Scher has spearheaded an effort to standardize the design of clinical trials that clearly demonstrate meaningful clinical benefits that can lead to drug approvals in their own right, in addition to a survival benefit. “This requires a sequence of dedicated trials focused on the biomarker question, analogous to trials designed for drug approvals,” Dr. Scher said.

Now Enrolling A Randomized Phase 3 Trial

Key Principle A key principle of the Prostate Cancer Working Group guidelines was to better align clinical practice and clinical research by enabling physicians to continue treating patients on a trial as long as the patient was benefiting. A particular problem in prostate cancer is that the first bone scan obtained after a patient has started a new treatment may appear worse, when in fact it is a sign that the treatment is working. The Working Group guidelines account for this “pseudoprogression” by requiring confirmatory imaging that shows further worsening before discontinuing a drug. “This approach helps to ensure that a drug is not stopped prematurely. Stopping a drug can be the fastest way to ensure it doesn’t work,” noted Dr. Scher. It is unknown at this point whether drugs such as MDV3100 should be continued even after a patient has shown signs of disease progression. “Patients with breast cancer who are on trastuzumab (Herceptin) do not stop treatment; the next drug is simply added. MDV3100 may be in this same category, similar to what is done with gonadotropin-releasing hormone analogs used to maintain castrate levels of testosterone for patients enrolling on trials,” Dr. Scher explained. “Often we see dramatic declines in [prostate-

R A N D O M I Z E D

Placebo Q2W + Gemcitabine Ganitumab 12 mg/kg Q2W + Gemcitabine Ganitumab 20 mg/kg Q2W + Gemcitabine

OS Primary endpoint

Ganitumab (AMG 479) is an investigational IGF1R inhibitor that has not been approved by the FDA.

KEY INCLUSION CRITERIA: • Histologically or cytologically conﬁrmed metastatic adenocarcinoma of the pancreas (AJCC Stage IV) • Previously untreated with chemotherapy or radiation • ECOG Performance Status 0 or 1 For Additional Information: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com (20060540) • www.ClinicalTrials.gov (NCT01231347)

ASCO 2011 Journal Ad_AMG479_090611.indd 1

Oncology

9/6/2011 5:08:17 PM

The ASCO Post | MAY 15, 2012

PAGE 20

Journal Spotlight Genitourinary Oncology

Study Shows Continued Benefit of PSA Screening in Reducing Prostate Cancer Mortality By Matthew Stenger

tudies assessing the effect of prostate-specific antigen (PSA) testing on prostate cancer mortality have produced conflicting results, and recommendations regarding PSA screening vary among authorities. The recently published 11-year follow-up of the European Randomized Study of Screening for Prostate Cancer (ERSPC) indicates

that offering PSA-based screening to a core age group of men aged 55 to 69 years at study entry is associated with a significant 21% reduction in risk of death from prostate cancer.1

Study Background ERSPC involved 182,160 men aged 50 to 74 years at entry from eight Euro-

EXPERT POINT OF VIEW

By Fritz H. Schröder, MD, International Co-Coordinator of the ERSPC Study

any of the almost 100 reports in various journals and newspapers refer to the lack of effect on overall mortality with screening in ERSPC in a very critical fashion. Clarification is necessary. Our trial did not intend to and is not powered to study the effect of screening on overall mortality. Mortality from all causes contributes about 30% to overall male mortality. To decrease cancer mortality in general is an explicit goal in most countries of the world. Prostate cancer morFritz H. Schröder, MD tality is in most countries the second or third most frequent cause of cancer-related death in males. We wished and still wish to contribute to its decrease at an acceptable price in terms of harm and costs. Unfortunately, as stated in the conclusions in our New England Journal of Medicine article, the time of population-based screening has not (yet) come.

Role of Risk Calculators The decrease of harms, mainly overdiagnosis and overtreatment in large proportions of men with screening-detected prostate cancers, which is quantified reliably through ERSPC data for the first time, requires the intensive cooperative efforts of our profession and of related basic research. As long as a simple blood test or another means of selective identification of the more aggressive but still curable lesions does not exist, available risk calculators that allow avoiding “unnecessary” diagnostic steps should be widely applied in a concerted way. An example is the risk calculator available at www.prostatecancer-riskcalculator.com. This calculator is based on ERSPC data and has been repeatedly externally validated.

Implications of the Data So, how should the public and how should our colleagues deal with the new information? The authors feel that for men who consider being screened, the positive side of the argument has changed: We showed that in men actually screened, there was a highly significant prostate cancer mortality reduction. The downside has remained unchanged. This requires rather difficult informed decision-making. There is a need for international standardization of the related information for “the man on the street” and for his consulted health professionals. Fortunately, the International Society of Urology, which represents 111 countries, has decided to produce and to distribute such information in 2012-2013.

■

Disclosure: Dr. Schröder reported no potential conflicts of interest with respect to this commentary or the ERSPC study report.

Dr. Schröder is Professor of Urology at Erasmus Medical Center, Rotterdam, the Netherlands.

pean countries, including a core group jects in the screening group who unof 162,388 men aged 55 to 69 years. derwent screening and that corrected Subjects were randomized to a screenfor selection bias showed an adjusted ing group that was offered PSA-based rate ratio for prostate cancer mortality screening or a control group that was of 0.71 (95% CI = 0.58–0.86, P = .001) not offered screening. The primary in the screening group, a relative risk outcome measure was prostate cancer reduction of 29%. For the study popumortality. All-cause mortality was not lation truncated at 11 years, the time an endpoint of this study, and, as exof the median follow-up, the “number pected, no difference was seen. needed to invite to screening” to prevent Over a median follow-up of 11 years 1 death from prostate cancer was 1,055, in the core age group, 136,689 screenand the “number of cancers needed to ing tests were performed—an average be detected” to prevent 1 death was 37. of 2.3 tests per subject with a median When all available follow-up was screening interval of 4 years. Of these considered, the number needed to intests, 16.6% were vite to screening positive, and 85.9% was 938 and the Over the 11-year of men with posinumber of canfollow-up, death from tive tests undercers needed to be went prostate biopprostate cancer occurred detected was 33, sy. A total of 6,963 with these data folin 299 subjects in the prostate cancers lowing the pattern were diagnosed predicted by sevscreening group and eral independent in the screening 462 subjects in the statistical analyses group, a cumulative of 2009 ERSPC incidence of 9.6% control group, with data. The rate ratio (9.66 cases/1,000 death rates of 0.39 and for mortality in the person-years), and a total of 5,396 0.50/1,000 person-years, screening group from 1 to 9 years of cases were diagrespectively. follow-up was 0.85, nosed in the concompared with trol group, a cumu0.79 over 1 to 11 lative incidence of years of follow up; during the 10th and 6.0% (5.95/1,000 person-years). The 11th years of follow-up, the relative rate ratio in the screening group was reduction in risk for death was 38% in 1.63, with a rate difference of 3.71 casthe screening group. es/1,000 person-years. The excess incidence in the screening group was largely Prostate Cancer Mortality attributable to small, well-differentiated The total rate ratio for prostate cantumors. Advanced tumors (T3, T4, or cer death in the screening group was distant metastases) and aggressive cansignificantly below 1.00 in the core age cers (Gleason score of 8–10) were more group—the group for which the study common in the control group. was statistically powered—and for all Follow-up Findings ages. However, subgroup analyses inOver the 11-year follow-up, death dicated that at the time of follow-up, from prostate cancer occurred in 299 the risk ratio was significant only for subjects in the screening group and subjects between the ages of 65 and 69 462 subjects in the control group, with years—a new finding if compared to death rates of 0.39 and 0.50/1,000 perthe 2009 report. son-years, respectively. The rate ratio in Although the rate of screening in the screening group was 0.79 (95% CI the control group was not reported = 0.68–0.91, P = .001), a relative risk for the 11-year follow up, prior reports reduction of 21% in favor of screenfrom ERSPC indicate that approxiing. The absolute reduction in mormately 20% of subjects per year in the tality in the screening group was 0.10 control group had undergone PSAdeaths/1,000 patient-years, or 1.07 based screening during an early followdeaths per 1,000 randomized subjects. up period.2 Nearly half the prostate cancer An analysis that included only sub-

ASCOPost.com | MAY 15, 2012

PAGE 21

Journal Spotlight

deaths in the screening group occurred among men with cancer detected during screening; See Page 89 in three-quarters of these men, the diagnosis was made in the first round of

screening. Approximately one-quarter of deaths in this group occurred in subjects with cancer detected between screenings, with a similar number occurring in subjects in the screening group who were unscreened. There was no difference in overall mortality in the two groups. Mor-

tality rates were 18.2/1,000 person years in the screening group and 18.5/1,000 person-years in the control group (rate ratio = 0.99, 95% CI = 0.97–1.01).

■

References 1. Schröder FH, Hugosson J, Roobol

MJ, et al: Prostate cancer mortality at 11 years of follow-up. N Engl J Med 366:981990, 2012. 2. Ciatto S, Zappa M, Villers A, et al: Contamination by opportunistic screening in the European Randomized Study of Prostate Cancer Screening. BJU Int 92 (suppl 2):97-100, 2003.

SFRP2 and Breast Cancer continued from page 14

(P = .03). Bevacizumab treatment resulted in a nonsignificant 32% reduction in growth compared with control (P = .32). No effect on tumor growth was observed with an IgG-negative control treatment.

Therapeutic Target The finding that SFRP2 activated both β-catenin and NFATc3 in endothelial cells and β-catenin in breast cancer cells suggests that SFRP2 is not a tumor suppressor. Further, as stated by the investigators, “SFRP2 antagonism with a monoclonal antibody resulted in a reduction in breast tumor growth in tumors that were [relatively insensitive] to bevacizumab. This suggests that SFRP2 is a therapeutic target for breast cancer.”

FDA approves simplified ZEVALIN treatment. RITUXIMAB INDIUM-111 BIOSCAN RITUXIMAB ZEVALIN

RR Less steps. More convenience.

That’s ZEVALIN today.

Learn more at www.ZEVALIN.com INDICATIONS AND USAGE: Nancy Klauber-DeMore, MD

Nancy Klauber-DeMore, MD, principal investigator for the study, noted “This is our second study that has demonstrated the antitumor effects of SFRP2 antagonism. We recently presented findings at the Association of Academic Surgeons meeting showing that the SFRP2 monoclonal antibody inhibits the growth of angiosarcoma tumors in vivo. Our future studies will focus on studying the role of SFRP2 on tumor growth and Wnt signaling in a wide variety of tumor types.”

■

Disclosure: Dr. Klauber-DeMore and coauthor Dr. Cam Patterson have cofounded Enci Therapeutics, Inc, to support the clinical development of a monoclonal antibody to SFRP2 for cancer.

Reference 1. Fontenot EM, Mumper R, Shen X, et al: Therapeutic targeting of SFRP2 is a strategy to reduce triple negative breast tumor growth. Society of Surgical Oncology 65th Annual Cancer Symposium. Abstract 4. Presented March 23, 2012.

ZEVALIN is a CD20-directed radiotherapeutic antibody administered as part of the ZEVALIN therapeutic regimen indicated for the treatment of patients with: • Relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL). • Previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy. WARNING: SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, and SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion. Discontinue rituximab and Y-90 ZEVALIN infusions in patients who develop severe infusion reactions. Prolonged and Severe Cytopenias: Y-90 ZEVALIN administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 ZEVALIN to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve. Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the ZEVALIN therapeutic regimen. Discontinue rituximab and Y-90 ZEVALIN infusions in patients experiencing severe cutaneous or mucocutaneous reactions. Dosing: The dose of Y-90 ZEVALIN should not exceed 32.0 mCi (1184 MBq).

Please see Brief Summary, including BOXED WARNINGS and additional safety information on the following pages.

0111-041100

The ASCO Post | MAY 15, 2012

PAGE 22

Symptom Management

Managing Febrile Neutropenia continued from page 3

than 21 indicates high risk (Table 1).4 “The MASCC Risk Index score has very robust evidence for its ability to distinguish between high- and low-risk patients. It is probably the most highly

validated tool,” Dr. Freifeld commented. High-risk patients are typically those undergoing induction for acute myeloid leukemia or hematopoietic stem cell transplantation, and are generally treated as inpatients with intravenous antibiotic therapy. Guidelinerecommended therapy includes any

of several broad-spectrum beta-lactam monotherapy options: imipenem (with cilastatin), meropenem, or another carbapenem; piperacillin (with tazobactam), ceftazidime, or cefepime. Guidelines also list as an option intravenous combination therapy, such as an aminoglycoside plus an antipseudo-

monal beta-lactam antibiotic. “Although numerous well-performed clinical trials have been conducted over several decades, no single therapeutic regimen for initial treatment of febrile neutropenia has emerged as clearly superior to others,” Dr. Freifeld noted. “All effective

ZEVALIN® (ibritumomab tiuxetan) for Intravenous Injection BRIEF SUMMARY. Please see full Prescribing Information, including BOXED WARNINGS for ZEVALIN and rituximab INDICATIONS AND USAGE: ZEVALIN is a CD20-directed radiotherapeutic antibody administered as part of the ZEVALIN therapeutic regimen indicated for the treatment of patients with: • Relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL). • Previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy. WARNING: SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, and SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion. Discontinue rituximab and Y-90 ZEVALIN infusions in patients who develop severe infusion reactions. Prolonged and Severe Cytopenias: Y-90 ZEVALIN administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 ZEVALIN to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve. Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the ZEVALIN therapeutic regimen. Discontinue rituximab and Y-90 ZEVALIN infusions in patients experiencing severe cutaneous or mucocutaneous reactions. Dosing: The dose of Y-90 ZEVALIN should not exceed 32.0 mCi (1184 MBq). DOSAGE AND ADMINISTRATION: Day 1: Administer rituximab 250 mg/m2 IV. Day 7, 8, or 9: Administer rituximab 250 mg/m2 IV infusion. If platelets ≥ 150,000/mm3: Within 4 hours after rituximab infusion, administer 0.4 mCi/kg (14.8 MBq per kg) Y-90 ZEVALIN IV. If platelets ≥ 100,000 but ≤ 149,000/mm3 in relapsed or refractory patients: Within 4 hours after rituximab infusion, administer 0.3 mCi/kg (11.1 MBq per kg) Y-90 ZEVALIN IV. DOSAGE FORMS AND STRENGTHS: 3.2 mg per 2 mL, single-use vial. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS (Please also see BOXED WARNING) Serious Infusion Reactions: See also prescribing information for rituximab. Rituximab, alone or as a component of the ZEVALIN therapeutic regimen, can cause severe, including fatal, infusion reactions. These reactions typically occur during the first rituximab infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reactions may include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. Immediately discontinue rituximab and Y-90 ZEVALIN administration for severe infusion reactions. Prolonged and Severe Cytopenias: Cytopenias with delayed onset and prolonged duration, some complicated by hemorrhage and severe infection, are the most common severe adverse reactions of the ZEVALIN therapeutic regimen. When used according to recommended doses, the incidences of severe thrombocytopenia and neutropenia are greater in patients with mild baseline thrombocytopenia (100,000 to 149,000 /mm3) compared to those with normal pretreatment platelet counts. Severe cytopenias persisting more than 12 weeks following administration can occur. Do not administer the ZEVALIN therapeutic regimen to patients with ≥ 25% lymphoma marrow involvement and/ or impaired bone marrow reserve. Monitor patients for cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months after use of the ZEVALIN therapeutic regimen. Avoid using drugs which interfere with platelet function or coagulation following the ZEVALIN therapeutic regimen. Severe Cutaneous and Mucocutaneous Reactions: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis, some fatal, were reported in post-marketing experience. The time to onset of these reactions was variable, ranging from a few days to 4 months after administration of the ZEVALIN therapeutic regimen. Discontinue the ZEVALIN therapeutic regimen in patients experiencing a severe cutaneous or mucocutaneous reaction. Altered Biodistribution: In a post-marketing registry designed to collect biodistribution images and other information in reported cases of altered biodistribution, there were 12 (1.3%) patients reported to have altered biodistribution among 953 patients registered. Leukemia and Myelodysplastic Syndrome: Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-

access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to the diagnosis of MDS or AML was 1.9 years following treatment with the ZEVALIN therapeutic regimen; however, the cumulative incidence continues to increase. Among 204 patients receiving Y-90 ZEVALIN following first-line chemotherapy, two patients (1%) were diagnosed with AML within 3 years of receiving ZEVALIN. Embryo-fetal Toxicity: Based on its radioactivity, Y-90 ZEVALIN may cause fetal harm when administered to a pregnant woman. If the ZEVALIN therapeutic regimen is administered during pregnancy, the patient should be apprised of the potential hazard to a fetus. Advise women of childbearing potential to use adequate contraception for a minimum of twelve months. Extravasation: Monitor patients closely for evidence of extravasation during ZEVALIN infusion. Immediately terminate the infusion if signs or symptoms of extravasation occur and restart in another limb. Immunization: The safety of immunization with live viral vaccines following the ZEVALIN therapeutic regimen has not been studied. Do not administer live viral vaccines to patients who have recently received ZEVALIN. The ability to generate an immune response to any vaccine following the ZEVALIN therapeutic regimen has not been studied. Laboratory Monitoring: Monitor complete blood counts (CBC) and platelet counts following the ZEVALIN therapeutic regimen weekly until levels recover or as clinically indicated. Radionuclide Precautions: During and after radiolabeling ZEVALIN with Y-90, minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures. Creutzfeldt-Jakob Disease (CJD): The ZEVALIN therapeutic regimen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, ZEVALIN carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. ADVERSE REACTIONS: Common adverse reactions (≥40%) in clinical trials were: neutropenia, leucopenia, thrombocytopenia, anemia, infection, asthenia, musculoskeletal symptoms and gastrointestinal symptoms. The most common adverse reactions of ZEVALIN are cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea and pyrexia. The most serious adverse reactions of ZEVALIN are prolonged and severe cytopenias (thrombocytopenia, anemia, lymphopenia, neutropenia) and secondary malignancies. Because the ZEVALIN therapeutic regimen includes the use of rituximab, see prescribing information for rituximab. Prolonged and Severe Cytopenias: Patients in clinical studies were not permitted to receive hematopoietic growth factors beginning 2 weeks prior to administration of the ZEVALIN therapeutic regimen. The incidence and duration of severe hematologic toxicity in previously treated NHL patients (N=335) and in previously untreated patients (Study 4) receiving Y-90 ZEVALIN are shown in the table on the following page.

ASCOPost.com | MAY 15, 2012

PAGE 23

Symptom Management

regimens, both monotherapies and combination therapies, share certain features that are essential. Bactericidal activity in the absence of white cells is extremely important; this is provided most effectively by cephalosporins and penicillins. And antipseudomonal coverage also remains a linchpin of the ini-

tial regimen,” she added. “Whilst each of these regimens may have a little bit of a niche advantage, one over the other, for specific reasons, by and large, they all perform fairly well, predictably, and safely,” Dr. Bow agreed. “The guidelines are intended to give physicians an understanding of

the principles upon which they could choose any number of products to achieve the same outcome.” Low-risk patients are usually those with solid tumors undergoing chemotherapy regimens that result in brief durations of neutropenia. They may present with evidence of systemic Brahm H. Segal, MD

Severe Hematologic Toxicity in Patients Receiving ZEVALIN

Baseline Platelet Count

Y-90 ZEVALIN Dose ANC Median nadir ( per mm3) Per Patient Incidence ANC <1000/mm3 Per Patient Incidence ANC <500/mm3 Median Duration (Days)* ANC <1000/mm3 Median Time to Recovery** Platelets Median nadir (per mm3) Per Patient Incidence Platelets <50,000/mm3 Per Patient Incidence Platelets <10,000/mm3 Median Duration (Days)# Platelets <50,000/mm3 Median Time to Recovery**

Group 1 (n=270) ≥ 150,000/mm3

Group 2 Study 4 (n=65 ) (n=204) 100,000 to ≥ 150,000/mm3 149,000/mm3

0.4 mCi/kg 0.3 mCi/kg 0.4 mCi/kg (14.8 MBq/kg) (11.1 MBq/kg) (14.8 MBq/kg) 800

600

721

57%

74%

65%

30%

35%

26%

41,000

24,000

42,000

61%

78%

61%

10%

14%

* Day from last ANC ≥1000/mm3 to first ANC ≥1000/mm3 following nadir, censored at next treatment or death ** Day from nadir to first count at level of Grade 1 toxicity or baseline # Day from last platelet count ≥50,000/mm3 to day of first platelet count ≥50,000/mm3 following nadir, censored at next treatment or death Cytopenias were more severe and more prolonged among eleven (5%) patients who received ZEVALIN after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non-fludarabine containing regimens. Among these eleven patients, the median platelet nadir was 13,000/mm3 with a median duration of platelets below 50,000/mm3 of 56 days and the median time for platelet recovery from nadir to Grade 1 toxicity or baseline was 35 days. The median ANC was 355/mm3, with a median duration of ANC below 1,000/mm3 of 37 days and the median time for ANC recovery from nadir to Grade 1 toxicity or baseline was 20 days. The median time to cytopenia was similar across patients with relapsed/ refractory NHL and those completing first-line chemotherapy, with median ANC nadir at 61-62 days, platelet nadir at 49-53 days, and hemoglobin nadir at 68-69 days after Y-90-ZEVALIN administration. Information on hematopoietic growth factor use and platelet transfusions is based on 211 patients with relapsed/refractory NHL and 206 patients following first- line chemotherapy. Filgrastim was given to 13% of patients and erythropoietin to 8% with relapsed or refractory disease; 14% of patients receiving ZEVALIN following first-line chemotherapy received granulocyte-colony stimulating factors and 5% received erythopoiesis-stimulating agents. Platelet transfusions were given to approximately 22% of all ZEVALIN-treated patients. Red blood cell transfusions were given to 20% of patients with relapsed or refractory NHL and 2% of patients receiving ZEVALIN following first-line chemotherapy. Infections: In relapsed or refractory NHL patients, infections occurred in 29% of 349 patients during the first 3 months after initiating the ZEVALIN therapeutic regimen and 3% developed serious infections (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infections were reported in 2% (sepsis, empyema, pneumonia, febrile neutropenia, fever and biliary stent-associated cholangitis). From 3 months to 4 years after ZEVALIN treatment, 6% of patients developed infections; 2% were serious (urinary tract infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, and intravenous drug-associated viral hepatitis) and 1% were life-threatening infections (bacterial pneumonia, respiratory disease, and sepsis). When administered following first-line chemotherapy, Grade 3-4 infections occurred in 8% of ZEVALIN treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection. 0102-017901 111114

Leukemia and Myelodysplastic Syndrome: Among 746 patients with relapsed/refractory NHL, 19 (2.6%) patients developed MDS/AML with a median follow-up of 4.4 years. The overall incidence of MDS/ AML among the 211 patients included in the clinical studies was 5.2% (11/211), with a median follow-up of 6.5 years and median time to development of MDS/AML of 2.9 years. The cumulative KaplanMeier estimated incidence of MDS/secondary leukemia in this patient population was 2.2% at 2 years and 5.9% at 5 years. The incidence of MDS/AML among the 535 patients in the expanded access programs was 1.5% (8/535) with a median follow-up of 4.4 years and median time to development of MDS/AML of 1.5 years. Multiple cytogenetic abnormalities were described, most commonly involving chromosomes 5 and/or 7. The risk of MDS/AML was not associated with the number of prior treatments (0-1 versus 2-10). Among 204 patients receiving Y-90-ZEVALIN following first-line treatment, 2 (1%) developed AML at approximately 2 and 3.3 years after ZEVALIN administration, respectively. Immunogenicity: As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of HAMA/HACA to the ZEVALIN therapeutic regimen with the incidence of antibodies to other products may be misleading. HAMA and HACA response data on 446 patients from 8 clinical studies conducted over a 10-year time period are available. Overall, 11/446 (2.5%) had evidence of either HAMA formation (N=8) or HACA formation (N=4). Six of these patients developed HAMA/HACA after treatment with ZEVALIN and 5 were HAMA/HACA positive at baseline. Of the 6 who were HAMA/HACA positive, only one was positive for both. Furthermore, in 6 of 11 patients, the HAMA/HACA reverted to negative within 2 weeks to 3 months. No patients had increasing levels of HAMA/HACA at the end of the studies. Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of the ZEVALIN therapeutic regimen in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to the ZEVALIN therapeutic regimen. • Cutaneous and mucocutaneous reactions: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis. • Infusion site erythema and ulceration following extravasation. • Radiation injury in tissues near areas of lymphomatous involvement within a month of ZEVALIN administration. DRUG INTERACTIONS: No formal drug interaction studies have been performed with ZEVALIN. Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category D Based on its radioactivity, Y-90 ZEVALIN may cause fetal harm when administered to a pregnant woman. Immunoglobulins are known to cross the placenta. There are no adequate and well-controlled studies in pregnant women. Animal reproductive toxicology studies of ZEVALIN have not been conducted. Advise women of childbearing potential to use adequate contraception for a minimum of twelve months. Inform women who become pregnant while receiving ZEVALIN of the potential fetal risks. Nursing Mothers: Because human IgG is excreted in human milk, it is expected that ZEVALIN would be present in human milk. Because of the potential for adverse reactions in nursing infants from Y-90 ZEVALIN, a decision should be made to discontinue nursing or not administer the ZEVALIN therapeutic regimen, taking into account the importance of the drug to the mother. OVERDOSAGE: Severe cytopenias which may require stem cell support have occurred at doses higher than the recommended maximum total dose of 32 mCi (1184 MBq). © 2012 Spectrum Pharmaceuticals, Inc. All Rights Reserved. SPECTRUM PHARMACEUTICALS, INC.® and ZEVALIN® are registered trademarks of Spectrum Pharmaceuticals, Inc. and its subsidiaries. The Spectrum Pharmaceuticals logo and ZEVALIN logo are trademarks owned by Spectrum Pharmaceuticals, Inc. and its subsidiaries.

www.sppirx.com

inflammatory response syndrome, possibly with an infection focus, but without evidence of hypoperfusion or organ dysfunction. These patients may be treated as inpatients with the above intravenous therapy options but may also be eligible for oral combination therapy, namely, ciprofloxacin plus amoxicillin with clavulanate, if they are deemed stable and able to tolerate oral medications. Outpatient management is a particularly attractive prospect for some low-risk patients, although eligibility depends on their ability to tolerate an oral regimen, their access to a telephone and transportation, and the availability of a caregiver. Because there is less intensive monitoring outside the hospital, the potential for complications and drug safety become especially important considerations, noted Brahm H. Segal, MD, Professor of Medicine at the University of Buffalo School of Medicine and Chief of the Division of Infectious Diseases at Roswell Park Cancer Institute in New York. Yet, when feasible, outpatient therapy has the advantages of greater patient convenience and lower cost, he added. Perhaps equally important in selecting an initial antibiotic therapy are certain drugs that are not recommended for routine use in this setting. “The use of antibiotics with extended activity against gram-positive organisms, like vancomycin and daptomycin [Cubicin], is generally not required. One should not prescribe these antimicrobials unless there’s a specific indication as outlined in the guidelines, so as to avoid overuse, due mainly to our concerns about resistance among the gram-positive organisms, primarily Staphylococcus aureus,” Dr. Freifeld advised. Situations in which guidelines recommend vancomycin are those in which there is a high local prevalence of methicillin-resistant S aureus (MRSA) infections or in which the febrile neutropenia is more likely due to MRSA, continued on page 24

The ASCO Post | MAY 15, 2012

PAGE 24

Symptom Management

Managing Febrile Neutropenia continued from page 23

such as central venous catheter–related infections, and skin and soft-tissue infections. Importantly, guidelines recommend discontinuing vancomycin if, after 48 to 72 hours, cultures do not show any pathogen warranting this antibiotic. “Such a strategy can prevent toxicity and selection for resistant bacteria,” Dr. Bow commented.

Additional Considerations A variety of other factors are helpful in selecting among the above options for initial antibiotic therapy. These include the drug interactions and adverse effects of a given antibiotic. “Antibacterial agents are generally well tolerated,” Dr. Segal noted. Overall, they have known adverse effects that include nausea, rash, and the potential for allergic reactions and predisposition to Clostridium difficile colitis. “However, there are some that have specific toxicities—for example, aminoglycosides as a class have renal toxicity.” In selecting an initial regimen, clinicians must also now consider resistance issues, including MRSA, vancomycinresistant enterococci, fluoroquinolone resistance among gram-negative bacilli, and extended-spectrum beta-lactamase– and carbapenemase-producing gram-negative bacilli—all of which have the potential to seriously reduce the effectiveness of initial empiric antibiotic therapy, Dr. Bow noted. Prior prophylaxis can limit op-

tions for initial antibiotic therapy as well. For example, patients with febrile neutropenia who have been receiving fluoroquinolone prophylaxis are not candidates for the oral antibiotic combination therapy above (ie, ciprofloxacin plus amoxicillin with clavulanate). Finally, the site of known or suspected infection may help guide antibiotic choice, as well as suggest the need for additional coverage. For example, “if the patient has new abdominal pain and signs and symptoms suggesting an abdominal process, then I’d chose a regimen with greater an-

spite up to 5 days of broad-spectrum antibacterial therapy.

Modifying Initial Therapy “Further modifications to initial antibiotic regimens should be based on clinical and microbiologic findings, rather than on the persistent presence of fever alone. In other words, we always emphasize this: No changes in the initial antibiotic regimen are required in stable patients who have persistent fever,” Dr. Freifeld said. “The only exception to that is the use of empiric

No changes in the initial antibiotic regimen are required in stable patients who have persistent fever. —Alison G. Freifeld, MD

aerobic coverage, such as imipenem or meropenem,” Dr. Freifeld explained. On the other hand, she continued, “if they have an infiltrate on chest xray and clinical evidence of pneumonia, they would require a multidrug regimen for health care–acquired pneumonia. That would include vancomycin and a macrolide or fluoroquinolone, as well as a beta-lactam drug.” Similarly, guidelines recommend that clinicians consider viral testing and adding antiviral therapy targeting herpes simplex viruses for patients with suspicious oral lesions, and antifungal therapy for those with persistent neutropenic fever syndrome de-

antifungal therapy; typically, patients who continue to be febrile beyond 96 hours of empiric antibacterial therapy are candidates for antifungal therapy.” Dr. Segal added, “The rationale for empiric antifungal therapy is to treat a possible occult fungal infection that may be unrecognized by physical exam and routine cultures. In addition, a broad-spectrum antifungal agent (eg, a mold-active azole or echinocandin) is commonly used as prophylaxis in patients with prolonged neutropenia at high risk for invasive fungal diseases, such as those receiving induction or reinduction regimens for acute myeloid leukemia. In patients receiving prophylaxis with a broad-spectrum antifungal

agent, modifying the antifungal regimen solely based on persistent fever is of unclear value. Some See Page 89 centers perform surveillance testing for early fungal disease (eg, serial serum galactomannan and/or beta-glucan testing) in high-risk patients, to guide decisions about when to begin or modify the antifungal regimen.”

■

Disclosure: Drs. Freifeld, Bow, and Segal reported no potential conflicts of interest.

References 1. Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 52(4):e56-e93, 2011. 2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prevention and Treatment of Cancer-Related Infections. Version 2.2011. Available at http://www. nccn.org/professionals/physician_gls/ pdf/infections.pdf. Accessed Feb. 18, 2012. 3. Bullard MJ, Unger B, Spence J, et al: Revisions to the Canadian Emergency Department Triage and Acuity Scale (CTAS) adult guidelines. Can J Emerg Med 10:136-151, 2008. 4. Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for Supportive Care in Cancer Risk Index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038-3051, 2000.

Don’t Miss These Important Reports Inside this Issue of The ASCO Post James A. Stewart, MD, FACP, on Maintenance of Certification in Medical Oncology, page 1

Alison G. Freifeld, MD, on Managing Febrile Neutropenia, page 3

Kanti R. Rai, MD, on Treating Chronic Lymphocytic Leukemia, page 27

Alfred L. Goldberg, PhD, on Cancer Cachexia, page 62

Stuart M. Lichtman, MD, on Geriatric Oncology and Older Patients with Cancer, page 79

Michael P. Link, MD, on the Oncology Drug Shortage, page 97

Visit The ASCO Post online at ASCOPost.com

Now Enrolling

The Medical Division at Lilly Oncology is currently enrolling patients in a phase 3 trial of the VEGF receptor-2 antagonist ramucirumab (IMC-1121B)

REACH*: A Second-line Hepatocellular Carcinoma (HCC) Trial

Randomization

• H CC after progression on or intolerance to first-line sorafenib • C hild-Pugh score of <9 (Child-Pugh A or B [B7 or B8]) • A t least 1 measurable or evaluable viable lesion not previously treated with locoregional therapy

N=~544

Best supportive care + blinded ramucirumab 8 mg/kg IV infusion every 2 weeks

Best supportive care + blinded placebo 8 mg/kg IV infusion every 2 weeks

Treat until progressive disease, intolerable toxicity, noncompliance, withdrawal of consent, or investigator decision

Study Objectives Primary endpoint:

Secondary endpoints:

• Overall survival (OS)

• Progression-free survival (PFS)

• Safety profile of ramucirumab

• Best objective response rate (ORR)

• Ramucirumab serum concentrations

• Time to radiographic progression

• Pharmacodynamics of ramucirumab

• P atient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life

• Immunogenicity of ramucirumab

For further information, please contact ImClone Systems by e-mail at ClinicalTrials@imclone.com or visit www.clinicaltrials.gov (identifier number NCT01140347). Note that, for an investigator to participate, the study must be approved by the investigator’s country competent health authority. Ramucirumab (IMC-1121B) is an investigational new drug. The safety and efficacy of ramucirumab have not been established for the use under investigation. There is no guarantee that ramucirumab will receive regulatory approval and become commercially available for the use under investigation.

* REACH: A Multicenter, Randomized, Double-blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) versus Placebo and BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma Following First-line Therapy With Sorafenib

The ASCO Post | MAY 15, 2012

PAGE 26

Perspective

Maintenance of Certification in Medical Oncology continued from page 1

physician, teacher, team player, and administrator. Like many physicians, I think of myself as a self-starter, motivated to keep learning both because it is necessary to keep up and because it also can be fun. But over time I have realized it is more and more difficult to sort out the best literature and to develop what might be the most useful personal curriculum. It is also clear that to provide optimal oncologic care in the future, I will need to learn more about how best to shape my work setting for efficiency and patient-centeredness. Oncology care is a team event, and communication pathways, group function, and the handling of increasing amounts of clinical data will be as important as how much I remember about the results of the latest phase III clinical trial. Systems-based practice skills will be as important as my traditional medical expertise. Two types of documents—my state medical license and certificates from the American Board See Page 89 of Internal Medicine (ABIM) for Internal Medicine and Medical Oncology— serve as validation for the public, my affiliated hospital, my employer, and health insurance companies, confirming that I am qualified to work as an oncologist, at least as defined by those review mechanisms. To maintain my state license, I must complete a certain amount of CME activities with appropriate documentation on a regular basis. I can collect CME credits by attending my department’s weekly Medicine Grand Rounds, and I do so, though oncology topics are uncommon and I attend in large part for “citizenship” reasons, ie, to support the department and serve as a role model for house staff.

Vigorous Debate More attractive are the developing systems for maintenance of certification (MOC) in my own specialty. In recent years, there has been vigorous debate in the literature regarding the state of maintenance of certification, with concerns about relevance, financial cost, time cost, and the effort needed to maintain certification from the American Board of Internal Medicine. A few articles summarize

well the issues in this conversation and are worth reviewing to understand the history and issues.1-5 Key elements required for the ABIM-based maintenance of certification in both Internal Medicine and Medical Oncology include licensure, self-assessment and CME, cognitive expertise, and performance in practice.6 For many of us, doing something related to assessment or improvement in our practice can be the most cumbersome. Practice settings are more “corporate” than ever, and making changes that influence the overall business can be difficult.

membership suggestions. A variety of educational modules are available online, including some specifically geared toward maintenance of certification (eg, breast cancer, lung cancer, and ethics). Through the QOPI program, ASCO also continues to develop meaningful and highly relevant measures of practice quality.7 It is important to remember that the practice performance assessment can be one of the more intimidating and challenging elements of maintenance of certification. QOPI is ideal for this activity as the only oncology-

A consistent concern in the MOC debate relates to how meaningful and relevant the assessment and testing tools are to the practicing oncologist. —James A. Stewart, MD, FACP

There is general agreement that we need some kind of system offering guided, structured, lifelong learning; that the system be highly relevant to what we do in our professional lives; and that it be built and controlled by oncologists rather than outside agencies. A consistent concern in the maintenance of certification debate relates to how meaningful and relevant the assessment and testing tools are to the practicing oncologist. With this in mind, I think we are fortunate in having available the tools being developed by ASCO to enhance maintenance of certification in medical oncology. I refer specifically to the components of ASCO University and the Quality Oncology Practice Initiative (QOPI®).

Online Resources Lisa Johnson, MHS, MT(ASCP) SC, Director of the Department of Integrated Media & Technology at ASCO, describes ASCO University as an oncology e-Learning site and online educational home. The MOC Overview (university.asco.org/ascouniv-MOC) is a great place to start when planning your maintenance of certification schedule. It is a resource that has grown and improved dramatically over the past 2 years and is now a preferred resource, not only for fellow training but also for those out of training at any age. Disease-oriented content continues to expand, and ease of website navigation is steadily improving in response to ASCO

specific program approved by the ABIM as a data source for practice performance. I have worked with QOPI with two fellowships and two attending groups, and I can confirm that its potential as an educational and practice improvement tool is outstanding. Our Baystate multispecialty clinical practice group of nearly 500 physicians is piloting innovative divisionoriented incentive plans. Our cancer program is QOPI-certified, and our Hematology-Oncology Division has successfully convinced senior leadership we should use elements of QOPI to incentivize our group financially in one of the pilot programs. QOPI will be a natural mechanism for assessing practice success and creation of improvements.

In Summary Maintenance of certification is in a transition-and-development phase in all medical areas, and as oncologists we are well positioned, with ASCO ahead of the game in having developed an exciting e-based resource (ASCO University) and a growing practice assessment and improvement structure (QOPI). ASCO is also well situated to develop navigator tools to assist us in creating maintenance of certification timetables, guide us to the right resources, and enhance our lifelong learning. We all need to learn better how to budget time for these activities. As our maintenance of certification “concierge,” ASCO can be a great help in this effort.

■

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

References 1. Cassell CK, Reuben DB: Specialization, subspecialization, and subsubspecialization in internal medicine. N Engl J Med 364:1169-1173, 2011. 2. Levinson W, King TE: Enroll in the MOC program as currently configured. N Engl J Med 362:949-950, 2010. 3. Goldman L, Coroll AH, Kessler B: Do not enroll in the current MOC program. N Engl J Med 362:50-52, 2010. 4. Steinbrook R: Renewing board certification. N Engl J Med 353:1994-1997, 2005. 5. Johnson DH: Maintenance of certification: Confession of a grandfather. J Oncol Pract 8:203-204, 2012. 6. American Board of Internal Medicine: Maintenance and recertification guide. Available at www.abim.org/moc/ default.aspx. Accessed April 18, 2012. 7. McNiff KK, Bonelli KR, Jacobson JO: Quality Oncology Practice Initiative Certification program: Overview, measure scoring methodology, and site assessment standards. J Oncol Pract 5:270-276, 2009.

Maintenance of Certification in Medical Oncology Don't miss the May 2012 issue of Journal of Oncology Practice for Dr. David Johnson's paper, "Maintenance of certification: Confession of a grandfather."

See Page 89

FOR PATIENTS WITH ADVANCED BCC

IS IT TIME FOR A CHANGE? The first and only FDA-approved Hedgehog pathway inhibitor

Turn the page to see more... Indication Erivedgeâ&#x201E;˘ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS See full prescribing information for complete boxed warning. Erivedge can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of Erivedge. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of Erivedge exposure through semen. Please see additional Important Safety Information, including BOXED WARNING, on following page and Brief Summary of Prescribing Information on back.

Simulated image based on locally advanced BCC patient at Week 24. Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Boxed Warning and Additional Important Safety Information • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider

immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1 Objective response rates (ORR) by IRF from ERIVANCE1* laBCC (n=63) ORR (95% CI) Complete response

43% (n=27) (30.5-56.0) 21% (n=13)

mBCC (n=33) 30% (n=10) (15.6-48.2) 0%

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

Median response duration (months) (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. For laBCC, complete response was defined as objective response with no residual BCC on sampling biopsy. IRF=Independent Review Facility. CI=confidence interval. laBCC=locally advanced BCC. mBCC=metastatic BCC. NE=not estimable.

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

References: 1. Erivedge™ (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754.

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

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

73858ge_a.indd 3

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

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

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

4/23/12 3:27 PM

ASCOPost.com | MAY 15, 2012

PAGE 27

Expert’s Corner Hematology

Progress in Treating Chronic Lymphocytic Leukemia Has Led to Across-the-board Improvements in Survival A Conversation with Kanti R. Rai, MD By Jo Cavallo

Kanti R. Rai, MD

our decades ago, Kanti R. Rai, MD, was determined to figure out why some of his patients with chronic lymphocytic leukemia (CLL) died within 2 years after their diagnosis, while others lived for 20 or even 30 years. At the time, Dr. Rai was a young scientist doing research in leukemia at Brookhaven National Laboratory in Upton, New York. He started examining the records of over 100 of his patients, separating them into three categories: those who died rapidly after diagnosis, those who were alive 10 to 15 years beyond their diagnosis, and those who fell in between. Soon, patterns began to emerge. Dr. Rai found that patients with the lowest red corpuscle and platelet counts had the poorest survival rates (high risk); those with normal platelet and red blood counts had the best chances of long survival (low risk); and those with little bone marrow involvement but who had swollen lymph nodes, spleen, or liver fell in the middle (intermediate risk). Today, the Rai System is one of the gold standards for staging CLL and determining which patients should be treated immediately and which ones should be put on a watch-and-wait approach. The staging system is now also used to help investigators choose which CLL patients are likely to have the best outcomes in clinical trials testing new agents. Dr. Rai is now Director of the Chronic Lymphocytic Leukemia Research and Treatment Program at North Shore–Long Island Jewish Health System and the Joel Finkelstein Cancer Foundation Professor of Medicine and Professor of Molecular

Medicine at Hofstra North Shore–LIJ School of Medicine. In June, he will be recognized for his work in cancer research and for his impact on the treatment of patients with cancer with the David A. Karnofsky Memorial Award and Lecture, which will be presented at ASCO’s Annual Meeting. Dr. Rai talked with The ASCO Post about the progress that has been made in more effective treatments for CLL, which have resulted in doubling median overall survival rates, and new therapies being tested in clinical trials.

Prognostic Factors What advances have been made since the development of your staging system in identifying additional prognostic factors that predict which patients with chronic lymphocytic leukemia will have progressive disease? In 1999, my colleague at The Fein-

Similarly, within the high-risk group, as well as in the intermediaterisk group, patients with IgVH mutations had a better prognosis than those with unmutated IgVH.

Watch-and-Wait Approach Is watch-and-wait still an appropriate strategy for asymptomatic patients, or is there an advantage to early treatment in CLL? The answer is complicated. To be categorical, yes, watch-and-wait is still appropriate for some patients with chronic lymphocytic leukemia. But the numbers of people who are likely to be kept on observation alone are decreasing, because the molecular prognostic factors that have been added to the clinical staging factors are enabling us to identify prospectively those patients in the good prognosis group or in the intermediate prognosis group (whom

Because of better treatments, high-risk patients who 25 or 30 years ago had a median life expectancy of 2 years, now have a median life expectancy of 5 years. And intermediate-risk patients, who had a median life expectancy of 7 or 8 years, now have a median life expectancy of 10 or 12 years. —Kanti R. Rai, MD

stein Institute for Medical Research, Nicholas Chiorazzi, MD, and his team, discovered molecular distinctions within the groups of CLL patients with good prognosis and bad prognosis. A good-prognosis/low-risk-group patient can have mutated IgVH genes on the lymphocyte or unmutated IgVH genes. Patients with the unmutated genes tended to have a worse prognosis, and the patients with the mutated genes tended to have an excellent prognosis. So, within each of the three categories of our staging system, we could improve these prognostic factors. For example, patients in the low-risk group with mutated IgVH genes could be assured that they were not likely to die from their disease, whereas low-risk patients with IgVH unmutated genes are the ones who in 5 or 10 years are likely to need chemotherapy.

we normally assign to watch-and-wait) if they happen to have unmutated IgVH genes or are ZAP-70–positive or CD38-positive. ZAP-70–negative patients also have as good a prognosis as patients who have mutated IgVH genes or are CD38-negative, or have chromosomal abnormalities like 13q deletion. So if patients in the low-risk group have any of these good prognostic markers, then we feel a greater sense of security keeping them on observation. Whereas if patients in the intermediate-risk group have negative prognostic markers, such as trisomy 12 or 11q deletion, then we do not feel comfortable keeping them on watchful waiting and want to get control of their disease right away. Therefore, we are shrinking the numbers of people kept on observation.

Novel Agents Although alkylating agents such as chlorambucil (Leukeran) or cyclophosphamide are still used in the front-line treatment of CLL, they are being combined with newer agents such as FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) and the immunomodulatory agent lenalidomide (Revlimid) and are achieving complete responses in a higher percentage of patients. What are some new therapies in clinical trials in the relapsed/refractory setting? There are two novel kinase inhibitors that are being investigated in clinical studies that look promising as effective therapies for relapsed or refractory CLL. One is PCI-32765, which is the first drug to target Bruton’s tyrosine kinase (Btk), and the other agent is CAL101 (GS-1101), which targets PI3Kdelta. Both work on the B-cell receptor in CLL, which is a critical receptor that controls the signaling, proliferation, and survival of leukemic cells. In clinical studies of CAL-101, patients with advanced disease, in whom standard treatment failed, showed major improvement in the size of their greatly enlarged lymph nodes and spleen. But at the same time the drug pushed out all the leukemic cells from the lymph nodes and poured them into the circulating blood, so the white corpuscle number—which, usually, in a CLL patient may be between 75,000/μL and 100,000/μL— shot up to between 400,000/μL and 500,000/μL, and that was frightening. With continued use of CAL-101, the lymph nodes continued to remain small and the white count started to go down. PCI-32765 had exactly the same kind of initial results when used as a single agent in refractory CLL patients. Both of these drugs are continuing in clinical trials. But now the emphasis is not on them as single agents but in combination with rituximab, ofatumumab (Arzerra), bendamustine (Treanda), or fludarabine. These agents are making the future for patients with advanced CLL much more optimistic, but we still have a few more years to go with ongoing clinical trials before we can claim victory. continued on page 28

The ASCO Post | MAY 15, 2012

PAGE 28

Expert’s Corner

Kanti R. Rai, MD continued from page 27

Gene Therapy

Last year, researchers at the University of Pennsylvania published results of a pilot study of three patients with advanced CLL treated with genetically engineered versions of their own T cells, which resulted in sustained remissions of up to 1 year. How promising is gene therapy in CLL? That trial had an extremely dramatic result. This type of gene therapy reprograms a patient’s own T cells to recognize B cells so that when the T cells were put back into the patient’s veins, they went on a search-and-destroy mission to systematically find and kill B lymphocytes (leukemic cells in CLL are B lymphocytes). These reprogrammed T cells continued to multiply in the patient’s body, so they remained a powerful tool against the leukemic cells. That was an absolutely amazing study result, but when you manipulate cells in the lab and then put them back into the patient along with a virus as a vector, there is the potential for all kinds of catastrophic events to occur, including death. Everybody who is interested in curing CLL is getting in on this treatmentbandwagon, but unfortunately, this strategy is not simple. It’s not a pill that you give to a patient; it requires a lot of checks and balances, and it’s a complex treatment. But the researchers at the University of Pennsylvania are proceeding in a very systematic manner, and I believe they plan to treat 12 patients this year—not just patients with CLL but patients with other B-cell malignancies as well.

Impact on Survival Are the new therapies that you mentioned earlier extending overall survival in CLL patients? Yes, there is no question about this. All these newer drugs, including rituximab and fludarabine in combination with cyclophosphamide, as well as bendamustine, alemtuzumab (Campath), and lenalidomide (which is not yet approved for CLL), have resulted in a marked degree of improvement in the overall life expectancy of people with chronic lymphocytic leukemia. Because of these better treatments beyond chlorambucil, high-risk patients who 25 or 30 years ago had a median life expectancy of 2 years, now have a median life expectancy of 5 years. And the intermediate-risk patients, who had a median life expectancy of 7 or 8 years, now have a median life expec-

tancy of 10 or 12 years. So across the board there has been an improvement in life expectancy, and you have to give credit to improved treatment.

Stem Cell Transplantation With these novel therapies in use, what is the role of stem cell transplant?

There is still a role for stem cell transplant in CLL, but we use it selectively. Unfortunately, some people still do not respond well to the available chemotherapeutic agents. If we are fortunate and these patients have an HLAcompatible donor, then it is prudent to give them an allogeneic transplant with

reduced-intensity conditioning chemotherapy. A number of people who were given a “mini-allo” transplant are alive and well today but would have died if not for their transplant.

■

Disclosure: Dr. Rai serves on the medical advisory boards of Celgene, Cephalon, and Genentech.

ASCOPost.com | MAY 15, 2012

PAGE 29

News

Study Shows Steady Increases in Survival for Children with ALL

study by the Children’s Oncology Group (COG) reported that 5-year survival for acute lymphoblastic leukemia (ALL) among children treated through COG clinical trials increased from 83.7% during the pe-

riod 1990-1994 to 90.4% in the period 2000-2005. The improvements in survival were observed among all children over age 1 regardless of age, sex, ethnicity, or subtype of ALL. This analysis, which is the largest study to

date of ALL survival, showed similar gains in 10-year survival. The findings were published recently in the Journal of Clinical Oncology.1 “New drugs and new drug combinations have increased survival rates and

helped children live longer and better, and we continue to refine these therapies. Nevertheless, we still have important work to do to help the remaining 10% of patients who don’t survive,” said lead author Stephen Hunger, MD, Professor of Pediatrics at the University of Colorado School of Medicine and Director of the Center for Cancer and Blood Disorders at Children’s Hospital Colorado.

Study Details Dr. Hunger and his colleagues analyzed long-term surSee Page 89 vival among 21,626 individuals who were treated for ALL as children or adolescents (infancy to age 22) in COG clinical trials between 1990 and 2005, dividing this time period into three “eras” that included similar-sized patient groups to examine changes in 5- and 10-year survival over time. In addition to the gains in 5-year survival, they found that 10-year survival increased from 80.1% between 1990-1994 to 83.9% in 1995-1999. Survival improved significantly in all of the following subgroups: children ages 1-9 years; 10 years and older; 15 years and older; males and females; whites, blacks, and other races; Hispanics, nonHispanics, and persons of unknown ethnicity; those with B-precursor ALL and T-cell ALL; and those with standard-risk or high-risk disease Among infants (age 1 and younger), however, 5-year survival changed little between 1990-1994 (52.1%) and 20002005 (50.3%), while the causes of death changed considerably. Death rates from ALL relapse or progression decreased from 43% in 1990-1994 to 27.2 % in 2000-2005, while the incidence of treatment-related deaths increased from 3.9% to 13.9% during this period. Dr. Hunger emphasized that these data represent the advances that can be achieved against cancer through rigorous clinical trials. “Today, more than half of all children with cancer are treated through clinical trials, compared to less than 5% of adults with cancer,” he said. “Without a doubt, more and more children and older adolescents with leukemia are cured today because of the patients and parents who were willing to participate in clinical research.”

■

Reference 1. Hunger SP, Lu X, Devidas M, et al: J Clin Oncol. March 12, 2012 (early release online).

The ASCO Post | MAY 15, 2012

PAGE 30

Cancer Care in India: Complex Challenges in a Populous Nation A Conversation with Rakesh Chopra, MD By Ronald Piana

Rakesh Chopra, MD

ith 1.22 billion people, India is the second most populous country in the world. Experts project that cancer incidence in India will increase by more than two-thirds over the next 20 years, to approximately 1.7 million new cases per year. Due to a range of economic and social issues, most of India’s patients with cancer first present with advanced disease, adding another layer of complexity for the country’s oncology community. For this installment of the ongoing Oncology Worldwide series, The ASCO Post recently spoke with Rakesh Chopra, MD, a clinical oncologist at the Apollo Cancer Centre, New Delhi, India.

Medical Training What were the influences in your life that steered you toward a career in medicine? We have several physicians spanning four generations in my family. So, deciding to become a doctor actually came quite naturally. Please briefly describe your medical school experience in India. In addition to following a standard medical curriculum, as the first class at Delhi University College of Medical Sciences, we had the additional challenge of establishing the school as a highly competitive medical training institution. From the very beginning, our

class scored equal to or surpassed two other medical schools at Delhi University. In addition to the classroom experience, we were required to intern in the largest public hospital in India (almost 9,000 beds), which offered a huge range of clinical material and fostered the skills essential to making critical clinical decisions immediately. Following that experience, I did two 6-month stints, each focused on one specialty—internal medicine and dermatology. As a postgraduate, I did a fellowship in internal medicine at Armed Forces Medical College. In this very regimented environment, the academics were enhanced by a strong sense of discipline, which served me well later in my career.

of specialists severely constrains the delivery of treatment to rural areas. We also need more affordable medicines, supportive care, and supplements to be accessible in the vast rural communities. So far, all oncology protocols have been developed in the West. We need to develop protocols based on India’s own population characteristics, centered on the constitution of the country’s diverse peoples. However, because of difficult economic times, cancer research funds are severely limited, which also hampers the collaborative work that needs to be expanded, both within this country and with other parts of the world. Clinical

We need to develop protocols based on India’s own population characteristics, centered on the constitution of the country’s diverse peoples. —Rakesh Chopra, MD

Why did you choose oncology as a specialty? Early in my internal medicine practice, it was clear that Northern India had no real medical oncology specialists. I saw this field as an opportunity to pioneer and help fill a much-needed void in care for patients with cancer in a country that suffers from a severe shortage of oncology professionals.

Challenges for Oncology in India What are the greatest challenges facing the Indian oncology system? First, there are only two rural registries in all of India. Such data limitations prevent us from knowing accurately the true burden of cancer in the nation and the range of cancer types. Moreover, in the context of India’s massive population and geographic size, the limited number

trials present a huge opportunity here, as we have a large treatment-naive and younger population that would serve research well. There is also a need for smaller, multidisciplinary, well-equipped facilities to deliver comprehensive cancer care in the smaller townships and rural areas where much of the population remains underserved. Oncology needs to be taught by oncology specialists earlier in the medical education process. This applies to physicians, nurses, and other paramedical professionals. Further, education of the community at large about cancer risks should be expanded, along with cancer screening and other preventive strategies that need greater emphasis.

Current Practice Please describe your current clinical

practice, perhaps highlighting an interesting case report? I work out of the fourth largest corporate hospital in the world, which is also the largest corporate hospital outside the United States. My hospital practice, a tertiary cancer care facility, is combined with academic medicine, research, and a full-fledged, “superspecialty” training program. One of my more interesting and challenging cases was a 20-year-old patient with Gardner’s syndrome who was given 15 days to live in an Australian facility. He returned to India for terminal care and to be with his family. I was familiar with the specific treatment of this disease, and after giving him heavy supportive care, he has been well for more than 10 years.

Politics and Cancer Care Does the political climate in India affect access to quality care? Yes. The government has permitted use of biosimilar and other generic drugs to be available at a fraction of the cost. At the same time, the Indian government needs to create or otherwise incentivize the development of more multidisciplinary cancer facilities that provide radiation, surgical, and medical oncology care. This is a major political challenge.

Future of Oncology in India Any thoughts about the future of oncology practice in India? A great deal of progress has been made in Indian cancer care over the past 30 years. However, the future of cancer care in India and elsewhere lies in preventing the preventable cancers and developing more personalized medicine. We’re going from broadbased to increasingly targeted approaches, and, more and more, we are focused on organ preservation.

■

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

In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?

Jakafi™ (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b ≥35% reduction in spleen volume1,2,a

≥50% improvement in Total Symptom Score1,2,a,b

41.9

P < 0.0001

30 20 10 0

45.9 P < 0.0001

Patients (%)

30 20 10

0.7 Jakafi (n = 155)

Placebo (n = 154)

5.3 Jakafi (n = 148) Placebo (n = 152) Baseline mean TSS = 18.0 Baseline mean TSS = 16.5

Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive and JAK2 V617F-negative patients, relative to placebo2 Most patients not treated with Jakafi experienced increased splenomegaly and worsening of symptoms1

Visit www.jakafi.com/JAKtarget for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

TSS = Total Symptom Score. a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF, including abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. November 2011. 2. Data on file. Incyte Corporation.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference

C007 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

ASCOPost.com | MAY 15, 2012

PAGE 35

Perspective

Untreated Cancer Pain Remains a Significant Global Problem

International experts address causes and solutions to the lack of access to pain medication in the world’s poorest areas. By Ronald Piana “Physicians are afraid of morphine … Doctors [in Kenya] are so used to patients dying in pain … they think that this is how you must die. They are suspicious if you don’t die this way — [and feel] that you died prematurely.” —Human Rights Watch interview with Dr. John Weru of Nairobi Hospice, Kenya, June 2007

espite initiatives by the world’s major health and policy organizations, 80% of persons worldwide suffering from severe pain still lack adequate access to morphine or other opioid analgesics—morphine is virtually nonexistent in over 150 countries. The global scope of unnecessary suffering is difficult to quantify, and— considering that morphine, which can alleviate more than 90% of cancer pain, costs pennies to produce—some pain experts consider depriving people in severe pain access to opioids tantamount to cruel, inhuman, and degrading treatment by omission.

Epidemic in Developing Nations In desperately poor areas of the globe, providing opioids for late-stage cancer pain is often a low clinical and political priority, competing with limited medical resources allocated for younger, healthier patients with a better chance of survival. Moreover, in the developing world, absence of government commitment, fractured infrastructure, and complex cultural and regulatory factors add extra barriers to pain-relief efforts on the ground. “In areas such as sub-Saharan Africa, we’re dealing with ministries of health that are understaffed and underresourced, which leaves them little time to address an issue like access to morphine. At the same time, the ministry of health is the only governmental body with the authority and the skills to create and sustain change on a national level. In my experience, there’s no productive way to work around the government, so we need to be able to

Private/Public Health-care Divide Creates Disparity in Cancer Pain Treatment in South Africa By Daniel A. Vorobiof, MD Director, Sandton Oncology Centre, Johannesburg, South Africa pproximately 15% of South Africa’s people have private health-care insurance and use private hospitals and clinics; another 10% also use private care paid out of pocket. However, the remaining 75% of South Africans use public health care, which is spread out over rural and urban areas. Although the tertiary public institutions have modern equipment, regretfully, due to budget constraints, the availability of cancer pain treatment Daniel A. Vorobiof, MD is limited to a recommended dispensing drug list. Nonnarcotic and narcotic analgesics are available, but not long-acting transdermal patches. The most common analgesics are oral and injectable drugs. Some oral and intravenous bisphosphonates are available, as well as radiotherapy, for pain management. Roughly 40% of South Africans live in rural areas, making it difficult to travel for specialized cancer care. Instead, many rural patients turn to traditional practitioners called sangomas, who have several social and spiritual roles, including healer, diviner, and counselor. Distrust of Western medicine has rooted sangomas’ medicinal status in the community, providing ineffective pain control with herbs and other traditional medicines. Other than political and cultural barriers of note, the main constraint on adequate pain control remains financial, especially in poor public and rural areas.

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

■

level of coordination, we need to work closely with the ministries of health. It’s a time-consuming but necessary measure to bring relief to patients in pain.”

New Tools Needed

Meg O’Brien, PhD

maximize those connections,” said Meg O’Brien, PhD, Director of the Global Access to Pain Relief Initiative (GAPRI), a joint program of the Union for International Cancer Control (UICC) and the American Cancer Society. “At GAPRI, one of our chief strategic interventions, and the focus of our programmatic work, is actually placing technical staff inside ministries of health, such as a Special Assistant to the Director,” said Dr. O’Brien. This type of intervention, explained Dr. O’Brien, was borne of the assumption that ministries of health in developing nations are not opposed to broad access to pain relief; they are simply overwhelmed with red tape and administrative issues. “The health ministry simply doesn’t have anyone with capacity for navigating these quite complex bureaucratic issues. We give them someone who wakes up every day and focuses on a work plan that we’ve developed jointly with the ministry of health, following up on all the details, contracts, procurements, and such,” said Dr. O’Brien. Dr. O’Brien stressed that many of the barriers to pain products stem from a bureaucratic void. “Our mission suffers because there is never anyone in the ministries of health whose job title includes pain relief. Since there’s no department, no one gets penalized at the end of the year for underperformance,” commented Dr. O’Brien. “At UICC, we’ve found that a onecomponent intervention strategy doesn’t work. For instance, if we get the supply issue right, but we don’t work on demand; if we train clinicians, but we don’t work on procurement; if we raise awareness, but don’t provide training; it’s getting one right to the exclusion of the other, and things don’t move forward,” said Dr. O’Brien. She added, “For that

According to Willem Scholten, PharmD, MPA, Team Leader, Access to Controlled Medicines, World Health Organization (WHO), “Governments often create their own shortages by overregulating controlled substances on a national basis. The supply chains in these countries are delicate; any disruption can have severe consequences for pharmacies and patients.” In 2007, under Dr. Scholten’s lead,

Willem Scholten, PharmD, MPA

the WHO developed The Access to Controlled Medicines Program to improve availability of pain medicines controlled under the drug conventions. One initiative was to improve the clinical tools needed to advance pain control efforts. “The WHO cancer pain guidelines, more than 15 years old, were not evidence-based. To convince policymakers around the world about pain, we needed new treatment guidelines, also covering all types of pain. We have finished the first set, the pharmacological treatment of persistent pain in children. The adult guidelines will follow,” said Dr. Scholten. Another part of the program focused on policy guidelines: Ensuring Balance in National Policies on Controlled Substances. “The guidelines have a country checklist for methods to improve pain relief, using an even approach between prevention of drug misuse and the availability of opioid analgesics. The guidelines are an important tool for nations struggling with this challenge,” commented Dr. Scholten. continued on page 37

NOW ENROLLING

AGGRESSIVE NON-HODGKIN LYMPHOMA

INO-VATE NHL INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy A randomized, phase 3 trial in patients with CD22-positive aggressive non-Hodgkin lymphoma (NHL) who are not candidates for intensive high-dose chemotherapy This is a 2-armed, randomized, open-label, phase 3 study designed to evaluate the efficacy and safety of inotuzumab ozogamicin in combination with rituximab compared with the investigators’ choice of R-bendamustine or R-gemcitabine.

Selected inclusion criteria • Relapsed/refractory/persistent CD20+/CD22+ aggressive NHL (DLBCL, transformed indolent lymphoma with DLBCL, primary mediastinal large B-cell lymphomas) • Up to 3 prior regimens containing cytotoxic chemotherapies • Not candidates for intensive high-dose chemotherapy, with or without an autologous stem cell transplant

Selected exclusion criteria • Any prior allogeneic hematopoietic stem cell transplant; autotransplant within prior 4 months • Anti-CD22 treatment or radioimmunotherapy within prior 6 months • Contraindication to both investigator choice regimens • Chronic liver disease, history of veno-occlusive disease

Reference: ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01232556. Accessed April 25, 2012.

Inotuzumab ozogamicin is an investigational compound. This information is current as of April 25, 2012.

STW00067A

April 2012

Learn more about INO-VATE (B1931008) For more information about this trial, please visit www.clinicaltrials.gov (NCT01232556) or call: 1-877-369-9753 in the United States and Canada (toll-free) or +1-646-277-4066 outside the United States

ASCOPost.com | MAY 15, 2012

PAGE 37

Perspective

Untreated Cancer Pain continued from page 35

In addition to the guidelines, Dr. Scholten explained that WHO works with a variety of nongovernmental organizations and consortiums, conducting workshops in nations across the world, analyzing specific access barriers, whether cultural, economic, or political, and problem-solving ways to resolve inadequate pain control problems. “At the World Health Assembly in 2005, a resolution was adopted to improve access to pain control medicine worldwide. Prior to that, the issue received little attention. It remains a huge challenge, but I am confident that as awareness continues to grow, we will see vast improvements in how we treat patients in pain,” said Dr. Scholten.

Rethinking the UN Single Convention on Narcotic Drugs Opium is not only central to the relief of pain; it is also an internationally regulated substance. In the 18th and 19th centuries, the British expanded opium trade in Asia; by the end of the 1800s, growing consumption of the narcotic caused global concern, resulting in the 1909 International Opium Commission, setting the stage for the first international convention to regulate narcotics—the Hague Opium Convention of 1912. Flashforward to 1961, when the United Nations Single Convention on Narcotic Drugs led to highly restrictive international drug-control laws. According to Allyn Taylor, JSD, of the O’Neill Institute for National and Global Health Law at Georgetown

Allyn Taylor, JSD

Visit

University Law Center and former legal adviser to WHO, ensuring medical availability of opioids constitutes a key but historically neglected aim of the international drug regime and a core legal obligation of the 183 countries that have ratified the UN Single Convention. “The twin aims of the Single Convention, as specified in its preamble and text, are to control the use and trafficking of substances with abuse potential while assuring availability of these drugs for scientific and medical purposes,” stressed Professor Taylor. Implementing the aims of the Single Convention is a principal legal responsibility of the International Narcotics Control Board (INCB) under the Convention. But according to Professor Taylor, driven largely by concern over illicit use of pain narcotics, the INCB has been historically lopsided in its mission, focusing primarily on problems of diversion and abuse, not ensuring access to pain medication. “This strict criminal justice approach to the Single Convention has hindered the capacity of many countries, particularly lowincome nations, to ensure medical availability for their populations,” said Professor Taylor.

Onerous Burdens of Scheduling Professor Taylor explained that issues involved in the scheduling of drugs are just one example of aspects of the Single Convention that impede the legitimate availability of pain medication. Schedule One, which morphine falls under, is subject to numerous legal restrictions on the international and local level, including onerous export-import records and authorizations. In short, bureaucratic and regulatory burdens of the scheduling process create unintended barriers to pain relief. “It’s important to note that many developing countries lack the resources needed to comply with the scheduling requirements and the attendant regulatory burden of the Single Convention. If a medicine is scheduled or

Cancer and Morphine: A Snapshot of Disparity ■■ Approximately 89% of the total world consumption of morphine occurs in countries in North America and Europe.

■■ Low- and middle-income countries consume only 6% of the morphine used worldwide—while having 50% of all cancer patients.

■■ Over 80% of sub-Saharan Africans with cancer present with advanced disease.

■■ In Africa, 32 (of 53) countries have almost no morphine distribution at all, and only 14 have oral morphine.

Data from International Narcotics Control Board, World Health Organization, and Human Rights Watch.

rescheduled, poor states may simply ban a medicine with important public health purposes,” she stated. Professor Taylor emphasized that although the Single Convention and the INCB play an important role in limiting illicit diversion of analgesics, there has long been a need for better balance between criminal justice and humanitarian needs. The risk of diversion of pain medication into illegal channels has not traditionally been one of the most critical challenges in international drug control. However, over the past few years, nations as well as international organizations responsible for implementing the Single Convention, including the INCB and the UN Office on Drugs and Crime (UNODC), have begun to to address the imbalance at the international level. “Both the INCB and the UNODC are evolving in their application of the Single Convention and are working more effectively with state parties, WHO, and other stakeholders to improve access to pain medication,” concluded Professor Taylor.

An Essential Human Right According to Diederik Lohman, Senior Researcher, Health and Human Rights, Human Rights Watch, under international human rights law, governments must address a major public health crisis that affects millions of people every year; they must take steps to ensure that people have adequate access to pain treatment.

Mr. Lohman stressed that in many low-income countries, the bulk of policy and monetary allocations are spent on curative treatments, even though

Diederik Lohman

the vast majority of patients in these regions present with late-stage or incurable disease. “For example, in India, approximately 70% of cancer patients are first diagnosed with advanced disease; however, the resources spent on palliative care are negligible, which means that about 70% of Indian cancer patients are basically forgotten,” said Mr. Lohman. In pursuing steps to improve pain treatment, countries should draw on the expertise and assistance of the WHO Access to Controlled Medicines Programme and the International Narcotics Control Board. “To break out of this vicious cycle, individual governments and the international community must fulfill their obligations under international human rights law,” concluded Mr. Lohman.

■

Disclosure: Professor Taylor, Mr. Lohman, and Drs. O’Brien and Scholten reported no potential conflicts of interest.

website at ASCOPost.com

The ASCO Post | MAY 15, 2012

PAGE 38

European Lung Cancer Conference New Genetic Signature May Help Identify Risk of Relapse in Patients with Completely Resected Early Non–Small Cell Lung Cancer

new genetic signature identified by Spanish researchers may provide robust and objective information about which patients with completely

resected early stage non-small cell lung cancer are at low or high risk of relapse following surgery, according to Florentino Hernando, MD, who

presented the findings at the 3rd European Lung Cancer Conference held recently in Geneva, Switzerland. Dr. Hernando and a multidisci-

Oncotype DX reveals the underlying biology that changes treatment decisions 37% of the time ®

plinary team of investigators from Hospital Clinico San Carlos, Madrid, found a 50-gene predictor that appears to be capable of identifying which patients have the greatest risk of relapse. In a study of 84 patients with stage I and II non-small cell lung cancer, who had undergone surgery to remove their tumor, the gene signature accurately predicted which patients were at low risk of relapse.1 continued on page 39

EXPERT POINT OF VIEW

37%

changed

63% confirmed

Even when treatment decisions based on traditional measures seem conclusive, Oncotype DX can lead to a different approach • In a meta-analysis, treatment decisions were changed even when definitive treatment decisions had already been made*†1

▸ 33% switched from CT + HT to HT alone ▸ 4% switched from HT only to CT + HT

‡

• Only assay incorporated into major clinical practice guidelines to predict chemotherapy benefit For newly diagnosed patients with node-negative or node-positive, ER-positive, HER2-negative invasive breast cancer

www.oncotypeDX.com *This analysis included 912 patients with node-negative, ER-positive, early-stage invasive breast cancer. †Patients with unclear treatment decisions were excluded from this meta-analysis. Additionally, patients who did not want CT, those with poor performance status, and those who could not tolerate CT were excluded. ‡CT=chemotherapy; HT=hormone therapy. Reference: 1. Hornberger J, et al. Poster P2-09-06. Presented at: San Antonio Breast Cancer Symposium; 2010. Genomic Health, Oncotype DX, Recurrence Score, and Uncover the Unexpected are trademarks of Genomic Health, Inc. © 2012 Genomic Health, Inc. All rights reserved. GHI10100_0112

Now available for patients with ductal carcinoma in situ (DCIS)

David Carbone, MD, PhD

ommenting on the study, David Carbone, MD, PhD, of the Vanderbilt-Ingram Cancer Center, said that the Spanish group studied tumors from patients with completely resected stage I and II NSCLC for gene RNA expression profiles using 41,000 different probes. “Since over one-half of these patients relapse and die from their cancer in spite of complete resection, there is a pressing need for both defining those patients at the greatest risk of relapse for trials of adjuvant therapy, but also potentially avoiding the toxicity of adjuvant therapy in patients with a low risk of relapse,” Dr. Carbone said. “This is a potentially extremely important classifier, which if independently validated, could be the basis of such a test,” he said. Dr. Carbone noted that “It is interesting that the majority of the genes in the classifier are either immune-derived or immunomodulatory, suggesting a potential molecular basis for this observation.”

■

Disclosure: Dr. Carbone reported no potential conflict of interest.

ASCOPost.com | MAY 15, 2012

PAGE 39

European Lung Cancer Conference Study Reports on New Potential Biomarker of Response in Lung Cancer Chemoprevention Studies

iRNAs, negative post-transcriptional regulators of gene expression, are involved in bronchial carcinogenesis from the very early steps of this process. Endobronchial histology is currently considered as the best intermediate endpoint for chemoprevention studies. However, no intermediate biomarker has been validated for the prevention of lung cancer.

Lung Inflammation

While histologic grading is reproducible between specialized pathologists, more quantitative biomarkers of response are desirable. Therefore, a group of researchers analyzed the expression of selected miRNA as potential surrogate biomarkers in the iloprost (Ventavis, a synthetic analog of prostacyclin) phase II, placebo-controlled multicenter lung cancer chemoprevention trial. The phase II trial is the first to meet a predetermined primary endpoint of histology improvement.1 Results were presented recently by Celine Mascaux, MD, PhD, Assistant Research Professor and Medical Oncologist at the University of Colorado Cancer Center, at the 3rd European Lung Cancer Conference in Geneva, Switzerland.

Dr. Mascaux and colleagues hypothesized that miRNAs could be both potential surrogate endpoints and predictive biomarkers for chemoprevention trials. They tested this hypothesis in the iloprost chemoprevention trial, and in particular association of miRNA expression with histology, tobacco status, treatment effect, and prediction of response to treatment. Matched biopsies at baseline and the same site at follow-up after 6 months of iloprost or placebo were obtained in 125 high-risk individuals who completed the iloprost trial: 40 current smokers and 35 former smokers were in the iloprost arm, and 25 current smokers and 25 former smokers were in the placebo arm. The researchers planned to ana-

sociated with histologic response in lyze 500 biopsies but identified 496 the iloprost (P =.0022) and placebo biopsies with appropriate tissue. The arms (P = .0025). plan was to obtain four matched biMiR-34c is a transcriptional taropsy pairs per patient: the best and get of p53, which is upregulated in the worst histology at baseline, and lung formation, but downregulated the two biopsies from the same site during the whole process of carcinoat follow-up. For every biopsy, total genesis. In this analysis, the authors RNA was extracted from eight cuts showed that the change in miR-34c of formalin-fixed, paraffin-embedexpression between baseline and ded sections adjacent to the diagnosfollow-up bioptic section. Crisies was inversely teria for miRNA The change in miRcorrelated with to be tested were histology changes, selection from 34c expression between and this was inthe list of 69 miRbaseline and follow-up dependent of the NAs identified in treatment arm or bronchial human biopsies was inversely smoking status. biopsies as becorrelated with histology Thus, miR-34c exing differentially pression is a good expressed during changes. reflection of baselung squamous line histology and c a rc i n o ge n e s i s . histology changes. In responders, the Fourteen selected miRNAs previmiR-34c expression is significantly ously identified in high-grade bronlower at baseline and increased at chial preneoplasia were analyzed by follow-up, related with a worse hisquantitative reverse-transcriptase tology at baseline and its downgradpolymerase chain reaction assay. ing at follow-up. Therefore, the reMiR-34c Expression and searchers concluded that the change Histologic Response in miR-34c expression in follow-up In the earlier and current studies, biopsies is correlated with histologic miR-34c expression was inversely response and may be a quantitative correlated with baseline histology biomarker of response in lung chegrade (P < .001). The current study moprevention studies. Disclosure: Dr. Mascaux reported no demonstrated that the change in potential conflicts of interest. miR-34c expression between baseline and follow-up biopsies was also Reference inversely correlated with histology 1. Mascaux C, Keith RL, Feser WJ, et changes (P = .0003), and this was al: MIR-34C is a potential biomarker for independent of the treatment arm histological response in lung cancer cheor smoking status. In addition, a moprevention studies. European Lung lower miR-34c expression at baseCancer Conference. Abstract 65O. Preline, and consequently its increase sented April 19, 2012. at follow-up, was significantly as-

New Genetic Signature

Following patients for 6 years, the researchers were able to correlate gene expression patterns with the clinical course of the disease, as well as the risk of relapse. They reported that the genes of the predictor were overexpressed in roughly one-third of the patients, all of whom had a low risk of relapse. Further analysis showed that these genes were related to the activity of B lymphocytes. According to Dr. Florentino Hernando, the B cell-mediated immune response seems to have a very important role. The genetic profile identified by

the researchers suggests that low-risk patients have an enhanced immune response against the tumor. Thus, treatments that may interfere with this response, such as postsurgical chemotherapy, must be reconsidered for the low-risk subgroup, according to investigators. One-third of the patients showed an overexpression of an ‘immune’ genetic signature in their tumor specimens that was associated with better prognosis. The researchers concluded that expression of these 50 genes could make up a new genetic signature for

Celine Mascaux, MD, PhD

continued from page 38

Low Risk of Relapse and Enhanced Immune Response The researchers extracted RNA from frozen samples with more than 70% tumor cells. Tumors were analyzed using microarray expression. The data were normalized and subjected to unsupervised analysis to classify samples based on expression profiles. Association of identified molecular subgroups with clinical, pathologic, and molecular variables and diseasefree survival was analyzed.

The miRNA’s role in lung inflammation can be described as follows: ■■ Gene-expression profiles during successive steps of lung carcinogenesis have an important role in immune and inflammatory pathways when comparing low-grade and high-grade lesions. ■■ MiRNAs were shown to be upregulated in vivo following lung lipopolysaccharide-induced inflammation. ■■ MiRNAs are modulated in vivo following lung inflammation’s induction, and many reports showed miRNA expression involvement in immunity, and in the progression of chronic inflammatory lung disease.

Biopsies at Baseline and after Chemoprevention

■

non-small cell lung cancer and define subgroups of patients with different prognosis among those with completely resected early-stage NSCLC.

■

Disclosure: Dr. Hernando reported no potential conflict of interest.

Reference 1. Hernando F, Sanz J, Jarabo JR, et al: A new genetic signature defining two prognostic groups among patiens with completely resected early non-small cell lung cancer. European Lung Cancer Conference, April 2012, Geneva, Switzerland. Abstract 2500.

At diagnosis of metastatic colorectal cancer (mCRC)

Are you getting the full picture? Name: Age: Cancer: Specialty: Biomarker Status:

George 58 mCRC Storyteller

Not an actual patient.

At diagnosis of mCRC, testing a patient’s tumors for biomarkers can help determine predictive and/or prognostic information1 Colorectal cancer is the 3rd leading cause of cancer death in men and women in the U.S.2 Understanding the patient’s biomarker profile helps define the characteristics of the patient’s disease and their overall prognosis.1 Knowing a patient’s biomarker status at diagnosis may help guide clinical decisions.3,4 Understanding the biomarker pathways involved in mCRC tumorigenesis can help inform appropriate treatment planning.3,5,6

KRAS and BRAF signaling are involved with colorectal tumorigenesis and tumor progression3 The KRAS gene may be mutated or wild-type. When KRAS is mutated, it is permanently switched on, whereas wild-type KRAS protein is activated when the EGFR is stimulated.3,5 Increased BRAF signaling may occur due to mutations in the BRAF gene.5 BRAF mutations are limited to those tumors that do not have KRAS exon 2 mutations.7 Provides information on a patient’s likelihood of response or non-response to biomarker-directed treatment1

May help define the patient’s overall prognosis irrespective of therapy1

Provides information on a patient’s likelihood of response or non-response to Approximately 2 out of every 3 patients are 1 biomarker-directed treatment 5,7 KRAS wild-type vs mutant

May help define the patient’s overall prognosis irrespective of therapy1 Approximately 5%-9% of colorectal cancers are characterized by a specific mutation in the BRAF gene7

Approximately 2 out of every 3 patients are KRAS wild-type vs mutant5,7

Testing of biomarkers at diagnosis 3,7 * of CRC treatment planning Strongly recommends KRAS genotyping tumor tissue (either primary tumor or metastases) in all patients with mCRC at the time of stage IV disease diagnosis. Early establishment of KRAS status is appropriate in order to plan the treatment continuum.7 Strongly recommends KRASforgenotyping of CRC tumor tissue (either primary tumor or metastases) in all patients with mCRC at the time of stage IV disease diagnosis. Early establishment of KRAS status is appropriate in order to plan for the treatment continuum.7

T E S T

Approximately 5%-9% of colorectal cancers are by afor specific of mCRC ischaracterized important mutation in the BRAF gene7 BRAF genotyping can be considered for patients with tumors characterized by the wild-type KRAS gene. Such testing is currently optional and not a necessary part of decision making.7 BRAF genotyping can be considered for patients with tumors characterized by the wild-type KRAS gene. Such testing is currently optional and not a necessary part of decision making.7

T O

P L A N

EGFR = epidermal growth factor receptor. *In a CLIA-certified laboratory. References: 1. Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. 2. American Cancer Society. Cancer Facts & Figures: 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveillance/ documents/document/acspc-029771.pdf. Accessed March 1, 2012. 3. Monzon FA, Ogino S, Hammond EH, et al. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med. 2009;133(10):1600-1606. 4. Grossman AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy. Arch Pathol Lab Med. 2011;135:1278-1282. 5. Krasinskas AM. EGFR signaling in colorectal carcinoma. Pathol Res Int. 2011;2011:1-6. http://www.hindawi.com/journals/pri/2011/932932/cta. Accessed January 6, 2012. 6. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Accessed March 15, 2012.

The ASCO Post | MAY 15, 2012

PAGE 42

European Lung Cancer Conference Biomarker Analysis of the TORCH Study: First-line Erlotinib Only in Patients with EGFR-positive Non–Small Cell Lung Cancer

atients with advanced non–small cell lung cancer (NSCLC) should receive treatment with erlotinib (Tarceva) before receiving standard chemotherapy only if their tumor is known to harbor EGFR mutations, researchers reported at the 3rd European Lung Cancer Conference in Geneva, Switzerland.1 The recently reported results of biomarker analyses of the TORCH clinical trial confirm that patients with unknown or negative mutation status should be treated with the standard chemotherapy first.

Results of the TORCH Study The TORCH trial was a randomized phase III trial conducted in Italy and Canada, which compared the efficacy of treatment with the EGFR inhibitor erlotinib, followed at progression of disease by cisplatin and gemcitabine, against the standard reverse sequence.2 The primary endpoint of the original TORCH study was overall survival, and 900 patients were planned. The study was stopped early, however, when the first interim analysis showed that the erlotinib-first regimen was inferior to the standard approach. In the new study, Ming Tsao, MD, of the Princess Margaret Hospital, and colleagues conducted an exploratory analysis on the TORCH patient tumor

samples that were available for analysis, looking for molecular biomarkers known to be potential predictors of benefit from EGFR inhibitors. The results of this secondary analysis showed a significant interaction in progression-free survival favoring treatment with erlotinib first in patients with EGFR-mutated tumors and favoring treatment with chemotherapy first in patients whose tumors did not express the EGFR mutation. However they did not observe a significant interaction between treatment efficacy and overall survival. According to Dr Tsao this shows that using erlotinib to treat patients with a mutated tumor is effective, in both the first- and second-line settings; it is more convenient for these patients to receive it as first-line therapy. Patients with EGFR-mutated tumors benefit from the erlotinib-first regimen because their tumors are very sensitive to the antitumor activity of the drug. According to Dr. Tsao, treatment with erlotinib first should only be applied to patients whose tumor is known to harbor the EGFR mutation.

■

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

References 1. Tsao MS, Gallo C, Saieg M, et al:

EXPERT POINT OF VIEW

etsuya Mitsudomi, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan, discussed the study presented by Tsao and colleagues1 and said that many previous trials have already shown that EGFR mutation is the most reliable predictive marker for treatment with EGFR tyrosine kinase inhibitors. The current analysis confirmed the importance of EGFR mutation testing when considering the use of erlotinib (Tarceva), especially in consideration of the shorter progresTetsuya Mitsudomi, MD, PhD sion-free survival obtained with erlotinib when the mutation was absent. Consequently, although it was thought that erlotinib is active even in lung cancer patients without EGFR mutation if compared with gefitinib (Iressa), this study suggests that erlotinib should be avoided when treating patients without EGFR mutation, at least in the first-line setting.

■

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

Reference 1. Tsao MS, Gallo C, Saieg M, et al: Biomarkers of TORCH trial of first-line erlotinib followed by second-line chemotherapy in advanced non-small cell lung cancer patients. European Lung Cancer Conference. Abstract 163O. Presented April 19, 2012. Biomarkers of TORCH trial of first-line erlotinib followed by second-line chemotherapy in advanced non-small cell lung cancer patients. European Lung Cancer Conference. Abstract 163O. Presented April 19, 2012. 2. Gridelli C, Ciardiello F, Feld R, et

al: International multicenter randomized phase III study of first-line erlotinib followed by second-line cisplatin plus gemcitabine versus first-line cisplatin-gemcitabine followed by second-line erlotinib in advanced non-small cell lung cancer. J Clin Oncol 28(15s):Abstract 7508, 2010.

Analysis Suggests CT Screening Could Save Lives at Relatively Low Cost By Charlotte Bath

esults of an actuarial analysis suggest that offering lung cancer screening with low-dose spiral computed tomography (CT) as a commercial insurance benefit to individuals who are 50 to 64 years old and have a smoking history of 30 pack-years or more could save lives at relatively low cost.

Cost-benefit Calculations “Assuming current commercial reimbursement rates for treatment, we found that screening would cost about $1 per insured member per month in 2012 dollars,” according to a report of the analysis in Health Affairs.1 Not only should commercial insurers consider lung cancer screening of high-risk individuals to be high-value coverage and provide it as a benefit to high risk people, but “payers and patients should demand screening from high-quality, low-cost providers,

thus helping set an example of efficient system innovation,” the authors wrote. The authors noted that low-dose spiral CT has improved greatly in the past 20 years and “reduced the need for invasive procedures to determine the presence or absence of cancer.” Tobacco cessation counseling was included in the screening cost calculation. “Previous studies have found that lowdose spiral CT screening can provide a ‘teachable moment’ that is associated with increased success in tobacco cessation efforts,” the authors stated. They estimated that the cost per life-year saved with low-dose spiral CT scanning for high-risk individual “would be below $19,000, an amount that compares favorably with screening for cervical, breast, and colorectal cancers.” The study model estimated the cost and cost-benefit of lung cancer screening

for smokers and former smokers between the ages of 50 and 64 with a smoking history of 30 pack-years. The estimated total is 18 million people or about 30% of the U.S. population aged 50 to 64. “The baseline screening scenario would lead to more than 130,000 additional lung cancer survivors in 2012,” the authors stated. “This increase is attributable to screening. It does not include the more than 64,000 ‘lead-time people’ who would be living with lung cancer and would have first become symptomatic within 2 years of the screening. Some of these 64,000 people would avoid death from lung cancer in years beyond 2012 because of screening, but we did not include them in our 2012 figure of survivors, because— with or without screening—they would have been alive in 2012.” The authors noted that their analysis

was completed before the results of the National Lung Screening Trial were published and that their “estiSee Page 89 mates of the proportion of early-stage lung cancer that would be detected by screening and of mortality reduction as a result of screening are more optimistic than the results of the trial. We attribute these differences partly to the design of the trial, which required that it be terminated as soon as significant mortality differences of greater than 20% appeared, and partly to our assumptions based on the use of current, improved imaging and screening workup approaches that emerged after the trial began.”

■

Reference 1. Pyenson BS, Sander MS, Jiang Y, et al: Health Affairs 31:770-779, 2012.

Resistance to CML therapy may occur. In some cases, repeatedly. Even today, with a number of available options for treating refractory CML, a gap in therapy exists. One post-imatinib study found 65% of patients discontinued dasatinib as a second-line therapy after 5 years.1 Another post-imatinib study found 70% of patients discontinued nilotinib after 4 years. 2 Additionally, a small study showed approximately a quarter of patients responded when treated sequentially with 2 second-generation tyrosine kinase inhibitors (TKIs) after imatinib. But in those patients that did respond, the median response rate was 16 months.3 It’s clear that for refractory patients, unmet medical needs persist.

Visit the CML Response Project Resource Center at Booth #17080. CMLResponseProject.com

ASCO BOOTH #17080

References: 1. Shah NP, Cortes JE, Schiffer CA, et al. Five-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2011; Chicago, IL. 2. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. 3. Garg RJ, Kantarjian H, O’Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361-4368. ©2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5344812

The ASCO Post | MAY 15, 2012

PAGE 44

In the Clinic Head/Neck Cancer

Vandetanib: New Drug for Unresectable Medullary Thyroid Cancer By Matthew Stenger

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

95% CI = 0.25–0.66). At the time of progression-free survival analysis, 15% of patients had died and there was no difference between groups in overall survival. Overall response rates were 44% with vandetanib and 1% with placebo (all partial responses).

How It Works

Indication

he oral kinase inhibitor vandetanib (Caprelsa) was recently approved for treatment of symptomatic or progressive unresectable locally advanced or metastatic medullary thyroid cancer. The use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease should be carefully considered due to the treatment-related risks of the drug (see Safety Profile, below). Approval of vandetanib was based on a randomized trial comparing vandetanib at See Page 89 300 mg/d (n = 231) vs placebo (n = 100) in 331 patients with unresectable locally advanced or metastatic medullary thyroid carcinoma. Median progression-free survival, the primary endpoint of the trial, was significantly prolonged with vandetanib, with risk of progression reduced by 65% (HR = 0.35, P < .0001). Median progressionfree survival was not reached in the vandetanib group vs 16.4 months in the placebo group. Subgroup analysis showed similar increases in progression-free survival with vandetanib in symptomatic patients (HR = 0.31, 95% CI = 0.19–0.53) and in patients with progression within the 6 months preceding study entry (HR = 0.41,

OF NOTE Vandetanib carries a boxed warning for QT prolongation, torsades de pointes, and sudden death, and adverse reactions include diarrhea/colitis, rash, acneiform dermatitis, nausea, and hypertension.

Vandetanib is a multikinase inhibitor that selectively targets RET (rearranged during transfection), vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR) signaling. Both RET and VEGFR are rational targets in medullary thyroid cancer. Mutations in RET, which are found in virtually all patients with hereditary medullary thyroid cancer and approximately half of sporadic cases, result in constitutive activity of kinase function and activation of downstream pathways that induce neoplastic transformation of parafollicular C cells in the thyroid. Increased expression of the proangiogenic factor VEGF is characteristic of thyroid tumors and is associated with increased tumor growth and invasiveness.

How It Is Given The recommended daily dose of vandetanib is 300 mg orally. Vandetanib may be taken with or without food. The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥ 30 to < 50 mL/min) and severe (creatinine clearance < 30 mL/min) renal impairment. Dose reduction may be necessary for severe toxicities or QTc interval prolongation. Only prescribers and pharmacies certified through the Vandetanib Risk Evaluation Mitigation Strategy Program, a restricted distribution program, are able to prescribe and dispense vandetanib.

Safety Profile Vandetanib carries a boxed warning for QT prolongation, torsades de pointes, and sudden death. Given the prolonged half-life of vandetanib (19 days), ECGs and levels of serum potassium, calcium, magnesium, and

Vandetanib in Thyroid Cancer ■■ Vandetanib is an oral kinase inhibitor approved for treatment of

symptomatic or progressive unresectable locally advanced or metastatic medullary thyroid cancer.

■■ The recommended dosage of vandetanib is 300 mg/d, but the starting

dose should be reduced to 200 mg in patients with renal impairment and dose reduction may also be necessary for severe toxicities or QTc interval prolongation.

thyroid-stimulating hormone should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment, and every 3 months thereafter. Electrolytes and ECGs may require more frequent monitoring in patients experiencing diarrhea. In the trial supporting vandetanib approval, the most common (≥ 20%)

OF NOTE Prescribers and pharmacies must be certified through the Vandetanib Risk Evaluation Mitigation Strategy Program to prescribe and dispense vandetanib. adverse reactions in vandetanib patients were diarrhea/colitis, rash, acneiform dermatitis, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. Laboratory abnormalities in more than 20% of patients included decreased calcium, increased ALT, and decreased glucose. The most common (≥ 5%) grade 3 or 4 adverse reactions were diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Adverse reactions resulting in death in patients receiving vandetanib (n = 5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. In addition, two deaths in patients receiving vandetanib (one sudden death and one death from cardiopulmonary arrest) were observed after the data cutoff.

Cost Vandetanib is estimated to cost

$198 per 100-mg tablet, which at a daily dose of 300 mg equals $17,820 for a 30-day supply.

■

Suggested Readings CAPRELSA® (vandetanib) tablets prescribing information. AstraZeneca Pharmaceuticals LP, June 2011. Available at http://www1.astrazeneca-us.com/pi/caprelsa.pdf. Accessed December 14, 2011. Commander H, Whiteside G, Perry C: Vandetanib: First global approval. Drugs 71:1355-1365, 2011. Deshpande H, Roman S, Thumar J, et al: Vandetanib (ZD6474) in the treatment of medullary thyroid cancer. Clin Med Insights Oncol 5:213-221, 2011. U.S. Food and Drug Administration: What’s New from the Office of Hematology Oncology Products: Vandetanib. Available at http://www.fda.gov/ AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ ucm250347.htm. Accessed December 14, 2011. Wells SA Jr, Gosnell JE, Gagel RF, et al: Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 28:767-772, 2010.

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

Endocrine therapy may be a challenge in some postmenopausal breast cancer patients if: • There are concerns about genetic CYP2D6 variations • Patients are receiving other medications that have known drug interactions with their endocrine therapy • Patients are experiencing intolerable side effects with current endocrine therapy

Fareston may be the answer FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

PROVEN CLINICAL PROFILE

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients

CYP2D6 does not play a significant role in the activity of FARESTON

In multiple clinical studies, less than 1% of women stopped taking Fareston due to joint pain

Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Black box warning and important safety information: FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. FARESTON is contraindicated in patients with known hypersensitivity to the drug. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2011. Data on file, GTx, Inc.

Please see brief summary of prescribing information including boxed warning on the following page. For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

FARESTON® (toremifene citrate) 60 mg Tablets oral administration Initial U.S. Approval: [1997] BRIEF SUMMARY OF PRESCRIBING INFORMATION WARNING: QT PROLONGATION FARESTON has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided [see Warnings and Precautions]. INDICATIONS AND USAGE FARESTON® is an estrogen agonist/antagonist indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. DOSAGE FORMS AND STRENGTHS Tablet is 60 mg, round, convex, unscored, uncoated, and white, or almost white, identified with TO 60 embossed on one side. CONTRAINDICATIONS Hypersensitivity to the Drug FARESTON is contraindicated in patients with known hypersensitivity to the drug. QT Prolongation, Hypokalemia, Hypomagnesemia Toremifene should not be prescribed to patients with congenital/acquired QT prolongation (long QT syndrome), uncorrected hypokalemia, or uncorrected hypomagnesemia. WARNINGS AND PRECAUTIONS Prolongation of the QT Interval Toremifene has been shown to prolong the QTc interval in a dose- and concentration- related manner [see Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called Torsade de pointes, which may result in syncope, seizure, and/or death. Toremifene should be avoided in patients with long QT syndrome. Caution should be exercised in patients with congestive heart failure, hepatic impairment and electrolyte abnormalities. Hypokalemia or hypomagnesemia must be corrected prior to initiating toremifene and these electrolytes should be monitored periodically during therapy. Drugs that prolong the QT interval should be avoided. In patients at increased risk, electrocardiograms (ECGs) should be obtained at baseline and as clinically indicated [see Drug Interactions and Clinical Pharmacology]. Hypercalcemia and Tumor Flare As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and, if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in animals treated with toremifene [see Nonclinical Toxicology]. General Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment [see Warnings and Precautions]. Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Laboratory Tests Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Use in Pregnancy Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. Women of Childbearing Potential FARESTON is indicated only in postmenopausal women. However, premenopausal women prescribed FARESTON should use effective non-hormonal contraception and should be apprised of the potential hazard to the fetus should pregnancy occur. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience Adverse drug reactions are principally due to the antiestrogenic actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 n = 221

TAM20 n = 215

Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4% Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse reactions (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse reactions occurring in at least 1% of patients receiving FARESTON in the three major trials are listed in the table below. Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively [see Clinical Studies]. Adverse Reactions Cardiac Cardiac Failure Myocardial Infarction Arrhythmia Angina Pectoris Ocular* Cataracts Dry Eyes Abnormal Visual Fields Corneal Keratopathy Glaucoma Abnormal Vision/Diplopia Thromboembolic Pulmonary Embolism Thrombophlebitis Thrombosis CVA/TIA Elevated Liver Tests** AST Alkaline Phosphatase Bilirubin Hypercalcemia

North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) 2 2 -

(1) (1)

1 (<1) 3 (1.5) -

1 1

22 20 8 4 3 -

(10) (9) (4) (2) (1.5)

16 (7.5) 16 (7.5) 10 (5) 2 (1) 2 (1) -

1 -

4 1

(2)

2 (1) 2 (1) 1 (<1) -

1 1 1 -

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

4 24 4 6

30 16 2 1

(19) (10) (1) (<1)

(<1)

11 (5) 41 (19) 3 (1.5) 6 (3)

(2) (11) (2) (3)

(<1) (<1)

(<1)

1 (<1) 2 (1) -

2 (1) 3 (1.5) 1 (<1)

3 (1.5) 1 (<1) 1 (<1) 2 (1)

3 (1.5)

5 (3) 1 (<1) 1 (<1) -

(<1)

4 (2) 3 (1.5) 4 (2)

1 (<1) 3 (1.5) 4 (2) 4 (2)

22 (15) 13 (9) 1 (<1) -

32 (15) 18 (8) 2 (1) -

35 (17) 31 (15) 3 (1.5) -

1 1

(<1)

* Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual ophthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: AST >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: AST, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse reactions included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritus, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. The incidence of AST elevations was greater in the 200 and 240 mg FARESTON dose arms than in the tamoxifen arms. Higher doses of FARESTON were also associated with an increase in nausea. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. Post-marketing Experience The following adverse reactions were identified during post approval use of FARESTON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported during post approval use of FARESTON have been consistent with clinical trial experience. The most frequently reported adverse reactions related to FARESTON use since market introduction include hot flash, sweating, nausea, and vaginal discharge. DRUG INTERACTIONS Drugs that Decrease Renal Calcium Excretion Drugs that decrease renal calcium excretion, e.g., thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. Agents that Prolong QT The administration of FARESTON with agents that have demonstrated QT prolongation as one of their pharmacodynamic effects should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that prolongs QT should be closely monitored for prolongation of the QT interval. Agents generally accepted to prolong QT interval include Class 1A (e.g., quinidine, procainamide, disopyramide) and Class III (e.g., amiodarone, sotalol, ibutilide, dofetilide) antiarrhythmics; certain antipsychotics (e.g., thioridazine, haloperidol); certain antidepressants (e.g., venlafaxine, amitriptyline); certain antibiotics (e.g., erythromycin, clarithromycin, levofloxacin, ofloxacin); and certain anti-emetics (e.g., ondansetron, granisetron). In patients at increased risk, electrocardiograms (ECGs) should be obtained and patients monitored as clinically indicated [see Boxed Warning and Warnings and Precautions]. Effect of Strong CYP3A4 Inducers on Toremifene Strong CYP3A4 enzyme inducers, such as dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s Wort, lower the steady-state concentration of toremifene in serum. Effect of Strong CYP3A4 Inhibitors on Toremifene In a study of 18 healthy subjects, 80 mg toremifene once daily coadministered with 200 mg of ketoconazole twice daily increased the toremifene Cmax and AUC by 1.4- and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC were reduced by 56% and 20%, respectively. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) increase the steady-state concentration in serum and should be avoided. Grapefruit juice may also increase plasma concentrations of toremifene and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with FARESTON be interrupted. If interruption of treatment with FARESTON is not possible, patients who require treatment with a drug that strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning and Warnings and Precautions]. Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%. Clinically relevant exposure changes in sensitive substrates due to inhibition or induction of CYP3A4 by toremifene appear unlikely. Effect of Toremifene on CYP2C9 Substrates In a study of 20 healthy subjects, 500 mg tolbutamide once daily (days 7 and 19) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 7 and 19 plasma tolbutamide Cmax and AUC were increased by less than 30%. A reduction of similar magnitude was observed for hydroxytolbutamide and carboxytolbutamide Cmax and AUC. Toremifene is a weak inhibitor of CYP2C9. Concomitant use of CYP2C9 substrates with a narrow therapeutic index such as warfarin or phenytoin with FARESTON should be done with caution and requires careful monitoring (e.g., substrate concentrations (if possible), appropriate laboratory markers, and signs and symptoms of increased exposure). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Based on its mechanism of action in humans and findings of increased pregnancy loss and fetal malformation in animal studies, FARESTON can cause fetal harm when administered to a pregnant woman. Toremifene caused embryo-fetal toxicities at maternal doses that were lower than the 60 mg daily recommended human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women using FARESTON. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In animal studies, toremifene crossed the placenta and accumulated in the rodent fetus. Administration of toremifene to pregnant rats during organogenesis at doses of approximately 6% the daily maximum recommended human dose of 60 mg (on a mg/m2 basis) resulted in signs of maternal toxicity and increased preimplantation loss, increased resorptions, reduced fetal weight, and fetal anomalies. Fetal anomalies include malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Maternal toxicity may have contributed to these adverse embryo-fetal effects. Similar embryo-fetal toxicities occurred in rabbits that received toremifene at doses approximately 40% the daily recommended human dose of 60 mg (on a mg/m2 basis). Findings in rabbits included increased preimplantation loss, increased resorptions, and fetal anomalies, including incomplete ossification and anencephaly. Animal doses resulting in embryo-fetal toxicities were ≥1.0 mg/kg/day in rats and ≥1.25 mg/kg/day in rabbits. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to effects seen with diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Neonatal rodent studies have not been conducted to assess the potential for toremifene to cause other DES-like effects in offspring (i.e., vaginal adenosis). Vaginal adenosis in animals occurred following treatment with other drugs of this class and has been observed in women exposed to diethylstilbestrol in utero. Nursing Mothers It is not known if toremifene is excreted in human milk. Toremifene is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARESTON, 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 There is no indication for use of FARESTON in pediatric patients. Geriatric Use The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Renal Impairment The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic Impairment The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Race The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

CLINICALPHARMACOLOGY Mechanism of Action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mammary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, i.e., its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Pharmacodynamics Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Effects on Cardiac Electrophysiology The effect of 20 mg, 80 mg, and 300 mg of toremifene on QT interval was evaluated in a double-blind, randomized study in healthy male subjects aged 18 to 45 years. The QT interval was measured at steady state of toremifene (Day 5 of dosing), including the time of peak plasma concentration (Tmax), at 13 time points (4 ECGs/time point) over 24 hours post dose in a time matched analysis. The 300 mg dose of toremifene (approximately five times the highest recommended dose 60 mg) was chosen because this dose produces exposure to toremifene that will cover the expected exposures that may result from potential drug interactions and hepatic impairment [see Drug Interactions]. Dose and concentration-related increases in the QTc interval and T wave changes were observed (see Table 1). These effects are believed to be caused by toremifene and N-demethyltoremifene. Toremifene had no effects on heart rate, PR and QRS interval duration [see Boxed Warning and Warnings and Precautions]. Table 1: QTc Prolongation in Healthy Male Volunteers Treatment Arm Toremifene 20 mg (N = 47) Toremifene 80 mg (N = 47) Toremifene 300 mg (N = 48)

Mean (90% CI) ΔΔQTc, ms 7 (0.9, 13.6) 26 (21.1, 31.2) 65 (60.1, 69.2)

ΔQTc > 60 ms (n, %) 0 2 (4.3%) 43 (89.6%)

QTc > 500 ms (n, %) 0 0 5 (10.4%)

Pharmacokinetics Absorption – Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady state concentrations were reached in about 4-6 weeks. Distribution – Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly albumin. Metabolism – Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Following multiple dosing with toremifene in 20 healthy volunteers, plasma toremifene exposure was lower on Day 17 compared to Day 5 by approximately 14%. N-demethyltoremifene exposure was higher on Day 17 compared to Day 5 by approximately 80%. Based on these data and an in vitro induction study in human hepatocytes, auto- induction of CYP3A4 by toremifene is likely. The effect of auto-induction on efficacy was likely captured following prolonged dosing in the clinical studies. Elimination – The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (Deaminohydroxy) toremifene, were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5 L/h. Toremifene is eliminated as metabolites primarily in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Renal insufficiency – The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and patients with impaired kidney function. Hepatic insufficiency – The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients – The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted. Food – The rate and extent of absorption of FARESTON are not influenced by food; thus FARESTON may be taken with or without food. Race – The pharmacokinetics of toremifene in patients of different races has not been studied. Fourteen percent of patients in the North American Study were non-Caucasian. No significant racerelated differences in FARESTON effectiveness or safety were noted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (approximately 1/50 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (approximately 1/15 to 2 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human estrogen agonists/antagonists that have primarily estrogenic activity in mice. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (approximately 1/3 and 1.4 times, respectively, the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (approximately 4 times and 1/50 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (approximately 1.5 times the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/3 the daily maximum recommended human dose of 60 mg, on a mg/m2 basis) for 52 weeks. PATIENT COUNSELING INFORMATION Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. FARESTON may harm the fetus and increase the risk for pregnancy loss [see Warnings and Precautions and Use in Specific Populations]. Premenopausal women using FARESTON should use nonhormonal contraception during treatment and should be apprised of the potential hazard to the fetus should pregnancy occur [see Warnings and Precautions]. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Patients who must take medications known to prolong the QT interval, or potent CYP3A4 inhibitors, should be informed of the effect of toremifene on QT interval. Toremifene has been shown to prolong the QTc interval in a dose-related manner [see Boxed Warning, Warnings and Precautions, and Clinical Pharmacology]. Specific interactions with foods that inhibit CYP3A4, including grapefruit juice, have not been studied but may increase toremifene concentrations. Patients should avoid grapefruit products and other foods that are known to inhibit CYP3A4 during FARESTON treatment. Certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s Wort) and toremifene, can reduce concentrations of coadministered drugs [see Drug Interactions]. Distributed by GTx, Inc. Memphis, TN 38103, USA Product covered by Orion Product Patents and related patent numbers. © 2012 GTx, Inc. All rights reserved. 2E Rev. 03/2011

ASCOPost.com | MAY 15, 2012

PAGE 47

Direct from ASCO

Philanthropy Spotlight

Photo by Sarah Hoag

Conquer Cancer Foundation Board Member Tom Roberts Cites Need to Grow Research Capacity as Opportunity for Discovery Accelerates

Thomas G. Roberts, MD

homas G. Roberts, MD, dedicates a shelf in his home to memories of patients—photographs, notes, expressions of gratitude, traces of lives linked with his through cancer treatment. He looks at it every day, he says, and the memories inform his mission. “In oncology, you become part of people’s lives, and they become part of yours,” he says. “I’m a different person for those interactions, and I’m privileged to have experienced them. I think that, on some level, many physicians feel that our work is a way of honoring our patients … those who are still with us, and those who are not.”

undergraduate degrees in biology and economics. “I became increasingly interested in looking for ways to make drug development more efficient and allocate capital more efficiently,” he says. “I started to publish and consult, and eventually made the transition.” Although Dr. Roberts left day-today clinical practice, he has never left oncology. A lecturer at Stanford’s and Berkeley’s business schools, Dr. Roberts also continues to serve on the Leadership Council of the Massachusetts General Hospital Cancer Center as well as the board of the Cancer Education Consortium. He is a section editor of The Oncologist. Dr. Roberts is also an active board member and philanthropic supporter of the Conquer Cancer Foundation of ASCO.

those criteria.” Dr. Roberts believes that the Conquer Cancer Foundation’s support of translational research, including the work of junior faculty, is essential to sustain momentum at a time when opportunities for development of new therapies are proliferating rapidly. “Throughout history, we’ve seen that scientific discovery doesn’t happen linearly and it doesn’t happen quickly, but that we occasionally find ourselves at tipping points where things really start to happen,” Dr. Roberts says. “This is one of those tipping points. The ability to harvest rapidly evolving opportunities is dependent on the people you have in place and the resources you have available. You see losers, winners, lost opportunities, and great triumphs. We’re in that moment now with cancer research. If we lose momentum now, we’ve lost a lot.”

I think that, on some level, many physicians feel that our work is a way of honoring our patients … those who are still with us, and those who are not. —Thomas G. Roberts, MD

Advancing Cancer Care from Outside the Clinic

Cancer Research at the Tipping Point

These days, Dr. Roberts’ shelf is located in San Francisco, where he works as a Managing Member of Farallon Capital Management, LLC. He joined the firm as a portfolio manager in 2005, having previously served as an attending oncologist at Massachusetts General Hospital, an instructor of medicine at Harvard Medical School, and a visiting scientist at the Massachusetts Institute of Technology. A graduate of Harvard Medical School, Dr. Roberts trained in internal medicine at MGH and in oncology through the Dana Farber/Partners Cancer Care Oncology Fellowship Program. As an oncologist, Dr. Roberts knew how important drug development and translational research were to his patients’ treatment and survival—and experienced the familiar frustration of progress never coming fast enough. He began to act on a long-standing interest in public policy first honed at the University of Pennsylvania, where he earned dual

As the father of two young daughters, with a full professional plate, Dr. Roberts doesn’t take board service lightly. He chose to invest time and resources in the Conquer Cancer Foundation, he says, because of the organization’s alignment with his own mission and interests—and because of the Foundation’s unique capacity to drive cancer care forward at what appears to be a critical inflection point in understanding, preventing, and treating the disease. “With such limited time, I wouldn’t make this level of commitment—including weekends away from my little girls—if the Foundation’s mission was not compelling,” Dr. Roberts says. “I always look to get involved in efforts that are led by teams I respect and admire, that are dynamic and going through change, and that are challenging and require multidisciplinary approaches to complex problems. The Conquer Cancer Foundation meets all of

“Fully exploiting the opportunities available to us now in translational research involves funding infrastructure … including support of interdisciplinary, creative work that doesn’t tend to get a lot of funding,” he continues. “For instance, the junior faculty in whom we invest today, through the Conquer Cancer Foundation’s Young Investigator Awards, will learn and be inspired and actually be the generation that

influences cancer care for the next 50 years. Whatever I can do to help build the mechanism to support that work … I’ll do it.”

Diversity of Talent Will Create a World Free from the Fear of Cancer For Dr. Roberts, it’s clear that the work of the Conquer Cancer Foundation will benefit from the diversity of talent and perspective that enriches his own work at the nexus of medicine, policy, and finance— and that the Foundation’s vision of a world free from the fear of cancer will be achieved only through the contributions of many. “To the extent that I can be a catalyst to attract collaborators who are interested in venture philanthropy, finance, and other fields … people who can complement our core strengths in medicine … I welcome that role,” says Dr. Roberts. “We embrace the knowledge that often the greatest innovations come from the intersection of different fields. While it’s essential that we all contribute financially to the Foundation … working together to grow its capacity for investment in research and other initiatives that will improve care … we also welcome valuable contributions of expertise and other tools that will help us move the work forward.” To learn more about the Conquer Cancer Foundation of ASCO, please visit www.conquercancerfoundation. org.

■

New Video Series Addresses Challenges Facing Young Survivors

ancer.Net has collaborated with LIVESTRONG to launch Moving Forward: Perspectives from Survivors and Doctors, a series of 13 videos focused on issues facing young adults with cancer. Topics covered include

managing bills and expenses, dealing with the fear of recurrence, navigating the dating world, and understanding body changes, sexuality, and fertility. New videos will be added monthly throughout 2012; watch them at www. cancer.net/movingforward.

■

The ASCO Post | MAY 15, 2012

PAGE 48

Direct from ASCO

New Conquer Cancer Foundation of ASCO Professorship Focuses on Teaching Drug Development to Young Oncology Researchers

espite a number of new drug approvals in 2011, there are still major challenges in developing effective oncology therapeutics and drug combinations that demonstrate significant survival advantages. Mechanisms are needed to ensure that the next generation of oncology researchers has the necessary skills and training to lead oncology drug development. With this in mind, the Conquer Cancer Foundation of the American Society of Clinical Oncology launched a new research grant opportunity in 2012 to extend its line of distinguished professorships. The

Drug Development Research Professorship (DDRP) is designed to support outstanding researchers who are dedicated to bringing advances into the clinical arena. These researchers are exploring new and promising therapeutic compounds that will lead to improved treatments, and they are committed to mentoring young researchers in the scientific and regulatory aspects of drug development. The 2012 DDRP is supported by Sanofi Oncology.

First DDRP Recipient The first DDRP recipient, Alex A. Adjei, MD, PhD, of Roswell Park Cancer Institute, is Senior Vice President of Clinical Research, Chairman of the Department of Medicine, and a Professor of Oncology at Roswell Park Cancer In-

stitute. His career has focused on preclinical and clinical experimental therapeutics and on evaluating mechanisms of drug activity and synergistic drug combinations in the laboratory, while performing phase I clinical trials in the clinic. In the spirit of the award, Dr. Adjei has decentralized his administrative responsibilities to dedicate more time to research and mentoring. “I’m honored to join the elite group who have received professorships from the Conquer Cancer Foundation of ASCO,” said Dr. Adjei, who joins five previous recipients of Conquer Cancer Foundation professorships. “This grant will greatly benefit our trainees and allow me to spend more of my time mentoring the research team.” Currently, Dr. Adjei mentors a

Alex A. Adjei, MD, PhD

phase I clinical trials group at Roswell Park, which includes four junior faculty members. He is also mentoring a fellow from the new Drug Development Fellowship Program at Roswell Park, and the DDRP will allow him to mentor more drug development fellows as the program expands.

■

ASCO Launches First Annual Quality Care Symposium November 30

o much health services research is underway in oncology that, rather than relegating it to just a portion of the Annual Meeting, ASCO has decided to launch a meeting devoted entirely to the emerging discipline. The first annual Quality Care Symposium will take place November 30 through December 1 in San Diego.

Douglas W. Blayney, MD

The time is right for focusing on quality in cancer care, said Douglas W. Blayney, MD, Ann and John Doerr Medical Director and Stanford Cancer Center Professor of Medicine, former President of ASCO, and currently Cochair of the symposium. “There is so much going on in the space that we figured this was a great time to bring together heath services researchers, quality researchers, and peo-

ple implementing quality programs in their practices,” he said, adding that the flurry of interest and activity dovetails nicely with ASCO’s Quality Oncology Practice Initiative (QOPI®), which is just finishing up an analysis of 5 years of data.

All Disciplines Welcome The 2-day symposium will bring together top leaders in the field to share strategies and methods for measuring and improving the quality of cancer care, with a particular focus on promoting innovation, strategic planning, engaging patients in quality improvement activities, and ways to eliminate disparities in quality improvement reporting. The meeting will also zero in on optimizing comparative effectiveness research and activities in oncology. As with all ASCO meetings, the new symposium will be multidisciplinary, welcoming academics, researchers, fellows, nurses, physician assistants, radiation oncologists, medical oncologists, and surgical oncologists.

200 Different Diseases In recent years, a number of conferences focusing on quality of care have been launched, but this is the only one that focuses on outcomes in cancer spe-

cifically. Measuring quality outcomes in oncology is a massive task compared to doing so in other disease groups, according to Dr. Blayney. “Oncology is over 200 different cancers; measuring processes and outcomes in 200 different diseases is a huge challenge.” One topic that he expects to be hot is the integration of information into quality improvement activities at the practice level—both in private practices and hospital settings. “Folks are eager to talk about what they’ve done that works,” he said. The interactive nature of the symposium sessions will offer the opportunity for networking and sharing experiences. Sessions at the conference will address topics such as these: ■■ Reengineering your practice to deliver quality and value ■■ Mining electronic medical record data for quality measurement ■■ Developing cancer care pathways ■■ Payers’ perspectives on value and quality ■■ Community, academic, and public models that work

Defining Value Dr. Blayney commented that a concerted focus on developing and

adhering to precise measurements for quality of care is just getting off the ground as a discipline, and consensusbuilding meetings like this will help those efforts make necessary leaps. “We’re good at studying processes and recording adherence to processes,” he said. “Where we need to go is to record our outcomes in care, develop outcomes in care to study, and figure out how this translates into cost savings with efficient care, and most importantly, care that is valuable to the patient. This is where we need to engage patients in determining outcomes that are meaningful to them.” Summaries of new, ongoing, and updated research in the area of quality and other health services research will be acceptable for submission and presentation. A limited number of merit awards will be given to fellows and residents who submit high-quality abstracts. Merit award winners will receive a monetary award, as well as complimentary registration. For a list of topic categories and to register for the symposium, go to quality2012.asco.org.

■

ASCOPost.com | MAY 15, 2012

PAGE 49

Direct from ASCO

ASCO Past President Highlights QOPI® Efforts to Improve Care in Michigan

SCO’s Quality Oncology Practice Initiative (QOPI®) can be used to assess the quality of care in a statewide consortium of oncology practices and ultimately can lead to better care for patients with cancer, said ASCO Past President Douglas W. Blayney, MD, at a recent briefing on cancer care value in Washington, DC. Dr. Blayney discussed the results of his recent study published by Health Affairs, “Michigan Oncology Practices Showed Varying Adherence Rates to Practice Guidelines, But Quality Interventions Improved Care,” at a briefing hosted by the journal. “We focused on how oncology practices in Michigan adhered to the measurements of QOPI. Process adherence indicates optimum survival of the patient,” said Dr. Blayney, the former Medical Director at the University of Michigan Cancer Center and the current Ann and John Doerr Medical Director of the Stanford University Cancer Institute.

tions to do so,” said Dr. Blayney. The paper noted that is it still too early to determine the effect of these

targeted interventions and the overall impact of the consortium, but it appears positive from early indications.

■

Increased Participation The acceptance and support of QOPI by Blue Cross Blue Shield of Michigan (BCBSM) has led to increased participation in the consortium, Dr. Blayney said. Before BCBSM agreed to reimburse the costs of data collection in 2007, only three medical practice groups in Michigan participated in QOPI. Afterward, 36 practices, ranging from large institutions to smaller practices, participated. Of those 36 practices, 20 participated in two or more data-collection rounds and were the focus of the study. The study identified high concordance with treatment-related quality metrics among the outpatient oncology practices. For breast and colorectal cancer care, there was a more than 85% rate of adherence to the quality care processes. However, there was higher variation in scores among participants and lower overall concordance within other domains of care. For end-of-life care, the adherence rate was 73%, and for symptom and toxicity management, adherence was 56%. “This observation of these snapshots of care has led us to ask if we can do better in end-of-life care, and we are working on targeted interven-

Unified in our uncompromising commitment to improving patient care in renal cell carcinoma For more information visit www.aveopharma.com or www.astellas.com.

011L-073-4740

12/11

Printed in the USA

The ASCO Post | MAY 15, 2012

PAGE 50

Direct from ASCO

Cancer.Net, ASCO’s Patient Education Website: Celebrating 10 Years of Trusted Cancer Education

“For 10 years, Cancer.Net has reflected the voice of the physician and given people with cancer and their loved ones the tools they need to actively participate in their cancer care. ASCO has used all the technological advances of the past decade to make information more accessible, interactive, and easier to understand. Now, patients can access Cancer.Net not just on their computers but on smartphones and other devices and use the resources of the website as they navigate the health-care system.” —Diane Blum, MSW Editor-in-Chief, Cancer.Net

ince ASCO’s patient education website was first launched in May 2002 as People Living With Cancer, a primary goal has been to provide a trusted resource that oncology professionals could feel confident referring their patients to. A key strength of the website—known today as Cancer.Net (www.cancer. net)—is the rigorous medical review process by its Editorial Board, which is made up of more than 150 oncologists of all subspecialties, other physician specialists, nurses, physician assistants, social workers, and patient advocates. The frequent, high-level review of Cancer.Net’s content by ASCO members allows it to stand out among the sea of cancer websites. As technology and progress in cancer research and treatment have evolved, so has Cancer.Net. The depth and range of topics covered by the site have increased, and the experience for website users has become more interactive. Read below to learn how ASCO’s patient education program has grown, and take a fresh look at all that Cancer. Net has to offer your patients. Guides to Cancer: In May 2002, Cancer.Net provided detailed sec-

tions on 22 different types of cancer. on special topics to those who sign Now, patients and their family and up at www.cancer.net/feeds. friends can learn about more than Printed Patient Education Mate120 types of cancer and cancer-rerials: While the use of the Internet to lated syndromes at www.cancer.net/ find health information has grown sigcancer. nificantly during the past 10 years, not Focus on Other Aspects of everyone has access to the Internet. Cancer Care: To help patients cope There is still a need for printed mawith all facets of a terials, especially cancer diagnosis, those that can be The efforts to Cancer.Net added easily given out in constantly improve specific sections the doctor’s office. addressing comTo meet this need, both the information mon concerns Cancer.Net offers on the site and how surrounding canGuides to Cancer cer care that paand ASCO Anit’s delivered have tients experience, swers fact sheets on helped Cancer.Net such as survivora variety of cancer ship (www.cancer. topics. In addition, receive several honors net/sur v ivors), Cancer.Net has for its content, design, physical, emoworked with varitional, and family ous ASCO comand ease of use in the issues (www.canmittees and task past 10 years. cer.net/coping), forces to develop costs of cancer booklets about care, (www.canspecific challenges cer.net/managingcostofcare), and people with cancer often face, such advanced cancer care and end-of-life as managing the cost of cancer care, care (www.cancer.net/advancedcanadvanced cancer care planning, and cer). Cancer.Net also includes a secsurvivorship. All of the printed patient tion on advocacy (www.cancer.net/ advocacy), recognizing that some survivors may wish to use their experience to help others with cancer. Multimedia: To learn about cancer in 2002, visitors to the site had one option—to read articles. Now, SCO has implemented a new patients can listen to podcasts (www. abstract distribution model cancer.net/podcasts), watch videos for its 2012 Annual Meeting to enwith ASCO’s members explaining sure simultaneous electronic and important aspects of cancer care print release of important scien(www.cancer.net/videos), and use tific information to attendees and the Cancer.Net mobile app on their the public. Plenary, Late-Breaking, iPhone, iPad, or Android phone and Clinical Review Abstracts (www.cancer.net/app). (or Newly Released Abstracts, as Social Media: In 2002, people they will be referred to during the didn’t use Twitter, Facebook, and Meeting) will be released online YouTube. Now people use these to on ASCO.org at 12:01 AM (EDT) interact and share knowledge, includon the day of their presentation. ing health information. Cancer.Net Late-Breaking and Clinical Review shares new and updated material on Abstracts will be featured in SecFacebook (www.facebook/cancertion D of ASCO Daily News Satdotnet), Twitter (www.twitter.com/ urday through Monday; Plenary cancerdotnet), and Google Plus abstracts will be included as well (www.plus.google.com), and posts in Sunday’s Section D. ASCO Daivideos on YouTube (www.youtube. ly News, the official news source com/cancerdotnet). Cancer.Net also of the ASCO Annual Meeting, is has an RSS feed to announce weekly feature articles, podcasts, and videos

education materials can be downloaded free from Cancer.Net or ordered in bulk for your waiting room through the ASCO University Bookstore (www.cancer.net/estore). The efforts to constantly improve both the information on the site and how it’s delivered have helped Cancer.Net receive several honors for its content, design, and ease of use in the past 10 years. In particular, the website has been honored seven times by the annual Web Marketing Association WebAwards program, most recently in September 2011. Cancer.Net is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology, which provides funding for breakthrough cancer research, professional education, and patient and family support. Learn more about how to support such patient-directed efforts at www.cancer.net/sitesupport.

■

Important Information Regarding Abstract Distribution for the 2012 ASCO Annual Meeting

available in bins throughout the Convention Center and online at chicago2012.asco.org/dn. The Newly Released Abstracts in Section D of each day’s ASCO Daily News takes the place of the Proceedings II booklet, which was available in the same location in prior years. Abstracts published in the 2012 ASCO Annual Meeting Proceedings Part I, as well as those published online but not presented, will be publicly released on ASCO.org on Wednesday, May 16, 2012, at 6:00 PM (EDT). Read more information about this change at chicago2012.asco.org.

■

FOCUSED ON YOUR

PATIENTS

February 2012

ZOM-1036266

The ASCO Post | MAY 15, 2012

PAGE 52

Journal Spotlight

JAMA Highlights New Comparative Effectiveness Studies By Ronald Piana

recent press briefing moderated by Phil B. Fontanarosa, MD, MBA, Executive Editor, JAMA, presented new findings on comparative effectiveness research, and two of the studies discussed focused on cancer. Dr. Fontanarosa started by defining comparative effectiveness research, which gained prominence in 2009 as a $1.1 billion chunk of the 2009 American Recovery and Reinvestment Act. “[Comparative effectiveness research] is comparing the benefits and harms of available interventions or therapies to prevent, diagnose, treat, or monitor clinical conditions, and then apply the information to make informed decisions that result in better health-care outcomes,” Dr. Fontanarosa explained.

Bevacizumab in NSCLC Deborah Schrag, MD, MPH, Associate Professor of Medicine, Harvard Medical School, presented a retrospective cohort study looking at survival in patients with advanced non–squamous cell non–small cell lung cancer (NSCLC), aged 65-years or older, who were treated with carboplatin/paclitaxel with or without bevacizumab (Avastin).1 The motivation for the study was a 2006 phase�� III NCI-sponsored trial showing that the addition of bevacizumab

Surveillance, Epidemiology and End Results (SEER) cancer registries data; 94% of SEER patients aged 65 or older are linked with Medicare claims. “Our research question was simple: Does adding bevacizumab to standard chemotherapy improve survival in these NSCLC patients?” Dr. Schrag said. The answer, in a nutshell: “In Medicare-insured patients with advanced non–squamous cell NSCLC aged 65 years and older, we did not find that adding bevacizumab provides a substantial survival advantage over the standard combination. This matters to overall health care because lung cancer, the leading cause of U.S. cancer death, is a disease of the elderly, and there is a critical need for better treatments,” Dr. Schrag said. Dr. Schrag emphasized that the distinction between efficacy and effectiveness gets to the gut of comparative effectiveness research. “Efficacy studies ask can this intervention work, relying on randomized controlled trials for the answer, whereas effectiveness studies ask does this intervention work, usually relying on real-world observational data sets,” said Dr. Schrag. She acknowledged that population-based data banks such as SEER, have high generalizability, but provide less

Efficacy studies ask can this intervention work, relying on randomized controlled trials for the answer, whereas effectiveness studies ask does this intervention work, usually relying on real-world observational data sets. — Deborah Schrag, MD, MPH

to carboplatin/paclitaxel gave a slight survival advantage in stage IIIB/IV non–squamous cell NSCLC. “On the strength of this trial, FDA approved bevacizumab for this indication. However, although NSCLC is a disease of the elderly, only a minority of trial participants were 65 years or older. And in fact, the trial showed no advantage in that age group,” commented Dr. Schrag. The researchers analyzed NCI

clinical detail than randomized trials.

Coverage Decision Time The Centers for Medicare & Medicaid Services (CMS) had a major coverage decision to make, and unlike regulatory agencies elsewhere in the world the agency does not factor cost into its policy, only a drug’s efficacy. “Even though there was no survival advantage in the 65-plus

The results of both comparisons support the use of IMRT as the current standard radiation technique in prostate cancer. Moreover, there is no evidence demonstrating that proton therapy is superior to IMRT. —Ronald Chen, MD, PhD

group, because the overall results of the clinical trial showed a minimal advantage, CMS, based on the reasonable and necessary criteria in the statute, covered bevacizumab,” Dr. Schrag said. “We wanted to know the consequences of FDA’s approval and subsequent CMS coverage in 2006,” Dr. Schrag said, adding, “In other words, did doctors and their NSCLC patients read the results of the NCI trial and adopt bevacizumab? Also, does bevacizumab provide an incremental benefit when used in routine practice?” In answer, Dr. Schrag noted that when carboplatin/paclitaxel was prescribed for advanced NSCLC, only 22% of the Medicare patients received bevacizumab added to the regimen. “We found that younger Medicare enrollees with fewer comorbidities were more likely to receive bevacizumab. The data also suggest that physicians and their patients are judicious in using new therapies with marginal or unclear benefits,” concluded Dr. Schrag.

Comparing Treatments in Localized Prostate Cancer Prostate cancer, largely because of the wide variability of treatments and costs, has drawn the attention of those involved in initiatives, such as comparative effectiveness research, that strive to identify the most effective intervention for a specific health issue. In the second presentation, Ronald Chen, MD, MPH, Assistant Professor, Department of Radiation Oncology, University of North Carolina, discussed a study that compared conformal radiation, intensity-modulated radiation therapy (IMRT), and proton therapy.2 “Using SEER-Medicare data, we performed two direct comparisons of conformal radiation vs IMRT

and IMRT vs proton therapy. We gauged the side effects after receiving radiation, including bowel and urinary morbidity, hip fracture, and erectile dysfunction. We also examined whether patients required or received further cancer treatments, which would be considered an indicator for possible cancer recurrence,” Dr. Chen said. “Because this was an observational study, there could be significant patient selection biases for different treatments. Therefore, to minimize any confounding factors, we used a sophisticated analytical method called propenSee Page 89 sity score adjustment,” Dr. Chen explained. Propensity scores provide a means of tweaking data for selection bias in observational studies of causal effects. In the first comparison, the investigators looked at conformal radiation vs IMRT. “We included patients who were diagnosed with prostate cancer between 2002 and 2006, so it was a fairly recent cohort of participants. They all had localized, potentially curable disease. Each arm had more than 6,000 patients,” Dr. Chen commented.

Rapid Adoption of IMRT “One of our first findings was the rapid and almost complete adoption of IMRT as the prominent radiation technique for prostate cancer in the United States. For instance, in 2000, almost all patients with prostate cancer who received radiation received conformal radiation, but in the following 8 years, IMRT usage increased significantly. In fact, today more than 95% of radiation treatments given for prostate cancer in the Medicare population are done

ASCOPost.com | MAY 15, 2012

PAGE 53

Journal Spotlight

with IMRT,” observed Dr. Chen, adding that this near full adoption of IMRT over conformal radiation was done without comparative effectiveness data. After analyzing the data, Dr. Chen reported that IMRT was associated with less additional cancer therapy compared with conformal radiation, suggesting better cancer control. IMRT also resulted in fewer bowel side effects and hip fractures, but slightly more erectile dysfunction. In the IMRT vs proton therapy comparison, the investigators found that proton therapy was associated with more bowel side effects compared to IMRT. There were no other significant differences in side effects or in the need for additional therapy

between the two therapies. “The results of both comparisons support the use of IMRT as the current standard radiation technique in prostate cancer. Currently, there is no evidence demonstrating that proton therapy is superior to IMRT,” concluded Dr. Chen.

■

Disclosure: Dr. Chen's study was funded by the Agency for Healthcare Research and Quality. Drs. Fontanarosa and Schrag reported no potential conflicts of interest.

References B:8.375” 1. Zhu J, Sharma DB, Gray SW, et al: T:7.63” Carboplatin and paclitaxel with vs withS:6.875” out bevacizumab in older patients with

advanced non-small cell lung cancer. JAMA 307:1593-1601, 2012. 2. Sheets NC, Goldin GH, Meyer AM, et al: Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307:1611-1620, 2012.

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

The truth hurts.

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

the healthcare system is broken. let’s put it back together. At Cardinal Health Specialty Solutions, we understand the financial complexities oncologists face. That’s why we’re working together with practices like yours to Specialty that Pharmaceutical Distribution develop solutions will enable you to offer the best treatment possible for GPO –Contracts Services reimbursement and reducing paperwork. your patients all while &optimizing By combining people with innovative technology, together we can Third intelligent Party Logistics Services Specialty Pharmaceutical Distribution help heal the system. Clinical Pathways GPO Contracts & Services RX Specialty Pharmacy Specialty Pharmaceutical Distribution Third Party Logistics Services

Cardinal HealtH SpeCialty SolutionS

We help healthcare professionals their practices by offering: Web-based Decisionstrengthen Support Tools GPO Contracts & Services

Clinical Pathways

Scientific & Regulatory Consulting Specialty Pharmaceutical Distribution Specialty Pharmaceutical Distribution

Third Party Logistics Services RX Specialty Pharmacy Specialty Pharmacy Healthcare Analytics & Marketing Communications GPO Contracts & Services Clinical Pathways Clinical Pathways GPO Contracts & Services Web-based Decision Support Tools Access Services Access Services Third Party Logistics Services

Clinical Pathways

Specialty & Pharmacy cardinalhealth.com/specialtysolutions Scientific Regulatory Consulting Web-based Decision Support Tools Healthcare Analytics & Marketing Communications

Specialty Pharmacy Web-based Decision Support Tools

Scientific & Regulatory Consulting Access Services Healthcare Analytics & Marketing Communications

The ASCO Post | MAY 15, 2012

PAGE 54

FDA Update

FDA Strengthens International Collaboration to Ensure Quality, Safety of Imported Products

DA Commissioner Margaret A. Hamburg, MD, recently released the agency’s Global Engagement Report, detailing the many activities and strategies FDA is using to transform from a domestic to a global public health agency. The report describes the steps the agency is taking to ensure that imported food, drugs, medical devices, and other regulated products meet the same rigorous standards for safety and quality as those manufactured domestically.

“As our world transforms and becomes increasingly globalized, we must come together in new, unprecedented, even unexpected, ways to build a public health safety net for consumers around the world,” said Dr. Hamburg. Global production of FDA-regulated goods and materials has exploded over the past decade and continues to grow. FDA-regulated products originate from more than 150 countries, 130,000 importers, and 300,000 foreign facilities. Each year from 2005 to 2011, imports of pharmaceutical products have increased at nearly 13% and device imports have grown more than 10%. More than 80% of the active pharmaceutical ingredients used to make medicines are imported.

Engagement Strategies The report outlines a variety of engagement strategies the FDA is using in partnership with other agencies, organizations, and coalitions around the world to strengthen global, regulatory capacity-building efforts; develop and harmonize science-based regulatory standards; increase awareness about the importance of regulatory systems; and share information and data globally to facilitate rapid identification of and response to public health emergencies. Through its international offices in Africa, Asia, Europe, Latin America, and the Middle East, the FDA is increasing its knowledge base about local regulatory systems and landscapes. The agency is also increasing the un-

derstanding of foreign governments and industry of FDA regulations and standards for products destined for U.S. consumers, and collaborating

to strengthen regulatory science and evidenced-based approaches to product safety and quality. All of this furthers the FDA’s implementation of its

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%),

global strategy, set forth in the agency’s special report, Pathway to Global Product Safety and Quality, released last year.

■

thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

ASCOPost.com | MAY 15, 2012

PAGE 55

FDA Update

Automated HER2 Immunohistochemical System Approved

eica Biosystems, a division of Leica Microsystems, announced that it has received premarket approval from the FDA for its Bond Oracle HER2 IHC System, a semi-quantitative immunohistochemical assay to determine human

epidermal growth factor receptor 2 oncoprotein status in formalin-fixed, paraffinembedded breast cancer tissue processed for histologic evaluation following automated staining on the BOND-MAX slide-staining instrument. The system is

indicated as an aid in the assessment of patients for whom trastuzumab (Herceptin) treatment is being considered. In clinical trials, the Leica Bond Oracle HER2 IHC System achieved 2�� ×�� 2 concordance of 87.6% and a posi-

INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical beneﬁt such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

tive agreement of 93.8% with the Abbott Molecular PathVysion HER2 DNA Probe kit, considered the gold standard for assessment of HER2 status. Full automation of HER2 IHC testing facilitates the delivery of consistent results.

■

The ASCO Post | MAY 15, 2012

PAGE 56

FDA Update

FDA Reminds Public about Potential for Life-threatening Harm from Accidental Exposure to Fentanyl Patches

he FDA has issued a statement reminding patients, caregivers, and health-care professionals of the importance of appropriate storage, use,

application, and disposal of fentanyl transdermal systems (including Duragesic and generic products) to prevent potential life-threatening harm from

accidental exposure to the active ingredient, fentanyl. Recently, FDA evaluated a series of 26 cases of pediatric accidental expo-

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients

sures to fentanyl patches reported over the past 15 years. Of these 26 cases, 10 resulted in death and 12 in hospitalization; 16 occurred in children 2 years

with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8) Cosmos Communications 718.482.1800

ASCOPost.com | MAY 15, 2012

PAGE 57

FDA Update

old or younger. Young children are at particular risk of accidental exposure to fentanyl patches. Their mobility and curiosity provide opportunities for them to find lost patches, take improperly discarded patches from the trash, or find improperly stored patches, all of which

may result in patches being placed in their mouths or sticking to their skin. Additionally, young children are at risk of exposure when being held by someone wearing a partially detached patch, which can then transfer to the child. As part of a broader public awareness campaign about the proper dis-

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

posal of medications in 2011, FDA advised consumers on the proper disposal of fentanyl patches when they are no longer needed. FDA recommends that the adhesive side of the patch should be folded together and then the patch should be flushed down the toilet.

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures Cosmos Communications 718.482.1800

Health-care professionals are urged to educate their patients and their caregivers about the appropriate use and disposal of fentanyl patches. Cases of accidental exposure should be reported to FDA's MedWatch Safety Information and Adverse Event Reporting Program.

■

The ASCO Post | MAY 15, 2012

PAGE 58

FDA Update

FDA Strengthens Monitoring of Postapproval Drug Safety

strengthened and modernized postmarket drug safety program has resulted in a substantial improvement in the FDA’s oversight of drugs once they reach the American public, according to a new report released by

the agency’s Center for Drug Evaluation and Research (CDER). The report, Advances in FDA’s Safety Program for Marketed Drugs, describes new scientific tools and enhanced capabilities that give the same priority to postmar-

(AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

ket drug safety monitoring as to premarket drug review. The report says CDER is also delivering earlier, more effective drug safety information to the public to protect patients from harm. In 2011, CDER is-

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. • Patients should be instructed to read the patient insert carefully. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.003/PPI.003 09/11

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

sued 68 drug safety communications— up from 39 in 2010. The communications provide early information to patients and health-care professionals about drug safety issues as they emerge. “Our oversight of the safety of marketed drugs has changed significantly over the past few years,” said Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research. “This report shows that the quality, accountability, and timeliness of postmarket drug safety decisions have been enhanced, and our public communication of this information is more effective.” CDER introduced a comprehensive plan to strengthen drug safety in 2004 that was further enhanced with the passage of the FDA Amendments Act of 2007. This legislation authorized major changes to how the safety of drugs would be monitored once on the market, giving FDA the authority to require postmarket studies of drug safety concerns and drug labeling changes when new drug safety information is identified.

Drug Safety Activities Since 2008, the FDA has:  ■■ required 65 safety-related labeling changes, in addition to the safety labeling changes done voluntarily by drug manufacturers ■■ required manufacturers to implement a variety of Risk Evaluation and Mitigation Strategies (REMS) to ensure that the benefits of a drug or biological product outweigh its risks. FDA has required 64 complex REMS, in addition to a number of less complex REMS. Some of these REMS include plans for restricted access to certain highrisk products. ■■ doubled staff in CDER’s Office of Surveillance and Epidemiology from 123 in 2007, to 245 in 2012. This group of drug safety specialists includes physicians, pharmacists, epidemiologists, and other professionals. ■■ established specific safety positions within each of the Office of New Drugs’ 18 divisions that review applications for new drugs. Each division’s deputy director for safety and safety regulatory project manager helps ensure the appropriate handling of postmarket safety issues related to the drugs approved within their division.

■

Cosmos Communications 718.482.1800

ASCOPost.com | MAY 15, 2012

PAGE 59

News

More New Data Support Use of Daily Aspirin to Prevent Cancers By Caroline McNeil

hree new studies have added data to the growing evidence that low-dose, daily aspirin helps prevent colorectal cancer and other malignancies and may be useful in preventing metastases as well.1-3 Coming on the heels of other recent studies, the results appear to strengthen the case for using aspirin to prevent colorectal cancer in the general population, as it is now used by many to prevent coronary heart disease. But conflicting evidence from two large randomized trials (which looked at alternate-day aspirin, not daily aspirin), plus concern about aspirin’s side effects, may keep population recommendations on hold for a while longer. In a commentary accompanying the

new studies,4 Andrew T. Chan, MD, of Massachusetts General Hospital and Harvard Medical School said that the additional data, though significant, still fall short of the level needed to change formal guidelines (see sidebar). The evidence is “gradually tipping toward the point of view where aspirin seems to make sense for many in the general population,” Dr. Chan said in an interview. “But the state of the data is still not definitive.”

Three Studies In the three new studies, which appeared online in The Lancet and Lancet Oncology on March 21, Peter M. Rothwell, MD, PhD, at Oxford University and colleagues reviewed and

Aspirin and Cancer Prevention ■■ New studies add to the growing evidence that low-dose, daily aspirin helps prevent colorectal cancer.

■■ The latest studies also suggest that it reduces the risk of other cancers and of metastatic cancer.

■■ Despite the additional data, there is still no definitive evidence that aspirin’s benefits outweigh its risks in the general population. Recommendations for aspirin use need to be individualized and to take into account its benefits and risks for both cardiovascular disease and cancer prevention.

analyzed data from trials and observational studies of daily aspirin to prevent coronary heart disease. In one of The Lancet studies,1 they looked at the short-term effects of daily aspirin in 51 randomized trials of aspirin (any dose and duration) vs no aspirin, finding that aspirin significantly reduced mortality from any cancer. Its effects were especially strong after 5 years. Aspirin increased the risk of major bleeding—its major side effect—but only for the first 3 years of follow-up. In a companion study in The Lancet,2 Dr. Rothwell and colleagues looked at the risk of metastases in five large randomized trials among participants who had newly diagnosed cancers during the trial follow-up period. They found that aspirin significantly reduced the risk. And in a third study, published in Lancet Oncology,3 Dr. Rothwell and coauthor Annemijn Algra, BSc, looked at the effects of aspirin on long-term incidence and metastases in observational studies and compared the results to those of randomized trials. In observational studies, regular aspirin use was associated with a lower incidence of colorectal cancer and mortality related to the disease. Regu-

Peter M. Rothwell, MD, PhD

lar aspirin use also was associated with fewer cancers that have produced distant metastases. The results correlated well with those of randomized trials and, like the results in the two Lancet studies, were statistically significant. These are novel contributions, Dr. Chan said. “They suggest that aspirin may have an effect in the later stages of carcinogenesis as well as the earliest stages of tumor initiation.” In earlier studies, also published in The Lancet, Dr. Rothwell and colleagues have shown that daily aspirin taken to prevent cardiovascular disease reduced deaths from colorectal cancer after 7 to 8 years’ follow-up and deaths from several other cancers including gastrointestinal, lung, and brain cancers, after 5 years. continued on page 60

Narratives in Oncology A Special Supplement to The ASCO Post Watch for your special supplemental edition of The ASCO Post, “Narratives in Oncology,” coming soon! Narratives in Oncology is a special edition of The ASCO Post and features personal profiles about oncology leaders who have made an important contribution to the clinical research and care of patients with cancer. This issue will be the first of a planned annual special edition of The ASCO Post profiling leaders in oncology. Watch for your copy of Narratives in Oncology mailing with the June 15, 2012, issue of The ASCO Post. Or visit The ASCO Post at ASCO's Annual Meeting, booth 6068, for your advance copy of this limited special edition.

The ASCO Post | MAY 15, 2012

PAGE 60

News

Aspirin and Cancer

EXPERT POINT OF VIEW

continued from page 59

Guidelines under Review In the wake of these reports, some groups are reviewing their current guidelines, which recommend aspirin to prevent coronary heart disease but not colorectal cancer. “We’re all aware of this issue,” said Virginia Moyer, MD, MPH, who chairs the United States Preventive Services Task Force. The Task Force, which reviews all its guidelines on a rotating schedule, will be looking at this one, though no date has been set. “It remains on the active topic list,” Dr. Moyer wrote in an e-mail, “and will be updated, but unfortunately, it’s waiting in line with a number of other important updates.” In the meantime, analysis continues in two large studies that did not show any benefit for aspirin in colorectal cancer after 10 to 12 years’ follow-up. Both the Women’s Health Study and the Physicians’ Health Study looked at aspirin taken every other day rather than daily. New data from these large and rigorous studies, when available, are expected to have a substantial in-

s it time to recommend aspirin for cancer prevention? “It’s the question we are asking,” said Andrew T. Chan, MD, Massachusetts General Hospital and Harvard Medical School, who wrote a commentary accompanying three new studies in The Lancet and Lancet Oncology. The studies, by Peter M. Rothwell, MD, of Oxford University, and colleagues, add new data to suggest that daily aspirin reduces the risk of colorectal cancer and other malignancies, including distant metastases (see article). The evidence in favor of aspirin is compelling, Dr. Chan said in an interview, but there are still some notable barriers to recommending it in the general population. One of these is the lack of supporting evidence, so far, from the Women’s Health Study and the Physicians’ Health Study. With tens of thousands of participants who have been followed for more than a decade, these are the largest primary prevention studies to have included cancer incidence as a prespecified

fluence on the evolution of future guidelines.

■

Virginia Moyer, MD, MPH

Disclosure: Dr. Rothwell has received honoraria for talks, advisory boards, and clinical trial committees from AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi-Aventis/ Bristol-Myers Squibb and Servier, and is on the executive committee of the ARRIVE Trial. Dr. Chan has served as a consultant to Bayer HealthCare and Millennium Pharmaceuticals. Dr. Moyer reported no potential conflicts of interest.

endpoint. Their findings have shown that aspirin is associated with a reduced risk of cardiovascular disease, but not colorectal cancer or overall cancer. Longer-term analyses of these data continue. Neither the Women’s Health Study nor the Physicians’ Health Study was included in The Lancet analyses, because their participants took aspirin on alternate days rather than every day. That makes them outlier studies, Dr. Chan said, “but important outlier studies.”

Individualize Recommendations The other major obstacle to population recommendations for regular aspirin use is the risk of bleeding, a sometimes serious, occasionally even fatal, side effect. “I don’t think we can make a population recommendation until there is a more formal assessment of the risks and benefits that also accounts for the limitations of the data at hand,” Dr. References 1. Rothwell PM, Price JF, Fowkes FGR, et al: Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: Analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. March 21, 2012 (early release online). 2. Rothwell PM, Wilson M, Price JF, et al: Effect of daily aspirin on risk of cancer metastasis: A study of incident cancers

Andrew T. Chan, MD

Chan said. “Based on the current state of the evidence, it remains prudent to individualize recommendations.” Most important, there needs to be a discussion by doctors and patients of possible benefits and possible risks, and that discussion needs to include both cancer and cardiovascular disease, he said. “It’s very difficult for physicians and patients to discuss aspirin for each disease in isolation.”

■

Disclosure: Dr. Chan previously served as a consultant to Bayer Healthcare and Millennium Pharmaceuticals.

during randomised controlled trials. Lancet. March 21, 2012 (early release online). 3. Algra AM, Rothwell PM: Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. March 21, 2012 (early release online). 4. Chan AT, Cook NR: Are we ready to recommend aspirin for cancer prevention? Lancet. March 21, 2012 (early release online).

Coming in Future Issues of The ASCO Post Comprehensive coverage of the 2012 ASCO Annual Meeting, including this year's plenary program:

■■ Abstract LBA1: Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. Kimberly L. Blackwell, author/speaker. ■■ Abstract 2: Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors (AOD). Martin J. Van Den Bent, author/speaker.

■■ Abstract 3: Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. Michael E. Williams, author/speaker. ■■ Abstract 4: Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial. Maha Hussein, author/speaker.

Visit The ASCO Post online at ASCOPost.com

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates: Taking targeted therapy to the next level ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent. ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.1-5

Monoclonal antibody

Stable linker

Cytotoxic agent

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

designed to allow an ADC to remain inactive while in circulation1,2,7-9

incorporated into an ADC, may be up to 1000-fold more potent than currently used chemotherapies7

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent.6

Visit www.ResearchADCs.com to learn more References:

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptidelinked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.

The ASCO Post | MAY 15, 2012

PAGE 62

Expert’s Corner Supportive Care

New Research Shows Promise in Cachexia, a Persistent Clinical Challenge A Conversation with Alfred L. Goldberg, PhD By Ronald Piana

Alfred L. Goldberg, PhD

n the late 1980s, researchers led by Alfred L. Goldberg, PhD, first isolated the large protein complexes now called 26S proteasomes, which are the sites where most cellular proteins are degraded back to amino acids. Protein degradation by the proteasome pathway is critical in regulating many processes—especially cell growth—and, thus, its proper function is important in the development of certain malignancies. Consequently, some blood cancers (eg, multiple myeloma) can be successfully treated with the inhibitor of the proteasome, bortezomib, and other such inhibitors are in clinical trials. More recent work by Dr. Goldberg and collaborators has led to a promising understanding of the mechanisms of cachexia, one of the most persistently troublesome and heretofore untreatable symptoms of cancer. Dr. Goldberg, Professor of Cell Biology at Harvard Medical School, spoke to The ASCO Post about possible breakthroughs in understanding and treating cachexia.

Recent Insights What have we learned over the past decade about cachexia that might help translate into treatment? The fundamental and most debilitating aspect of cachexia is muscle atrophy, which we now know results from very specific biochemical changes in the muscle. It is not simply a nonspecific effect from not eating sufficient nutrients, resulting from anorexia often seen in patients, or physical inactivity. Instead, cachexia develops through a specific set of biochemical adaptations in the muscle, including a well-defined set of changes in gene transcription that lead to an acceleration of muscle protein breakdown.

In the past, cachexia was largely ignored both by the oncology community and investigators interested in muscle or metabolic regulation. The major new insights into this process have come from studies in animal models. There is now a consensus that in cancer cachexia and a variety of other catabolic states (from severe burns to cardiac or renal failure), muscles express a specific set of atrophy-associated genes, which we have named “atrogenes” because they are turned on or off similarly in many conditions when muscles atrophy. For example, atrogene expression may be seen in bedridden patients with unused muscles, cases of nerve injury, fasting or tumorbearing animals, septic individuals, and so forth.

reduce or turn off these degradative processes.

Myostatin and Activin A In 2010, you were part of an Amgen team that published a study on cachexia in Cell.1 Can you describe how that work coincides with current studies? I was only a consultant on that study, which was led by H.Q. Han, MD, PhD, who once was a student in my lab. His team has been investigating ways to reverse cachexia. Their studies and several other research efforts in the pharmaceutical industry build upon a key regulator of muscle size, called myostatin. More than 10 years ago, work by Se-Jin Lee, PhD, at Johns Hopkins University showed that myostatin is a factor normally produced by muscle that con-

In many cases it appears to actually be the cachexia that causes death rather than the cancer itself. —Alfred L. Goldberg, PhD

vented them from acting on the muscle and thus blocked the induction of atrogenes, the accelerated protein breakdown, and the loss of muscle mass. This beneficial effect was notable because the tumor continued to grow and release catabolic factors. It later became clear that the soluble receptor was not only soaking up myostatin but was actually binding a closely related molecule called activin A, which the intestinal tumor had been making in large amounts. Activin A had been known for some time for its role in regulating the female menstrual cycle, but it also appears to be one of the cancer-released cachexiainducers. In addition to its other normal functions, it is highly catabolic to muscle. The idea that tumors were releasing this cytokine and that it was catabolic to muscle had not been appreciated. There are a number of cancers that produce activin A in large amounts, so this is a significant finding that should stimulate appreciable future work.

Potential Clinical Impact This common transcriptional program functions in muscles in a diversity of catabolic states to trigger muscle protein degradation and consequently the patient’s negative nitrogen balance. Although the factors signaling this response may vary in these different catabolic states (and there seem to be a number of cytokines that trigger the atrogene program in muscle), the consequences within the muscle are the same—an acceleration of protein breakdown, which leads to a loss of the contractile apparatus (and thus strength) and of mitochondria (and thus endurance). We believe this process in muscle, though deleterious when prolonged, actually evolved as a helpful adaptation to fasting or disease. For example, before medicine had evolved to be truly helpful to the patients, the breakdown of dispensable muscle proteins provided the fasting or diseased individual with a source of amino acids to convert into glucose or for wound repair, which is especially valuable when the individual may be too sick to forage for food. But presently in chronic disease, the continual breakdown of muscle proteins is certainly undesirable in patients, and now a number of efforts are underway to develop therapies to

tinually inhibits further muscle growth. Animals that lack myostatin have much more (up to twice as much) muscle mass. Conversely, excessive myostatin can induce a dramatic loss of muscle mass, which raises the obvious question: What is the physiologic role of myostatin or related polypeptides, both normally and in cachexia? Is this line of scientific inquiry being actively looked at? Using Dr. Lee’s work as a foundation, several companies are developing antagonists for myostatin or related TGF-family members that may be used to build up muscle in patients with cancer cachexia, bedridden patients, and perhaps in myopathies. This research is very promising, as illustrated by our paper,2 which showed that if an antagonist to myostatin can slow the process of cachexia in tumor-bearing mice or reverse the process completely, even in severely cachectic animals. In tumor-bearing mice that had lost over 10% of body weight, a single injection of a soluble decoy receptor that mimics the receptor on the muscle, but is floating free in the circulation, was enough to reverse the loss of weight and strength. By soaking up the myostatin and related cytokines, this treatment pre-

Did this team of researchers find anything that might influence clinical behavior down the line? Yes, there was one dramatic finding. The studies of Han’s group showed that when the cachexia process is reversed and muscle builds up again, the tumorbearing animals lived much longer even though tumor growth was unchanged.2 So, this is the first direct experimental evidence indicating the importance of cachexia in determining the host’s ability to withstand the impact of the cancer. Hopefully someday, in addition to treating the tumor, the oncologist will also be able to treat the host, because the cachexia itself appears to be highly deleterious and to affect the patient’s longevity. In other words, in many cases it appears to actually be the cachexia that causes death rather than the cancer itself. In light of this and other work, is cachexia getting enough attention in the medical community? Not yet in the medical community, but certainly there is growing interest among researchers. A growing number of academic investigators and a number of companies have finally recognized that cachexia is very damaging to patients on multiple levels in many disease states, and acknowledge a rationale for

ASCOPost.com | MAY 15, 2012

PAGE 63

Expert’s Corner

drug development. There is even a new specialized Journal of Cachexia, Sarcopenia and Muscle, and a Society for Sarcopenia, Cachexia and Wasting Disease that has annual meetings. This area used to be just the province of nurses, nutritionists, and others interested in supportive care, but now there’s growing involvement from industry and basic investigators in efforts to fully understand the mechanisms behind cachexia. The ultimate goal is to develop anticachexia therapies that could be used together with chemotherapy, and would also have multiple applications in medicine aside from patients with cancer.

cal trials, and I believe they will help tumor-bearing patients—not just by increasing muscular strength and thus improving quality of life, but also by enhancing the patient’s ability to withstand the disease process and the effects of cancer therapies through mechanisms we still do not

understand. This important therapeutic opportunity has been generally ignored, largely because of a lack of understanding of the underlying biology.

■

Disclosure: Dr. Goldberg was a consultant to Amgen on the cachexia study discussed in this article.

References 1. Tisdale MJ: Reversing cachexia. Cell 142:511-512, 2010. 2. Zhou X, Wang JL, Lu J, et al: Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142:531-543, 2010.

What you’re looking for is

right in front of you.

There is a unique situation facing physicians treating patients with advanced metastatic colorectal cancer (mCRC) today. For several years, 5-FU together with f Any last thoughts on the clinical issue acid has been a foundation of multi-agent treatments in mCRC. Evidence-based chemotherapy studies performed by the Mayo Clinic and the North Central Ca Treatment Group (NCCTG) have long-established the value of folinic acid in enhancing 5-fluorouracil (5-FU) treatment. Results from these studies have shown of cachexia? The recent insights discussedthat folinic acid enhances the therapeutic and toxic effects of 5-FU. Based on studies such as these, a multi-agent approach that includes fo here and others are finally stimu- 5-FU activity has become standard practice. As a pharmacologically active isomer of folinic acid, FUSILEV fits with 5-FU in the palliative acid to potentiate lating a great deal of interest in thetreatment of advanced mCRC. The rationale for adding folinic acid into 5-FU treatment derives from biochemical unders cachectic process that had been, for or modulating the anti-tumor behavior of fluoropyrimidines. The addition of folinic acid augments the clinic of its action in potentiating the most part, ignored by cancer activity of 5-FU by forming a stable ternary complex with FdUMP and thymidylate synthase. The National Comprehensive Cancer Netwo researchers and clinicians. Natutreatment guidelines for advanced mCRC support the use of folinic acid. 5-FU treatments recommended in the NCCN guidelines for mCRC all inc rally, oncologists focus (NCCN) their efforts of racemic folinic acid, commonly known in the United States as leucovorin, have not been resolved in over 4 on tumor shrinkage or elimination; folinic acid. Supply issues however, I think we’re getting a clear months—since December 2008. As an alternative to leucovorin, NCCN guidelines for mCRC treatment recommend levoleucovorin picture that building up the patient’s used at one-half the conventional dose of leucovorin. As recently as April 2012, leucovorin manufacturers continue to report suspended manufa strength seems to better enable him delays, and inability to produce to demand. Sustained and unresolved leucovorin supply issues may create logistical challenges that can resu to handle the challenges of cancer. in changes to clinical practice. According to a 2011 American Hospital Association survey, 82% of hospitals report they have delayed patient Much remains to be learned about to provide the patient with the recommended treatment. Ther the metabolism of the tumor-bear- result of a drug shortage and more than half were not always able mCRC without compromising an intended treatment as a resul ing patient and the pathophysiologic another choice for delivering 5-FU treatment for patients with advanced issues. The pharmacologically active isomer of folinic acid is readily available in the form of FUSILEV (levoleucovorin) for injection. T mechanisms of cancer cachexia. These promising myostatin-relat- is potential for dosing errors when interchanging leucovorin and levoleucovorin. FUSILEV is the levoisomeric form of d,l-leucovorin. FUSILEV is dosed ed therapies are now entering clini- at one-half the usual dose of conventional leucovorin. FUSILEV is FDA-approved for use in combination chemotherapy with 5-fluorouracil in the palliative treat patients with advanced metastatic colorectal cancer. FUSILEV continues to be in readily available supply. Learn how FUSILEV can fit your 5-FU treatment and FUSILEV has a practice. Sometimes the solution is right in front of you. unique J-code for FUSILEV is a folate analog FDA-approved for:

Closing Thoughts

reimbursement:

The ASCO Post Follow us on

Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of J0641 per 0.5 mg units patients with advanced metastatic colorectal cancer. of FUSILEV Important Safety Information: There is potential for dosing errors when interchanging leucovorin and levoleucovorin. FUSILEV is dosed at one-half the usual dose of the racemic form. Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. Levoleucovorin enhances the toxicity of fluorouracil. In addition, levoleucovorin may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. Allergic reactions were reported in patients receiving levoleucovorin. The most common adverse reactions (>50%) in patients with advanced CRC were diarrhea, nausea, and stomatitis. Please see Brief Summary on the adjacent pages. For full Prescribing Information visit FUSILEV.com. Order FUSILEV today: Call your wholesaler or specialty distributor or 1-877-FUSILEV (1-877-387-4538)

@ASCOPost Readily Available. Consistent Supply.

© 2012 Spectrum Pharmaceuticals, Inc. All Rights Reserved. May not be reproduced, altered, or distributed without express permission. SPECTRUM PHARMACEUTICALS, INC.® and FUSILEV® are registered trademarks of Spectrum Pharmaceuticals, Inc. and its subsidiaries. The Spectrum Pharmaceuticals logo and FUSILEV logo are trademarks owned by Spectrum Pharmaceuticals, Inc. and its subsidiaries. 0111-041600

The ASCO Post | MAY 15, 2012

PAGE 64

News

American Lung Association Provides Guidance on Lung Cancer Screening

he American Lung Association has released new interim guidelines to assist physicians, patients, and the public in their discussions about lung cancer screening. Devel-

oped by the American Lung Association’s Lung Cancer Screening Committee chaired by Jonathan Samet, MD, MS, from the University of Southern California, the report re-

views current scientific evidence on lung cancer screening and provides important guidance to physicians and the at-risk public about getting screened for lung cancer.

FUSILEV® (levoleucovorin) for Injection FUSILEV® (levoleucovorin) Injection Rx only BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE • FUSILEV® is a folate analog. • FUSILEV rescue is indicated after high-dose methotrexate therapy in osteosarcoma. • FUSILEV is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. • FUSILEV is indicated for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. 1.1 Limitations of Use • FUSILEV is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. 2 DOSAGE AND ADMINISTRATION 2.1 Administration Guidelines FUSILEV is dosed at one-half the usual dose of the racemic form. FUSILEV is indicated for intravenous administration only. Do not administer intrathecally. 2.2 Co-administration of FUSILEV with other agents Due to the risk of precipitation, do not co-administer FUSILEV with other agents in the same admixture. 4 CONTRAINDICATIONS FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. 5 WARNINGS AND PRECAUTIONS 5.1 Rate of Administration Because of the Ca++ content of the FUSILEV solution, no more than 16 mL (160 mg of FUSILEV) should be injected intravenously per minute. 5.2 Potential for Enhanced Toxicity with 5-Fluorouracil FUSILEV enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must

Low-dose computed tomography is a promising clinical strategy for the detection of presymptomatic lung cancer in individuals at the highest risk for lung cancer,

be lower than usually administered. Although the toxicities observed in patients treated with the combination of FUSILEV and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination. In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-FU alone or 5-FU in combination with 200 mg/m2 of d,l-leucovorin and 20% when treated with 5-FU in combination with 20 mg/m2 of d,l-leucovorin. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose d,l-leucovorin/5-FU combination than in patients treated with the high dose combination – 11% versus 3%. Therapy with FUSILEV and 5-FU must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In an additional study utilizing higher weekly doses of 5-FU and d,l-leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity. Seizures and/or syncope have been reported rarely in cancer patients receiving d,l-leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors. However, a causal relationship has not been established. 5.3 Potential for interaction with trimethoprimsulfamethoxazole The concomitant use of d,l-leucovorin with trimethoprimsulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebocontrolled study. 6 ADVERSE REACTIONS 6.1 Clinical Studies in High-Dose Methotrexate Therapy Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high dose methotrexate 12 grams/m2 followed by FUSILEV rescue for osteosarcoma in 16 patients age 6-21. Most patients received FUSILEV 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate.

Table 1 Adverse Reactions with High-Dose Methotrexate Therapy Body System/Adverse Reactions

Gastrointestinal Stomatitis Vomiting Nausea Diarrhea Dyspepsia Typhlitis Respiratory Dyspnea Skin and Appendages Dermatitis Other Confusion Neuropathy Renal function abnormal Taste perversion Total number of patients Total number of courses

11185 Fusilev 0911 CA Ad r4v2.indd 1

Number (%) of Patients with Adverse Reactions (N =16) All Grade 3+

Number (%) of Courses with Adverse Reactions (N =58) All Grade 3+

6 (37.5) 6 (37.5) 3 (18.8) 1 (6.3) 1 (6.3) 1 (6.3)

1 (6.3) 0 0 0 0 1 (6.3)

10 (17.2) 14 (24.1) 3 (5.2) 1 (1.7) 1 (1.7) 1 (1.7)

1 (1.7) 0 0 0 0 1 (1.7)

1 (6.3)

1 (1.7)

1 (6.3)

1 (1.7)

1 (6.3) 1 (6.3) 1 (6.3) 1 (6.3)

0 0 0 0

1 (1.7) 1 (1.7) 3 (5.2) 1 (1.7)

0 0 0 0

9 (56.3) 25 (43.1)

2 (12.5) 2 (3.4)

8/16/11 4:34 PM

ASCOPost.com | MAY 15, 2012

PAGE 65

News

reducing deaths by 20% compared to chest x-ray, according to findings from the National Lung Cancer Screening Trial (NLST) recently released by the National Cancer Institute.1 These findings have led to widespread use of CT for lung cancer screening.

Criteria for Lung Cancer Screening The American Lung Association’s Lung Cancer Screening Committee developed recommendations to facilitate decision-making, particularly for those with chronic lung diseases, while research on CT screening

continues. Based on the NLST findings, the Lung Association recommends lung cancer screening with low-dose CT scans for people who meet the criteria, which include the following: current or former smokers (aged 55 to 74 years), with a smoking history of at least 30 packNorman H. Edelman, MD

The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high dose methotrexate with FUSILEV rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Clinical Studies in Combination with 5-FU in Colorectal Cancer A randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with advanced colorectal

cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. The following table presents the most frequent adverse reactions which occurred in patients in the 2 treatment arms.

Table 2 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm Adverse Reactions Adverse Event N (%) Gastrointestinal Disorders Stomatitis Diarrhea Nausea Vomiting Abdominal Pain1 General Disorders Asthenia/Fatigue/Malaise Metabolism and Nutrition Anorexia/Decreased Appetite Skin Disorders Dermatitis Alopecia 1

Levoleucovorin/5FU n=318 Grade 1-4 Grade 3-4

d,l-Leucovorin/5FU n=307 Grade 1-4 Grade 3-4

229 (72%) 222 (70%) 197 (62%) 128 (40%) 45 (14%)

37 (12%) 61 (19%) 25 (8%) 17 (5%) 10 (3%)

221 (72%) 201 (65%) 186 (61%) 114 (37%) 57 (19%)

44 (14%) 51 (17%) 26 (8%) 18 (6%) 10 (3%)

91 (29%)

15 (5%)

99 (32%)

34 (11%)

76 (24%)

13 (4%)

77 (25%)

5 (2%)

91 (29%) 83 (26%)

3 (1%) 1 (0.3%)

86 (28%) 87 (28%)

4 (1%) 3 (1%)

Includes abdominal pain, upper abdominal pain, lower pain, lower abdominal pain, and abdominal tenderness

6.3 Postmarketing Experience Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where FUSILEV was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where FUSILEV was a suspected or interacting medication, there were 40 occurrences of “possible allergic reaction”. In an analysis where calcium levoleucovorin was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events). 7 DRUG INTERACTIONS Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs. Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. FUSILEV increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)].

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from FUSILEV, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Please see Clinical Studies (14) in the Package Insert 8.5 Geriatric Use Clinical studies of FUSILEV in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. In the NCCTG clinical trial of FUSILEV in combination with 5-FU in advanced colorectal cancer, adverse reactions were consistent with 5-FU related toxicity and were similar for patients age 65 and older and for patients younger than age 65. 10 OVERDOSAGE No data are available for overdosage with FUSILEV.

■

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. It is not known whether FUSILEV can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with FUSILEV. FUSILEV should be given to a pregnant woman only if clearly needed.

11185 Fusilev 0911 CA Ad r4v2.indd 2

years (that is, an average of a pack a day for 30 years) and with no history of lung cancer. The Lung Association recognizes that while low-dose CT scans may save lives, screening for lung cancer should not be recommended for everyone, as many known and unknown risks may be associated with the screening and subsequent medical evaluation. “Never starting smoking and quitting smoking still remain the best ways to prevent lung cancer,” said Norman H. Edelman, MD, Chief Medical Officer of the American Lung Association. Other recommendations made in ALA’s report include referring patients to facilities that have experience in conducting low-dose CT scans and that employ multidisciplinary teams to provide comprehensive follow-up. The Lung Association also urges hospitals and screening centers to establish ethical policies for advertising and promoting lung cancer CT screening services. Albert Rizzo, MD, Board Chair for the American Lung Association, said, “Our hope is that this report will See Page 89 guide the public on this very important personal and public health issue. We believe that the report and the educational materials that will stem from it will be invaluable to the tens of millions at risk for lung cancer.” The full American Lung Association Interim Report on Lung Cancer Screening and related educational materials are available at http://www.lung.org/lung-disease/ lung-cancer/lung-cancer-screeningguidelines.

05 August 2011 0102-005901

8/16/11 4:34 PM

Reference 1. The National Lung Screening Trial Research Team: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395409, 2011.

The ASCO Post | MAY 15, 2012

PAGE 66

Journal Spotlight Genitourinary Oncology

Chemoradiation with Fluorouracil and Mitomycin Reduces Recurrence of Muscle-invasive Bladder Cancer By Matthew Stenger

adiotherapy is an alternative to surgery in muscle-invasive bladder cancer, particularly in less-fit patients. However, it is associated with high rates of incomplete response or recurrence, with salvage surgery often being required. Although synchronous chemoradiotherapy has improved local control and survival in some cancers, there are few data from randomized trials of this approach in bladder cancer. One relatively small trial of chemoradiotherapy with cisplatin in this setting showed improved survival without pelSee Page 89 vic disease progres1 sion. However, cisplatin as a radiosensitizer may not be optimal for patients with bladder cancer, since many patients undergoing radiotherapy have renal impairment or poor performance status. As recently reported in The New England Journal of Medicine by James and colleagues for the BC2001 investigators, the UK phase III Bladder

Cancer 2001 (BC2001) trial showed that the addition of chemotherapy with fluorouracil (5-FU) plus mitomycin to radiotherapy significantly improved locoregional control of bladder cancer without significantly increasing adverse events.2

Design and Patient Population In this unblinded trial, 360 patients with muscle-invasive bladder cancer from 45 centers in the United Kingdom were randomly assigned to receive radiotherapy at 55 Gy in 20 fractions over 4 weeks or 64 Gy in 32 fractions over 6.5 weeks, with (n = 182) or without (n = 178) chemotherapy consisting of 5-FU at 500 mg/m2 per day given as a continuous infusion during fractions 1 to 5 and 16 to 20 (10 days total) plus mitomycin at 12 mg/m2 given as IV bolus on day 1.2 The primary endpoint was locoregional disease-free survival (defined as survival free of recurrence in the pelvic nodes or bladder), a second primary tumor, or death. Patients had to have histologically

confirmed stage T2 to T4a adenocarcinoma or transitional or squamous cell carcinoma with no lymph node involvement or metastasis, WHO performance status of 0 to 2, white blood cell count > 4,000/mm3, platelet count > 100,000/mm3, glomerular filtration rate >�� 25�� mL/min, �� and serum bilirubin and aminotransferase levels < 1.5 times the upper limit of normal. (In a separate randomization, patients were allocated to whole-bladder or modified-volume radiotherapy; results of this comparison were not reported in the current analysis.) Patients had a median age of 72 years. For the chemoradiotherapy group vs the radiotherapy group, 82% vs 79% were male, 63% vs 66% had performance status of 0, 85% vs 80% had pathologic stage 2 disease, 97% vs 98% had transitional cell carcinoma, 57% vs 53% had complete cystoscopic resection, 26% vs 38% had incomplete resection, 3% vs 2% had no resection, 12% vs 5% had biopsy (P = .01), 26% vs 29% had residual mass after cystoscopic resection, 31% vs 34% had

planned neoadjuvant therapy, and 39% vs 40% were planned to have the radiotherapy schedule consisting of 55 Gy in 20 fractions.

Key Results Patients were followed for a median of 69.9 months. Two-year recurrencefree survival was 67% with chemoradiotherapy vs 54% with radiotherapy, representing a 32% reduction in risk of recurrence with chemoradiotherapy (HR = 0.68, P = .03). Over 72 months of follow-up, risk of recurrence was reduced by 34% with chemoradiothera= .03), after adjustpy (HR = 0.66, P �� ment for neoadjuvant chemotherapy, age, radiotherapy dose, tumor stage, performance status, and tumor grade. Relapses consisted of invasive bladder cancer in 11% of patients in the chemoradiotherapy group vs 19% in radiotherapy group, noninvasive bladder cancer in 14% vs 17%, and pelvic node relapse in 5% vs 7%. Over 72 months, chemoradiotherapy was also associated with a significant 43% reduction in risk

EXPERT POINT OF VIEW

n an editorial accompanying the recently reported UK phase III Bladder Cancer 2001 (BC2001) trial, Shipley and Zietman, from Massachusetts General Hospital and Harvard Medical School, point out that this trial shows that “the addition of a very tolerable regimen of chemotherapy to radiotherapy cures significantly more patients than radiotherapy alone and at a rate similar to those in the best cystectomy series.” 1,2 It is noted that many patients with bladder cancer do not currently receive potentially curative therapy, including some 35% of patients aged 70 to 80 years and 55% of those aged 80 years or older, and that a large majority of such patients would probably tolerate the regimen used in BC2001. Indeed, this approach can likely be recommended for younger, healthier patients with invasive disease if it can be shown that long-term survival is not compromised and if patients accept that should salvage cystectomy be required, it may be a more challenging procedure after chemoradiotherapy.

In this regard, long-term followup of series of patients with invasive bladder cancer indicate similar 10year rates of disease-free survival of 55% to 60% irrespective of whether initial treatment was radical cystectomy or chemoradiotherapy, with rates of complications of salvage surgery

mors and cancer-specific survival after radiotherapy but not after cystectomy. Analysis of the effect of MRE11 expression on outcome after chemoradiotherapy with 5FU/mitomycin is planned in both an NCI Bladder Cancer Task Force project and a future BC2001 analysis.

Cystectomy will always remain part of an organsparing approach, but this trial shows that as a primary treatment, it can now be regarded as one of several options for the patient. —William Shipley, MD, and Anthony Zietman, MD

being somewhat higher with chemoradiotherapy, but not as high as predicted. Additional factors may eventually play a role in deciding between initial cystectomy and chemoradiotherapy. It recently has been found that high expression of the MRE11 protein (which is active in cellular response to radiotherapy) predicted improved eradication for bladder tu-

tients, who tend to have better renal function and overall health. Finally, the commentators state “The development of organ-sparing procedures in breast and prostate cancer was promoted by vocal patient advocacy groups with the use of the Internet and social networking. We anticipate that the publication of this important study will help patients with bladder cancer to find their voice. Cystectomy will always remain part of an organ-sparing approach, but this trial shows that as a primary treatment, it can now be regarded as one of several options for the patient.”

■

Disclosure: Drs. Shipley and Zietman reported no potential conflicts of interest.

Historical Perspective According to the commentators, given the important history of cisplatin as a radiosensitizer in invasive bladder cancer, its use should not be overturned rashly. Until a direct comparison of chemotherapy regimens is performed, it may be that physicians will use 5-FU/mitomycin in elderly patients and cisplatin in younger pa-

References 1. James ND, Hussain SA, Hall E, et al: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366:1477-1488, 2012. 2. Shipley WU, Zietman AL: Old drugs, new purpose—bladder cancer turning a corner. Editorial. N Engl J Med 366:15401541, 2012.

ASCOPost.com | MAY 15, 2012

PAGE 67

Journal Spotlight

for invasive recurrence (HR = 0.57, P = .01), and a nonsignificant reduction in risk for death (HR = 0.82, P = .16), with separation of the overall survival curves starting at approximately 2 years. Five-year overall survival was 48% in the chemoradiotherapy group and 35% in the radiotherapy group. Chemoradiotherapy was associated with a trend toward a reduction in performance of salvage cystectomy, with 2-year rates of 11% vs 17% (P = .07).

Adverse Events Acute grade 3 or 4 adverse events (assessed by NCI criteria) were somewhat more common with chemoradiotherapy, occurring in 36% vs 27.5% of the radiotherapy group (P = .07). Acute adverse events were primarily genitourinary and gastrointestinal side effects, with the latter occurring more frequently with chemoradiotherapy (10% vs 3%, P = .007). Late grade 3 or 4 adverse events, assessed by Radiation Therapy Oncology Group (RTOG) criteria over 6 months to 5 years after randomization in 120 patients in the chemoradiotherapy group and 108 in the radiotherapy group, were somewhat more common in the radiotherapy group (8% vs 16%, P = .07). Data on bladder volume were available for 78 patients at 1 year and 51 patents at 2 years. Reductions in bladder volume were 1.3 mL greater in the radiotherapy group at 1 year and 55.6 mL greater at 2 years, although the differences between groups were not significant at either time point.

Primary Conclusions Thus, the study showed that synchronous chemoradiotherapy resulted in reduced recurrence of cancer, with the benefit occurring irrespective of history of neoadjuvant chemotherapy and without any marked increase in adverse events. Chemoradiotherapy did not appear to be associated with late impairment of bladder function, a concern with more intensive therapy, particularly when given after neoadjuvant chemotherapy. As noted by the authors, reduced rates of invasive relapse might result in improved survival that would be expected to become evident after relatively long-term follow-up. The more frequent use of salvage surgery—which would also be expected to improve survival—in the radiotherapy group may have contributed to the absence of a significant overall survival benefit with chemoradiotherapy in the study. As stated by the authors, “Although further clinical trials to refine and im-

prove chemoradiotherapy schedules are warranted, our study shows that the addition of chemotherapy to radiotherapy improved local control, particularly freedom from invasive recurrence … and resulted in good longterm bladder function and low rates of salvage cystectomy, all of which are of

major importance in this elderly, relatively frail group of patients.”

■

Disclosure: The authors of the paper published in The New England Journal of Medicine reported no potential conflict of interest.

References 1. Coppin CM, Gospodarowicz MK,

James K, et al: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol 14:2901-2907, 1996. 2. James ND, Hussain SA, Hall E, et al: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366:1477-1488, 2012.

The ASCO Post | MAY 15, 2012

PAGE 68

JOP Spotlight

Before Accepting a ‘Friend’ Request on Social Media, Carefully Consider the Potential Pitfalls and Perils By Charlotte Bath

o friend or not to friend? That is the question many social networkers ponder daily. Oncologists and

other health professionals considering “friend” requests from patients would be wise to first consider the potential

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

pitfalls and perils of accepting such requests, according to an article written by a multidisciplinary group of health

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

65481-R1-V1

professionals from the National Cancer Institute and the National Institutes of Health and published by The Journal of Oncology Practice ( JOP).1 “Communicating with patients on social media sites can cross professional-patient boundaries, risking patient confidentiality, exposing patients to inappropriate details of physicians’ personal lives, and jeopardizing therapeutic relationships,” the authors pointed out. “Connecting with patients through online venues can also pose risks to providers’ reputations, safety, privacy, and work-life balance.” These social media include blogs, social networks such as Facebook, Twitter, and LinkedIn, multimedia sharing on YouTube, and private websites for people with specific health challenges.

Lori Wiener, PhD

Slippery Slope In an interview with The ASCO Post, Lori Wiener, PhD, the article’s lead author cautioned physicians and other health professionals to remember the respective roles of providers and patients. “They are not our friends. They come to us to be our patients and for us to be their providers,” she said. “It is a slippery slope when we introduce patients into our lives as ‘friends’ and they have access to a lot of information about their providers and we about them.” Dr. Wiener is Codirector of the Behavioral Science Core and Head of the Psychosocial Support and Research Program in the NCI’s Pediatric Oncology Branch. Patients (and not only those you directly “friend,” but friends of their friends as well) can discover personal information about your religious, political, and lifestyle choices or perhaps view unprofessional images. “The oncologist may discover personal information about a patient that places him or her in an awkward situation,” the JOP article noted. This could include

ASCOPost.com | MAY 15, 2012

PAGE 69

JOP Spotlight

information about patients’ recreational drug use and risky sexual behavior. “Moreover, information learned by either the provider or the patient via social networking can create ethical tensions,” according to the article.

Intense Relationships

cal responsibility. It became the law,” she said. “Many centers now have social media policies,” Dr. Wiener added, “and if they don’t, they are developing them quickly, because they are learning this can be a slippery road for them.” Some centers have institutional Facebook pages so patients can learn about new programs and protocols and connect to the person in charge. “At NIH, we can’t even access Facebook. It is denied. We can’t get it on our computers at all,” Dr. Wiener said. “But many centers really struggle with telling people what they can and cannot do once they are at home.”

“Especially in an oncology practice,” Dr. Wiener noted, relationships between patients and families and medical staff members “are quickly developed because care has to start quickly, and they can be very intense. Because of the amount of time spent between staff and families, discussions go past medication, toxicities, treatment, and So Why Would You Do It? prognosis to other things that are goEven professionals aware of the poing on in people’s lives. It is almost as tential pitfalls and perils of accepting a if a pseudo-family/friendship relationfriend request from a patient may do ship evolves.” This is particularly likely so anyway. “They are put in an uncomin pediatrics, she said, because parents fortable position. They don’t want to often need “to feel a sense of closeness hurt somebody’s feelings or make pato the staff who are taking care of their tients feel like they child.” don’t want to talk Before the wideThe inherent openness to them,” Dr. Wiespread use of soner said. cial media, “there in social networks In addition, she were pretty simple creates potential said, there can be rules,” Dr. Wiener boundary and privacy “a false safety persaid. “You don’t talk ception” that can about a patient in issues in the providerarise from having an elevator or the patient context. privacy settings on. cafeteria. You clearly “But your privacy don’t give out your —Lori Wiener, PhD settings today may telephone number. no longer be priThen in 1996, when vate tomorrow,” she noted. “And even Congress enacted the Health Insurif you decide that you just want to talk ance Portability and Accountability Act to someone and you are not giving any (HIPAA), there was a whole new set of personal information, that person now rules. We needed to safeguard all medihas access to your friends and what’s on cal information, and it wasn’t just an ethi-

Social Media: A Generational Thing?

verheard Monday morning conversations about concerns expressed by patients and family members over the weekend triggered the idea for the article about the challenges of using social media to communicate with patients in the oncology setting, according to the article’s lead author, Lori Wiener, PhD. “I would ask, ‘Did [the patients] come in over the weekend?’ and was told, ‘No, I read it on Facebook,’” Dr. Wiener explained. “Many of our staff members are in their 20s and 30s, so I was thinking, is this a generational issue? And where are the boundaries here? Because the way that people communicate today is very different from the way they communicated 5, 10, or 15 years ago.” Physicians should not shy away from using social media, as social media will continue to have an important and increasing role in health care. Reliance on social media by younger people can also mean that oncologists and other health professionals who don’t use social media may be cutting themselves off from an effective way of reaching adolescent, younger patients. “We always need to look at ways to reach adolescents and young adults, and they do frequently communicate electronically, “Dr. Wiener noted. “However, while utilizing the many benefits of social media, be mindful of the principles of patient confidentiality and privacy, respect for employers and colleagues, and patientprofessional boundaries.”

■

your site.” As the article points out, “the inherent openness in social networks creates potential boundary and privacy issues in the provider-patient context.” Dr. Wiener also advises against discussing work-related issues on personal sites or posting photographs depicting behavior that might be problematic, such as drinking. “Professionally, it is not wise, especially for people looking for new jobs.” Physicians and other health professionals should pause and think of the possible consequences before accepting a friend request, Dr. Wiener stressed. “Or if they have already accepted, they should give some thought

to ‘unfriending’ in a way that is respectful while maintaining those professional relationships, which is what everybody wants.” What would you do if the patient is expressing suicidal ideation? Boasts about not taking their medications? Says bad things about you, your practice, your staff?

■

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

Reference 1. Wiener L, Crum C, Grady C, et al: To friend or not to friend: The use of social media in clinical oncology. J Oncol Pract 8(2):103-106, 2012.

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

The ASCO Post | MAY 15, 2012

PAGE 70

2012 Oncology Meetings May AUA Annual Meeting May 19-23 • Atlanta, Georgia For more information: www.aua2012.org Keystone Symposia: The Role of Inflammation during Carcinogenesis May 20-25 • Dublin, Ireland For more information: www.keystonesymposia.org

June Society for Immunotherapy of Cancer Primer on Tumor Immunology and Cancer Immunotherapy™ From Biology to Treatment June 1 • Chicago, Illinois For more information: www.sitcancer.org/meetings/ primer12/06/ ASCO Annual Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org

Cambridge Healthtech Institute’s 10th Annual Meeting: Next-Gen Kinase Inhibitors June 4-6 • Cambridge, Massachusetts For more information: www.healthtech.com ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org Apoptosis and Cancer June 14-15 • Cambridge, United Kingdom For more information: www.abcam.com World Conference on Interventional Oncology June 14-17 • Chicago, Illinois For more information: www.wcio2012.org

Emerging Strategies in Treatment of Non-Small Cell Lung Cancer and Head & Neck Cancer June 16 • Atlanta, Georgia For more information: http://cancernetus.com 8th Central European Oncology Congress: Best of ASCO 2012 June 17-20 • Opatija, Croatia For more information: www.penta-pco.com/ceoc2012 Melanocytes and Melanoma: From Basic Science to Clinical Applications June 18-20 • Malmö, Sweden For more information: www.melanoma2012.org 4th Molecular Diagnostics for Cancer Drug Development June 25-28 • Boston, Massachusetts For more information: http://moleculardiagnostics-cancer. com Cancer Vaccines & Active Immunotherapeutics: 3rd Annual Summit June 26-28 • Boston, Massachusetts For more information: http://cancervaccines-meeting.com

Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma

Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org

13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com

10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com

5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org 11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

ICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec For more information: www.worldcancercongress.org

September

August Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org

Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org continued on page 72

MASCC/ISOO International Symposium on Supportive Care in Cancer June 28–30 • New York, New York For more information: www.kenes.com/mascc

Pan Pacific

British Gynaecological Cancer Society Annual Scientific Meeting July 5-6 • London, United Kingdom For more information: http://bgcsconference.com/ Best of ASCO® Chicago July 12-13 • Chicago, Illinois For more information: http://boa2012.asco.org

Lymphoma Conference

July 4th Asia-Pacific Gastroesophageal Cancer Congress and Singapore Gastric Cancer Consortium 5th Annual Scientific Meeting July 4-6 • Singapore For more information: www.apgcc.com

2012

Tuesday-Friday Tuesday-Friday

July July 17-20, 17-20, 2012 2012 Hyatt Hyatt Regency Regency Maui Maui Resort Resort & & Spa Spa Lahaina, Lahaina, Maui, Maui, Hawaii Hawaii

A A comprehensive comprehensive conference conference by by internationally internationally recognized recognized speakers speakers presenting presenting the the most most recent recent developments developments in in lymphoma lymphoma and and transplantation. transplantation.

Conference Directors James James O. O. Armitage, Armitage, MD MD

Joe Joe Shapiro Shapiro Professor Professor of of Medicine Medicine Division Division of of Oncology Oncology and and Hematology Hematology Department of Internal Medicine Department of Internal Medicine University University of of Nebraska Nebraska Medical Medical Center Center

Julie Julie M. M. Vose, Vose, MD, MD, MBA MBA

Chief, Chief, Division Division of of Oncology Oncology and and Hematology Hematology Neumann Neumann M. M. and and Mildred Mildred E. E. Harris Harris Professor Professor Department Department of of Internal Internal Medicine Medicine University University of of Nebraska Nebraska Medical Medical Center Center

CALL CALL FOR FOR ABSTRACTS: ABSTRACTS: April April 16, 16, 2012 2012

Scan Scan code code with with your your smartphone smartphone to to learn learn more! more!

unmc.edu/panpacificlymphoma

Stimulating

Possibilities

VISIT US at ASCO booth 19125

The potential of Dendritic Cell Mediated Immunotherapy (DCMI) in advanced NSCLC

BINDS

PROPOSED MECHANISM OF ACTION: Orally administered DCMIs are thought to bind in the gut epithelium and interact with dendritic cells in the gut wall1,2

STIMULATES

Binding produces an immunostimulatory cytokine cascade in the gut, stimulating the migration and maturation of tumor antigen-presenting dendritic cells2,3

ACTIVATES Matured dendritic cells present tumorassociated antigens to T lymphocytes and activate them2,3

INFILTRATES These effector T lymphocytes then make their way to distal tumors, where they inďŹ ltrate and inhibit tumor growth2,3

There is an unmet need for treatments in advanced NSCLC that work in a broad range of patients, regardless of tumor histology or mutation status.4 Agennix is investigating a novel oral DCMI in advanced NSCLC. Learn more at www.discoverDCMI.com

DCMI

References: 1. Suzuki YA et al. Biochem. 2001;40:15771-15779. 2. Spadaro M et al. Cancer Res. 2007;67:6425-6432. 3. Varadhachary A et al. Int J Cancer. 2004;111:398-403. 4. Kelly RJ, Giaccone G. Expert Opin Biol Ther. 2010;10:1379-1386.

The ASCO Post | MAY 15, 2012

PAGE 72

2012 Oncology Meetings 2012 Oncology Meetings continued from page 70

17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/conference/17th_ICCN 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu Congress of Oncologists September 20-22 • Sudak, Ukraine For more information: http://nbscience.com/congress-ofoncologists 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com Sydney Cancer Conference September 27-28 • Sydney, Australia For more information: sydney.edu.au/cancer-research/ SCC2012 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

October 27th Annual Critical Issues in Tumor Microenvironment, Angiogenesis, and Metastasis October 1-4 • Cambridge, Massachusetts For more information: http://steele.mgh.harvard.edu

ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org 14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer 44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org

Society for Immunotherapy of Cancer Workshop--Focus on the Target: The Tumor Microenvironment October 24-25 • North Bethesda, Maryland For more information: www.sitcancer.org/meetings/am12/ workshop12 12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org 9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com 3rd International Conference on Stem Cells and Cancer October 27-30 • New Delhi, Delhi, India For more information: www.iscc.in IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org

ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com

24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org 7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp

November 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

December 35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

FOR ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML IN CHRONIC PHASE (CP)

Choose TASIGNA first

TASIGNA provides superior MMR* rates vs imatinib at 12 months and <1% progression to AP/BC1† (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], P<0.0001)1 *Major molecular response (MMR)=≥3 logs below baseline (≤0.1% international scale [IS]).1 †

Progression to accelerated phase or blast crisis (AP/BC) includes patients with clonal evolution and CML-related death.2

INDICATION AND BOXED WARNING TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome. WARNING: QT PROLONGATION AND SUDDEN DEATHS ■ TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and follow any dose adjustments ■ Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome ■ Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors ■ Patients should avoid food 2 hours before and 1 hour after taking dose Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on the following pages.

IN THE TREATMENT OF ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML-CP Less than 1% of TASIGNA patients progressed to AP/BC1 Progression to AP/BC at 24 months

0.7%

■

17 6%

TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

TASIGNA

Imatinib

(n=282)

(n=283)

TASIGNA significantly improved the rate of MMR compared with imatinib at 12 months—the primary end point of the ENESTnd (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], 300trial mg bid 400 P<0.0001) mg qd1

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for RQ-PCR testing. The primary end point was MMR at 12 months.1,2

IMPORTANT SAFETY INFORMATION ■

■

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter

■

Caution is recommended in patients with a history of pancreatitis The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase

■

TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING) ■ ■

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Grapefruit products should also be avoided The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) TASIGNA must not be taken with food TASIGNA exposure is increased in patients with impaired hepatic function 3/12

AM7-1033710

TASIGNA maintained the difference in MMR rates through 24 months1,2 At 12 months

■

Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA The exposure of TASIGNA is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do. The safety and effectiveness of TASIGNA in pediatric patients have not been established

Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on adjacent pages.

At 24 months

■

In newly diagnosed Ph+ CML-chronic phase, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, headache, nausea, fatigue, and myalgia TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2011. 2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-851.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS • Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and follow any dose adjustments (5.2, 5.3, 5.6, 5.12). • Sudden deaths have been reported in patients receiving nilotinib (5.3). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2). • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors (5.7). • Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome. 1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information]. 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2) in the full prescribing information]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)]. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)]. 5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)]. 5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information]. 5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information]. 5.10 Tumor Lysis Syndrome Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. 5.11 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information]. 5.12 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption.

5.13 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.14 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)]. Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 25 months (range 0.1 – 35.4 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 2.5% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse events regardless of causality was observed in 9% of patients. Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse drug reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed. Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Skin and subcutaneous Rash 37 18 <1 2 tissue disorders Pruritus 20 7 <1 0 Alopecia 11 6 0 0 Periorbital edema <1 15 0 0 Gastrointestinal Nausea 20 39 1 1 disorders Constipation 17 6 0 0 Diarrhea 14 40 <1 2 Vomiting 11 24 0 <1 Abdominal pain upper 15 11 <1 <1 Abdominal pain 14 10 1 0 (continued)

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Nervous system Headache 30 18 3 <1 disorders General disorders Fatigue 21 16 1 1 and administration Pyrexia 11 12 <1 0 site conditions Asthenia 11 10 <1 0 Edema, peripheral 8 18 0 0 Face edema <1 11 0 <1 Musculoskeletal and Myalgia 14 18 <1 0 connective tissue Arthralgia 17 13 <1 <1 disorders Muscle spasms 11 31 0 <1 Pain in extremity 11 13 <1 <1 Back pain 14 11 <1 1 Respiratory, thoracic Cough 14 9 0 0 and mediastinal disorders Infections and Nasopharyngitis 22 17 0 0 infestations Upper respiratory tract infection 14 10 <1 0 Eye disorders Eyelid edema 1 16 0 <1 aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP CML-AP N=321 N=137 All CTC All CTC Grades Gradesb Grades Gradesb Body System and Preferred Term (%) 3 / 4 (%) (%) 3 / 4 (%) Skin and subcutaneous Rash 36 2 29 0 tissue disorders Pruritus 32 <1 20 0 Night sweat 12 <1 27 0 Alopecia 11 0 12 0 Gastrointestinal Nausea 37 1 22 <1 disorders Constipation 26 <1 19 0 Diarrhea 28 3 24 2 Vomiting 29 <1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 <1 12 <1 Dyspepsia 10 <1 4 0 Nervous system Headache 35 2 20 1 disorders General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17 11

2 <1 <1 2 2 <1

16 15 15 18 15 12

0 0 2 1 <1 1

Respiratory, thoracic and mediastinal disorders

Cough Dyspnea Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

Metabolism and nutritional disorders

Anorexia

Psychiatric disorders

Insomnia

Vascular disorders

Hypertension

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0

Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

Imatinib 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

10 12 4

9 21 5

301 312 11

423 424 27

7 6 5 4 4 2 1 <1 1 0 <1

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

18 12 17 7 4 6 7 2 3 4 2

18 6 15 9 4 4 7 9 2 3 5

0 0

<1 <1

1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (≥1% and <10%), uncommon (≥0.1% and <1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including nasopharyngitis, pharyngitis, rhinitis), pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: oral papilloma. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythaemia, leukocytosis, eosinophilia. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, decreased appetite. Uncommon: dehydration, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia. Psychiatric Disorders: Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, ocular surface disease. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatotoxicity, hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy. Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including noncardiac chest pain), pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations: Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, lipoprotein increased (including very low density and high density), blood parathyroid hormone increased. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ÂŠ Novartis T2011-126 November 2011

ASCOPost.com | MAY 15, 2012

PAGE 79

Expert’s Corner

Geriatric Oncologists: A Small but Passionate Group A Conversation with Stuart M. Lichtman, MD By Ronald Piana

Stuart M. Lichtman, MD

lthough age is the major risk fac� tor for developing cancer, geri� atric oncology is still a relatively new discipline within the oncology com� munity. To gain insight into this evolv� ing component of cancer care, The ASCO Post recently spoke with a leader in the field, Stuart M. Lichtman, MD, of the Clinical �� Geriatric Program, Me� morial Sloan-Kettering Cancer Center, New York.

Beginnings of Geriatric Oncology The International Society of Geriatric Oncology (SIOG) held its 11th annual meeting in Paris last year. When did awareness of geriatric oncology begin? The pre-SIOG impetus began in the early 1990s, when ad hoc meet� ings were held in Europe and the United States discussing cancer in the elderly. In 1995, I joined a Cancer and Leukemia Group B (CALGB) com� mittee on elder cancer care, and I’ve been on the committee ever since. Prior to that, Drs. B.J. Kennedy and Rosemary Yancik starting defining the research agenda for the future. However, during the first decade of its evolution, the vast majority of geriatric oncologists were European. Geriatric oncology in the United States is gaining momentum, but it still involves a relatively small group. We all know each other.

Evolving Discipline How has the perception of geriatric oncology changed since the first SIOG meeting? The first few SIOG meetings were basically like educational symposia conducted at ASCO, reviewing what we knew about elderly patients with

cancer, but without trial data—no one was doing studies in this area. In contrast, I was one of the chairs at the most recent SIOG meeting, and we presented a lot of clinical data. Fortunately, we’ve been doing more studies over the past 3 to 5 years, looking at assessment scales and treatment options in the elderly. Everyone finally agrees that oncolo� gists need to be aware of new data and ideas regarding the biology of aging and the various treatment programs relevant to geriatric patients with can� cer. That awareness has been a long time coming, but it’s changed the per� ception of geriatric oncology.

Trial Participation To that end, how do we increase research in the elderly? One chief barrier is physician con� cern about whether their older pa� tients can tolerate the side effects of therapies. Moreover, for many drug

therapy. On the other hand, if I saw an 80-year-old patient with colon cancer who was otherwise healthy, I would give that patient adjuvant therapy. Medically speaking, older patients are generally in better condition than they used to be. They exercise and are not as frail, and their comorbid ill� nesses are often well controlled. So if a patient is in his 70s and even 80s, as long as his functional status is good and he is not measurably weakened by disease, I will treat him as I would a younger patient with cancer. We’ve learned that aging is highly individu� alized and that chronologic age is not always a predictor of a patient’s thera� peutic needs. What are some of the clinical issues that oncologists need to be aware of in their older patients? First, prior to delivering any treat� ment in geriatric patients, the on� cologist must determine all the co�

Aging is highly individualized and chronologic age is not always a predictor of a patient’s therapeutic needs. —Stuart M. Lichtman, MD

studies, investigators want patients with normal kidney and liver func� tion, and no prior heart disease, ie, no comorbidity. Those criteria exclude a lot of older patients. To move past the current 5% enrollment of elderly per� sons, we would need to alter clinical trial design and the way the govern� ment and Pharma support trial en� rollment. There needs to be financial support, for both community doctors and patients.

Key Clinical Issues How does the lack of trials in the elderly affect the practice of geriatric oncology? We rely on assessment scales and a general sense of the older patient’s health status. I recently saw a 92-yearold man who’d had surgery for colon cancer. Is there a study to tell me how to treat this patient? Of course not. He told me that he’d fallen five times in the past month; he’s incontinent, along with some other issues. This patient is not a candidate for chemo�

morbidities and assess the patient’s functional status. Another issue is clinical pharmacology. Geriatric pa� tients are the largest users of pharma� ceutical agents, which can complicate a doctor’s decisions regarding dos� ing and drug toxicity. Being mindful of polypharmacy and knowledge of pharmacokinetics is important in the elderly. Also, older patients may be more sensitive to opioids used in pain control because of liver and kidney issues, so one must be careful when initiating analgesic treatment. And there’s the compliance problem, espe� cially with the growing emphasis on oral agents. In general, management of the el� derly can be based largely on an as� sessment of the patient’s frailty and life expectancy. Some patients need palliative care, but those whose po� tential life expectancy exceeds sur� vival from cancer without therapy should receive standard treatment. This is really where the art of oncol� ogy comes into clinical decisions.

Workforce Shortage Our aging population and an impending workforce shortage weigh heavily on the future of oncology. Is the International Society of Geriatric Oncology thinking of addressing this issue? The impending oncology work� force shortage will have greater ef� fects on geriatric care because there’s already a shortage in that area. SIOG’s position is that we have to give com� munity oncologists the tools to ef� ficiently and expeditiously evaluate their geriatric patients. Some assess� ment tools exist; however, we need to standardize the best aspect of cur� rent instruments and validate them for widespread use. Then we need to integrate more nurses, nurse practitioners, physical and occupational therapists, and social workers into the clinical care mix. Old� er patients with cancer often need a lot of assistance and support, and in order to address the challenge ahead, we’re essentially going to have to rethink the way we organize and deliver care.

Closing Thoughts Any last thoughts about the future of geriatric oncology? Despite all the challenges, the fu� ture of geriatric oncology looks good for a couple of reasons. One reason is that the work done by the Cancer and Aging Research Group led by Dr. Arti Hurria—who is also the Medical Editor-in-Chief of the Journal of Geriatric Oncology—is really advancing the field. The newly formed Alliance made up of the former CALGB, North Central Cancer Treatment Group, and American College of Surgeons Oncol� ogy Group has a dynamic geriatric oncology committee, and the Gyne� cologic Oncology Group has formed a task force on elderly patients. SIOG will continue to be very ac� tive with its annual meetings, task forces, and educational events. So in geriatric oncology, we have a small but dedicated group of physicians with several talented and driven lead� ers. The field is growing, not only in numbers but also in our scientific and sociologic understanding about the relationship between advanced age and cancer.

■

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

The ASCO Post | MAY 15, 2012

PAGE 80

Awards

State Oncology Societies Honored for Promising New Programs that Improve Patient Care

he State Affiliate Grant Program provides funding to ASCO State and Regional Affiliates to develop and implement new efforts that will lead

to improved medical practice, collab� oration, and research. ASCO’s State/ Regional Affiliates are a vital resource for addressing issues of concern to the

cancer community in specific regions of the country. The 2012 honorees and projects include:

■■ The Georgia Society of Clinical Oncology (GASCO) will help its members understand and imple� ment the 2012 American College of Surgeons Commission on Cancer’s new survivorship care standards. Its program includes the creation a toolbox to help providers imple� ment care plans across a diverse pa� tient population.

For HCC patients with or without partial or branch PVT.

Tough on HCC,

not on patients

TheraSphere® is a powerfula, well-tolerated Y-90 glass microsphere therapy for transarterial radioembolization (TARE) in HCC, providing demonstrated patient benefitsb and rapid administration set-up, leading to a safe and quicker infusion4.

Tough on HCC

Easy on patients

• Two independent studies reported median survival rates of 17.2 months in Child-Pugh A hepatocellular carcinoma (HCC) cirrhotic patients with various tumor characteristics (N=291, N=108)1,2

• The majority of adverse events were mild to moderate in severity4 and were manageable or resolved over time2

• WHO and EASL response rates were 42% and 57%, respectively (N=273)1

• Administered as an outpatient treatment

■■ The Maryland/DC Society of Clinical Oncology (MDCSCO) will focus its efforts on growing and enhancing its membership pool in an effort to ensure the Society rep� resents the interests of oncology and all professionals working in the field. MDCSCO hopes to expand its reach with small community practices, large practices, research institutions, academic and teaching hospitals and government agencies.

■■ The Northern New England Clinical Oncology Society will focus its new program on integrating pal� liative care into oncology practices in the region. Its program aims to introduce specific performance im� provement processes, new tools and educational programs designed to improve end-of-life cancer care. The Society will use ASCO’s Quality On� cology Practice Initiative (QOPI®) module to measure improvement of certain end-of-life measures.

• No ulcers or pulmonary toxicities were reported in two large independent studies (N=291, N=108)1,2

• 58% of TheraSphere patients were downstaged3

For more information, visit www.TheraSphere.com TheraSphere is authorized by Federal Law for use as a humanitarian device in radiation treatment or as a neoadjuvant to surgery or transplantation in patients with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters. The device is also indicated for HCC patients with partial or branch portal vein thrombosis/occlusion, when clinical evaluation warrants the treatment. The effectiveness of this device for this use has not been demonstrated.4 a - Refers to high specific activity. b - Patient benefits as indicated by Package Insert: HCC patients with PVT are eligible for treatment, majority of events graded as mild to moderate, treatment usually performed on an outpatient basis. References: 1. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report for long-term outcomes. Gastroenterology. 2010;138:52-64. 2. Hilgard P, Hamami M, Fouly AE, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology. 2010;52:1741-1749. 3. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9:1920-1928. 4. TheraSphere® [US package insert]. Ottawa, ON: Nordion (Canada) Inc.; 2011. Nordion, the logo and Science Advancing Health are trademarks of Nordion (Canada) Inc. and are used under license by Nordion Inc. Targeted Tough is a trademark of Nordion (Canada) Inc. TheraSphere® is a trademark of Theragenics Corporation used under license by Nordion (Canada) Inc. All rights reserved. January 2012, Printed in Canada. PCCS 503A

Manufactured by

The 2012 State Affiliate Grant Pro� gram is supported by Bristol-Myers Squibb and the American Society of Clinical Oncology.

■

ASCOPost.com | MAY 15, 2012

PAGE 81

JCO Spotlight Thoracic Oncology

Canadian Registry Study of Adjuvant Therapy for NSCLC Shows Increased Use in Elderly Patients and Improved Survival By Matthew Stenger

isplatin-based adjuvant therapy is recommended for patients with resected stage II–IIIA non–small cell lung cancer (NSCLC). There have been no trials of adjuvant therapy in elderly patients with NSCLC, who constitute a large part of the NSCLC population. A number of analyses indicate that older patients benefit from adjuvant therapy with acceptable toxicity, including a ret� rospective analysis of the National Can� cer Institute of Canada and Intergroup Study JBR.10 trial1 and the Lung Adju� vant Cisplatin Evaluation (LACE) metaanalysis.2 However, it remains unclear to what degree such patients are receiving adjuvant therapy in clinical practice. In a population-based, retrospective co� hort study recently reported in the Journal of Clinical Oncology, Cuffe and colleagues3 analyzed uptake of adjuvant therapy and outcomes by age in patients with NSCLC undergoing surgical resection during the periods 2001–2003 and 2004–2006. The study found that use of adjuvant therapy in elderly patients (age ≥ 70 years) increased across the two periods and appeared to be associated with a survival advantage. Nev� ertheless, the study also found that use of adjuvant therapy in the elderly still lags be� hind that in younger patients.

Patient Characteristics Using the Ontario Cancer Registry, the investigators identified 6,570 NSCLC cases treated with surgical resection from 2001 to 2006.3 Between the periods 2001–2003 and 2004–2006, the propor� tion of surgical cases who were elderly (age ≥ 70 years) increased from 42.5% to 45.0% (P = .006). After exclusion of pa� tients who received preoperative therapy, 2,763 (43.8%) of 6,304 surgical cases were aged 70 years or older, with 1,317 aged 70 to 74 years, 980 aged 75 to 79 years, and 466 aged 80 years or older. Elderly patients were significantly more likely to be male SEE PAGE 89 and to have comor� bidities, longer post� operative inpatient stays, and squamous histology. They were significantly less like� ly to be treated at regional cancer centers, to undergo pneumonectomy or postoper� ative radiotherapy, and to have adenocar� cinoma. For the periods 2001–2003 and 2004–2006, respectively, 1,697 and 1,844

patients were aged less than 70 years, 623 and 694 were aged 70 to 74 years, 446 and 534 were aged 75 to 79 years, and 184 and 282 were aged 80 years or older.

Key Findings Use of adjuvant chemotherapy in the elderly population increased from 3.3% to 16.2% between 2001–2003 (hence, the pre–adjuvant therapy adoption cohort) and 2004–2006 (postadoption cohort). However, the proportions of patients receving adjuvant therapy during 2004– 2006 still showed a significant decrease with increasing age, from 42.7% in those aged less than 70 years, to 23.1% in those aged 70 to 74 years, 13.3% in those aged 75 to 79 years, and 4.6% in those aged 80 years or more (P < .001). For elderly patients in the postadoption cohort, fac� tors associated with increased likelihood of adjuvant therapy use included shorter

Adjuvant Therapy for Older Patients with Lung Cancer ■■ A Canadian registry study revealed that use of adjuvant chemotherapy

for non-small cell lung cancer increased in patients aged 70 years or older after pivotal adjuvant chemotherapy trials were reported, but its use in older patients remained less frequent than for patients under 70.

■■ Adjuvant chemotherapy appears to be associated with a significant

survival benefit in older patients with NSCLC, and equally well tolerated across age groups.

■■ The investigators concluded that fit elderly patients should not be denied potentially curative therapy on the basis of age alone.

■■ It remains unclear whether such benefits extend to patients aged 80 years or older.

patients aged less than 70 years, compared with 18% of those aged 70 to 74 and 75 to 79 years and 29% of those aged 80 years or older (P = .007). Chemotherapy ap� peared to be equally well tolerated across age groups, with no significant age-related differences being observed in frequency

Significant efforts … are necessary to improve understanding of the reasons underlying this apparent low utilization in the elderly and to promote referral of such patients to medical oncology to ensure that fit elderly patients are not denied potentially curative therapy on the basis of age alone. postoperative inpatient stay and (consis� tent with guideline recommendations) stage II/III disease. Adjuvant therapy use varied significantly by region of Ontario, ranging from 9.3% to 28.4%. On multivariate analysis, factors sig� nificantly associated with likelihood of receiving adjuvant therapy among el� derly patients were geographic location, pathologic stage, and advancing age (all P < .001). The investigators found no significant association between Charl� son comorbidity score and use of ad� juvant therapy in the elderly, although they did see a trend toward decreased use of adjuvant therapy in patients with three or more comorbidities. Detailed data on chemotherapy were available from 584 patients treated at re� gional centers in 2004–2006. Cisplatin/ vinorelbine was the most commonly used regimen across all age groups. However, carboplatin-based regimens were used significantly more frequently in elderly pa� tients, accounting for treatment in 7% of

of changing from cisplatin to carboplatin or other drugs, or in frequency of dose re� duction or interruption.

Survival and Toxicity Four-year overall survival improved from 52.5% in the preadoption cohort (patients undergoing resection in 2001– 2003) to 56.1% in the postadoption cohort (those undergoing resection in 2004–2006; P = .001). Overall survival in elderly patients improved from 47.1% in the preadoption cohort to 49.9% in the postadoption cohort (P = .01). Com� pared with the preadoption cohort, risk for death in the postadoption cohort was significantly reduced by 15% (HR = 0.85, P = .0029) in patients aged less than 70 years and by 13% (HR = 0.87, P = .0122) in all patients aged 70 years or older. In the elderly patient age groups, risk for death was significantly reduced by 17% (HR = 0.83, P = .0271) in those aged 70 to 74 years and by a borderline significant 16% (HR = 0.84, P = .0517) in those

aged 75 to 79 years, whereas there was no reduction in risk in patients aged 80 years or older (HR = 1.00, P = NS). Treatment-related toxicity was as� sessed by evaluating hospital admis� sions within 6 months after surgery. Compared with the preadoption co� hort, hospitalizations within 6 months after surgery declined in elderly patients in the postadoption cohort (40.0% vs 38.3%), suggesting that more common use of adjuvant therapy did not increase treatment-related toxicity. In the postadoption cohort, elderly patients were more likely than younger patients to be hospitalized within 6 weeks after surgery, with hospitalization occur� ring in 11.1% of patients aged less than 70 years, compared with 12.1% of those aged 70 to 74 years, 17.2% of those aged 75 to 79 years, and 17.7% of those aged 80 years or older (P = .0002). This find� ing suggests that surgical morbidity was greater in elderly patients, at least those aged 75 years or older. However, during the period from 6 weeks to 6 months af� ter surgery—ie, the period during which patients were most likely to be receiving adjuvant therapy—there was no differ� ence in rates of hospitalization between nonelderly and elderly patients. Dur� ing this period, 28.0% of patients aged less than 70 years were admitted to the hospital, compared with 26.6% of those aged 70 to 74 years, 27.6% of those aged 75 to 79 years, and 31.5% of those aged 80 years or older.

Study Implications As stated by the authors, these find� ings suggest that the benefits of adjuvant therapy in elderly patients that have been identified in analyses of clinical trials are continued on page 84

In Advanced Renal Cell Carcinoma...

INDICATION VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. • Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Concomitant use of

VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions]. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. • QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. • Hemorrhagic Events: Fatal hemorrhagic events have been reported (all Grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. • Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all Grades [3%] and Grades 3 to 5 [2%]) were

observed. Use with caution in patients who are at increased risk for these events. • Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. • Hypertension: Hypertension, including hypertensive crisis, has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (39% of cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). In the case of persistent hypertension despite antihypertensive therapy, the dose of VOTRIENT may be reduced. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. • Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence.

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1.3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines® Category 1 recommendation4 • As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than VOTRIENT as first-line treatment options

WARNING: HEPATOTOXICITY

Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. VOTRIENT: Safety Profile Summary1 • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% of patients — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% of patients • For any individual adverse reaction in the VOTRIENT arm, the rate of Grade 3/4 adverse events is ≤4%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% of patients; all grades, 53% of patients • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the first 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

• Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. • Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. • Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. • Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient

develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT or discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%).

Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline. 4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc 2012. All rights reserved. Accessed March 22, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

VOTRIENT.com

The ASCO Post | MAY 15, 2012 B:22.5”

PAGE 84

JCO Spotlight

Adjuvant Therapy for NSCLC continued from page 81

being realized in general practice—al� though it remains unclear whether such benefits extend to patients aged 80 years or older. However, the findings also in� dicate that adoption of adjuvant therapy lags in the elderly. The investigators not�

T:21” S:19.25”

ed, “Significant efforts … are necessary to improve understanding of the reasons underlying this apparent low utilization in the elderly and to promote referral of such patients to medical oncology to ensure that fit elderly patients are not de� nied potentially curative therapy on the basis of age alone.”

■

BRIEF SUMMARY

References 1. Pepe C, Hasan B, Winton TL, et al: Adjuvant vinorelbine and cisplatin in el� derly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25:1553-1561, 2007. 2. Fruh M, Rolland E, Pignon JP, et al: Pooled analysis of the effect of age on

adjuvant cisplatin-based chemotherapy for completely resected non-small-cell lung cancer. J Clin Oncol 26:3573-3581, 2008. 3. Cuffe S, Booth CM, Peng Y, et al: Adjuvant chemotherapy for non-small cell lung cancer in the elderly: A populationbased study in Ontario, Canada. J Clin On� col. April 23, 2012 (early release online).

hepatic impairment, the starting dose of VOTRIENT should be reduced or SUMMARYis not hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. TreatmentBRIEF with VOTRIENT recommended in patients with pre-existing severe hepatic impairment, defined alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not VOTRIENT (pazopanib) tablets total bilirubin >3summary X ULN with anysee level ALT. [See Dosage and for Administration recommended in patients with pre-existing severe hepatic impairment, defined The as following is a brief only; fullofprescribing information (2.2), product Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full as total bilirubin >3 X ULN with any level of ALT. [See Dosage and Administration complete information. (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information.] 5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified prescribing information.] 5.2 QT Prolongation and Torsades de Pointes: In WARNING: HEPATOTOXICITY on routineHEPATOTOXICITY electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified WARNING: de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades Severe and fatal hepatotoxicity has been observed in clinical studies. de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the Severe and fatal hepatotoxicity has beenclinical observed clinical studies. monotherapy studies. In the randomized trial, in 3 of the 290 patients Monitor hepatic function and interrupt, reduce, or discontinue dosing Monitor hepatic function and interrupt,values reduce, or discontinue receiving VOTRIENT had post-baseline between 500 to 549dosing msec. None monotherapy studies. In the randomized clinical trial, 3 of the 290 patients as recommended. [See Warnings and Precautions (5.1).] asofrecommended. Warnings andhad Precautions (5.1).] the 145 patients[See receiving placebo post-baseline QTc values ≥500 msec. receiving VOTRIENT had post-baseline values between 500 to 549 msec. None VOTRIENT should be used with caution in patients with a history of QT interval of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. prolongation, in patients taking antiarrhythmics or other medications that may VOTRIENT should be used with caution in patients with a history of QT interval 1 INDICATIONS AND USAGE 1 INDICATIONS AND USAGE prolong QT interval, and those with relevant pre-existing cardiac disease. When prolongation, in patients taking antiarrhythmics or other medications that may ® VOTRIENT is indicated for the treatment of patients with advanced renal cell ® is indicated for theand treatment patients with advanced renal cell and prolong QT interval, and those with relevant pre-existing cardiac disease. When VOTRIENT using VOTRIENT, baseline periodicofmonitoring of electrocardiograms carcinoma (RCC). carcinoma (RCC). of electrolytes (e.g., calcium, magnesium, potassium) within the using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance 2 DOSAGE AND ADMINISTRATION normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the 2 DOSAGE ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is studiesAND of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC dose of VOTRIENT is (0.9%) studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) 800 mg orally once daily without food (at least 1 hour before or 2 hours after 2.1 Recommended and Grades 3 to Dosing: 5 (2%)]. The Fatalrecommended hemorrhage has occurred in 5/586 800 [see mg orally once daily without (at least 1 hour before or 2 hours after who and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The Adverse Reactions (6.1)].food VOTRIENT has not been studied in patients ClinicalofPharmacology (12.3) of or fullclinically prescribing information]. The [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the a meal) have[see a history hemoptysis, cerebral, significant gastrointestinal of VOTRIENTinshould not6 exceed Do not not be crush tablets duepatients. to the have a history of hemoptysis, cerebral, or clinically significant gastrointestinal potential for increased rate of absorption which may affect systemic exposure. dosehemorrhage the past months800 and mg. should used in those potential for increased rate of Events: absorption which may systemic exposure. hemorrhage in the past 6 months and should not be used in those patients. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is 5.4 Arterial Thrombotic In clinical RCCaffect studies of VOTRIENT, [Seemyocardial Clinical Pharmacology (12.3) ofischemic full prescribing a dose isattack 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, missed, it should not be taken if it is less than 12 hours until the next dose. infarction, angina, stroke, information.] and transientIfischemic it should notand be taken if it3 is thanwere 12 hours until the next dose.have been myocardial infarction, angina, ischemic stroke, and transient ischemic attack 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, missed, [all Grades (3%) Grades to less 5 (2%)] observed. Fatal events Modification Guidelines: dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on 2.2 Dose observed in 2/586 (0.3%). In theInitial randomized study, these events were observed [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been and more additional dose decrease or increase shouldtobe in 200[see mg steps based on observed in 2/586 (0.3%). In the randomized study, these events were observed individual tolerability. The dose of VOTRIENT should not exceed 800 mg. frequently with VOTRIENT compared placebo Adverse Reactions individual The dose of VOTRIENT should exceed 800 Hepatic Impairment: No dose adjustment is required in patients with mild (6.1)]. tolerability. VOTRIENT should be used with caution in not patients who aremg. at increased more frequently with VOTRIENT compared to placebo [see Adverse Reactions No dose adjustment patients withVOTRIENT mild hepatic impairment. In patients with moderate hepatic impairment, alternatives Hepatic risk Impairment: for these events or who have hadisa required history ofinthese events. has (6.1)]. VOTRIENT should be used with caution in patients who are at increased hepatic alternatives risk for these events or who have had a history of these events. VOTRIENT has to VOTRIENT should be considered. If VOTRIENT is used in patients with not impairment. been studiedIninpatients patientswith whomoderate have had hepatic an eventimpairment, within the previous 6 should be considered. is used patients with not been studied in patients who have had an event within the previous 6 moderate hepatic impairment, the dose should be reduced to 200 mg per day. to VOTRIENT months and should not be used IfinVOTRIENT those patients. 5.5inGastrointestinal moderate hepaticand impairment, theclinical dose should be reduced to 200 mg per day. months and should not be used in those patients. 5.5 Gastrointestinal VOTRIENT is not recommended in patients with severe hepatic impairment. Perforation Fistula: In RCC studies of VOTRIENT, gastrointestinal VOTRIENT is notorrecommended in patients hepatic [See Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of perforation fistula has been reportedwith in 5severe patients (0.9%).impairment. Fatal perforation Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal [Seeevents Use in have Specific Populations (8.6) and Clinical of perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation full prescribing information.] Concomitant Strong CYP3A4 Inhibitors: The occurred in 2/586 (0.3%). MonitorPharmacology for symptoms(12.3) of gastrointestinal full prescribing Strong CYP3A4studies, Inhibitors: Theof events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, perforationinformation.] or fistula. 5.6Concomitant Hypertension : In clinical events use ofincluding strong CYP3A4 inhibitors ritonavir, perforation or fistula. 5.6 Hypertension : In clinical studies, events of clarithromycin) may increase pazopanib concentrations and should be avoided. concomitant hypertension hypertensive crisis(e.g., haveketoconazole, occurred. Blood pressure may increase pazopanib concentrations andPatients should be avoided. hypertension including hypertensive crisis have occurred. Blood pressure If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose clarithromycin) should be well-controlled prior to initiating VOTRIENT. should be If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose should be well-controlled prior to initiating VOTRIENT. Patients should be of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse monitored for hypertension and treated as needed with anti-hypertensive of VOTRIENT to 400 mg. Further dose reductions beorneeded if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib therapy. Hypertension (systolic blood pressuremay ≥150 diastolic blood pressure monitored for hypertension and treated as needed with anti-hypertensive effects occur therapy. Thisindose to adjust pazopanib therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure AUC to the range observed without inhibitors. However, there are no clinical ≥100 mmduring Hg) was observed 47%isofpredicted patients with RCC the treated with to the rangeHypertension observed without However, are no clinical ≥100 mm Hg) was observed in 47% of patients with RCC treated with data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. AUCVOTRIENT. occursinhibitors. early in the course there of treatment (39% of datacases with this dose adjustment in 88% patients receiving stronginCYP3A4 VOTRIENT. Hypertension occurs early in the course of treatment (39% of [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The occurred by Day 9 and of cases occurred the first inhibitors. 18 weeks). [See[See DrugAdverse Interactions (7.1).] (6.1).] Concomitant Strong CYP3A4 Inducer: The despite cases occurred by Day 9 and 88% of cases occurred in the first 18 weeks). concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease Reactions In the case of persistent hypertension concomitant use of strong CYP3A4 inducers (e.g., rifampin) decrease pazopanib concentrations and should be avoided. VOTRIENT should not be anti-hypertensive therapy, the dose of VOTRIENT may bemay reduced [see Dosage [See Adverse Reactions (6.1).] In the case of persistent hypertension despite pazopanib concentrations andVOTRIENT should be should avoided. should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. and Administration (2.2)]. beVOTRIENT discontinued if there is evidence anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage usedofinhypertensive patients whocrisis can not chronic use of strong inducers. and Administration (2.2)]. VOTRIENT should be discontinued if there is evidence [See Drug Interactions (7.1).] or ifavoid hypertension is severe andCYP3A4 persistent despite [Seeanti-hypertensive Drug Interactions therapy (7.1).] and dose reduction of VOTRIENT. 5.7 Wound of hypertensive crisis or if hypertension is severe and persistent despite 4 CONTRAINDICATIONS Healing: No formal studies on the effect of VOTRIENT on wound healing have anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound 4 CONTRAINDICATIONS None. Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) None. been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with 5 WARNINGS AND PRECAUTIONS inhibitors such as pazopanib may impair wound healing, treatment with PRECAUTIONS VOTRIENTAND should be stopped at least 7 days prior to scheduled surgery. 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested 5 WARNINGS VOTRIENT should be stopped at least 7 days prior to scheduled surgery. 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, The decision to resume VOTRIENT after surgery should be basedmanifested on clinical as increases in serum transaminases (ALT, AST) and bilirubin, was observed The decision to resume VOTRIENT after surgery should be based on clinical as increases transaminases (ALT,VOTRIENT AST) and bilirubin, observed in judgmentinofserum adequate wound healing. should bewas discontinued [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. [see patients Adverse with Reactions This hepatotoxicity can be severe and fatal. wound(6.1)]. dehiscence. 5.8 Hypothyroidism: In clinical RCC studies judgment of adequate wound healing. VOTRIENT should be discontinued in Transaminase elevations occur early in the course of treatment (92.5% of all elevations occur early in the course of treatment (92.5% of all (4%) patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 transaminase elevations of any grade occurred in the first 18 weeks). Across all Transaminase elevations of any grade occurred in the firstof18 weeks). Acrosstests all is of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring thyroid function monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was transaminase [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is monotherapy studies5.9 with VOTRIENT, ALT >3 X upper limit of with normal (ULN) was recommended. Proteinuria: In clinical RCC studies VOTRIENT, reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of reported in 138/977 (14%)reported and ALT in >844/586 X ULN was 40/977(<1%) (4%) and of Grade recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been (8%)reported [Grade 3,in5/586 patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and who received VOTRIENT. elevations in ALT >3periodic X ULN and 4, 1/586 (<1%)] [see AdverseConcurrent Reactions (6.1)]. Baseline and urinalysis proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in patients 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis >2treatment X ULN regardless of alkalineVOTRIENT phosphatase levels detectedif inthe during is recommended. should be were discontinued 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these bilirubin during treatment is recommended. VOTRIENT should be discontinued if the (1%)develops of patients. Four4 of the 13 patients no other VOTRIENT explanationcan for these patient Grade proteinuria. 5.10 had Pregnancy: cause elevations. Two of 977 (0.2%) patients died with disease progression and hepatic 13/977 patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause Two when of 977administered (0.2%) patients with disease andmechanism hepatic fetal harm to adied pregnant woman.progression Based on its failure. Monitor serum liver tests before initiation of treatment with VOTRIENT elevations. fetal harm when administered to a pregnant woman. Based on its mechanism MonitorVOTRIENT serum liver tests before initiation of treatment with VOTRIENT of action, is expected to result in adverse reproductive effects. In and at least once every 4 weeks for at least the first 4 months of treatment or as failure. of action, VOTRIENT is expected to result in adverse reproductive effects. In and pre-clinical at least oncestudies every 4inweeks forrabbits, at leastpazopanib the first 4 was months of treatment or as rats and teratogenic, embryotoxic, clinically indicated. Periodic monitoring should then continue after this time indicated. Periodic monitoring should then continue after this time studies pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may clinically period. Patients with isolated ALT elevations 3 X ULN and 8 X ULN may of VOTRIENT in pregnant women. If this between drug is used during pregnancy, or if the fetotoxic, and abortifacient. There are no adequate and well-controlled studies be continued on VOTRIENT with weekly monitoring of liver function until ALT on VOTRIENT withwhile weekly monitoring of the liverpatient function until be ALTapprised of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant taking this drug, should return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN be continued 1 or hazard baseline. Patients isolated ALT elevations of >8 should X ULN be patient becomes pregnant while taking this drug, the patient should be apprised of to theGrade potential to the fetus.with Women of childbearing potential should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the return of the potential hazard to the fetus. Women of childbearing potential should be should have VOTRIENT interrupted until they to VOTRIENT. Grade 1 or [See baseline. If the advised to avoid becoming pregnant whilereturn taking Use in potential benefit for reinitiating treatment with VOTRIENT is considered to advised to avoid becoming pregnant while taking VOTRIENT. [See Use in benefit for reinitiating Specific Populations (8.1).] treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced potential Specific Populations (8.1).] dose of no more than 400 mg once daily and measure serum liver tests weekly outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced 6 ADVERSE REACTIONS for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of dose of no more than 400 mg once daily and measure serum liver tests weekly 6 ADVERSE REACTIONS Clinical Because(2.2)]. clinical trials arereintroduction conducted under for 86.1 weeks [see Trials DosageExperience: and Administration Following of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be widely varying conditions, adverse reaction rates observed in thebeclinical trials 6.1 Clinical Trials Experience: Because clinical trials are conducted under VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should permanently discontinued. If ALT elevations >3 X ULN occur concurrently with 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 bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. permanently discontinued. If ALT elevations >3 X ULN occur concurrently with of a drug cannot be directly compared to rates in the clinical trials of another drugelevations and may not reflect the rates observed in permanently practice. Potentially serious bilirubin >2 X ULN, VOTRIENT should be discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, hyperbilirubinemia hemorrhagic events, arterial thrombotic events, Mild, indirect (unconjugated) may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing gastrointestinal perforation and fistula, and(12.5) hypertensive crisis [see Warnings and torsades de pointes, hemorrhagic events, arterial thrombotic events, Gilbert’s syndrome [see Clinical Pharmacology of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 gastrointestinal perforation and fistula, and hypertensive crisis [see Warnings Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per information]. Patients with only a mild indirect hyperbilirubinemia, known and Precautions (5.1-5.5)]. The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy included RCC Gilbert’s syndrome, and elevationstudies in ALT which >3 X ULN should586 be patients managedwith as per the recommendations outlined for isolated ALT elevations. Concomitant use of patients in the monotherapy studies which included 586 patients with RCC at the time of NDAoutlined submission. With a median durationConcomitant of treatmentuse of 7.4 the recommendations for isolated ALT elevations. of VOTRIENT and simvastatin increases the risk of ALT elevations and should be at the time of NDA submission. With a median duration of treatment of 7.4 monthsand (range 0.1 to 27.6), the most commonly observed adverse reactions VOTRIENT simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) with in thecaution 586 patients were diarrhea, [see hypertension, hair color change, undertaken and close monitoring Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea,data fatigue, anorexia,toand vomiting. Theofdata describedadministration below reflect Insufficient are available assess the risk concomitant of alternative statins and VOTRIENT. In patients with pre-existing moderate nausea, fatigue, anorexia, and vomiting. The data described below reflect the safetystatins profileand of VOTRIENT RCC patients who participated in a of alternative VOTRIENT.inIn290 patients with pre-existing moderate the safety profile of VOTRIENT in 290 RCC patients who participated in a VOTRIENT (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

B:22.5”

ASCOPost.com | MAY 15, 2012

PAGE 85

Awards

T:21” S:19.25”

Oncology Practices Recognized for Important Work in Clinical Trials

he Conquer Cancer Founda� tion of ASCO is recognizing six oncology practices from around the country for their work in improving access to clinical trials for patients in

their communities. In addition, three ASCO State Affiliate societies are be� ing honored for new projects that en� hance cancer care in their state and region (see sidebar).

The Conquer Cancer Founda� tion of ASCO Clinical Trials Par� ticipation Award and State Affiliate Grant Program recipients will be formally recognized at ASCO’s An�

nual Meeting in Chicago, June 1-5, 2012. More than $5 million in grants and awards will be presented by the Foundation at this year’s meeting. continued on page 86

randomized, double-blind, placebo-controlled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT.

T:13”

B:15”

S:12”

placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients randomized, double-blind, placebo-controlled study [see (14) of who received VOTRIENT and in <1% of patients who Clinical receivedStudies placebo. full prescribing The>3 median of treatment 7.4 absence months of who received VOTRIENT and in <1% of patients who received placebo. Concurrent information]. elevation in ALT X ULNduration and bilirubin >2 X ULNwas in the (range 0 to 23) alkaline for patients who received andin3.8 months 0 on Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant phosphatase >3 X VOTRIENT ULN occurred 5/290 (2%)(range of patients to 22) for the placebo arm.(1%) Forty-two percent of patients on VOTRIENT VOTRIENT and 2/145 on placebo. [See(42%) Dosage and Administration (2.2) of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) of required a dose interruption. Thirty-six percent (36%) of patients on Hypertension: VOTRIENT full prescribing information and Warnings and Precautions (5.1).] wereIndose reduced.clinical Table 1study presents most common adverse reactions a controlled with the VOTRIENT for the treatment of RCC, 115/290 full prescribing information and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 occurring in ≥10% patientsVOTRIENT who received VOTRIENT. patients (40%)ofreceiving compared with 15/145 patients (10%) Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on1.placebo experienced hypertension. Grade 3ofhypertension was reported in ≥10% Patients who Received Table Adverse Reactions Occurring in VOTRIENT 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo experienced hypertension. Grade 3 hypertension was reported in VOTRIENT on placebo. The majority of cases of hypertension were manageable with anti- 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) VOTRIENT Placebo hypertensive agents or dose reductions (<1%) permanently on placebo. The majority of cases of hypertension were manageable with antiVOTRIENT with 2/290 patients Placebo hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT (N = 290) (N = 145) discontinuing treatment with VOTRIENT because of hypertension. VOTRIENT (N = 290) crisis in patients with (N = 145) has been associated with hypertensive various cancer has been associated with hypertensive crisis in patients with various cancer All All types including RCC. In the overall safety populationAll for RCC (N = 586), one All a a types including RCC. In the overall safety population for RCC (N = 586), one Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 patient had hypertensive crisis on VOTRIENT. Warnings and Precautions a a Grades Grade 3 Grade[See 4 Grades Grade 3 Grade 4 patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical % % % % % % Adverse Reactions (5.6).] QT Prolongation and Torsades de Pointes: In a controlled clinical % (≥500 % msec) % % on routine % Adverse study Reactions with VOTRIENT, QT%prolongation was identified Diarrhea 52 3 <1 9 <1 0 study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine Diarrhea 52 in 3/290 3 <1of patients 9 treated <1with VOTRIENT 0 electrocardiogram monitoring (1%) electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT Hypertension 40 4 0 10 <1 0 compared with no patients Torsades de10 pointes was Hypertension 40 on placebo. 4 0 <1 reported 0 in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings compared with no patients on placebo. Torsades de pointes was reported in Hair color changes 38 <1 0 3 0 0 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings Hair changes(5.2).] Arterial 38 <1 0Events: In 3 a controlled 0 0 andcolor Precautions Thrombotic clinical Nausea 26 <1 0 9 0 0 and Precautions (5.2).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the events Nausea 26incidences <1 of arterial 0 thrombotic 9 0 such0as study with VOTRIENT, the incidences of arterial thrombotic events such as Anorexia 22 2 0 10 <1 0 myocardial infarction/ischemia [5/290 (2%)], Anorexia 22 2 0 cerebral 10 vascular <1accident0 [1/290 myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients Vomiting 21 2 <1 8 2 0 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients Vomiting 21 2to the placebo <1 arm8(0/145 for 2 each event). 0 treated with VOTRIENT compared Fatigue 19 2 0 8 1 1 treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Events: In1a controlled Fatigue 19 2 Hemorrhagic 0 8 1 [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled Asthenia 14 3 0 8 0 0 clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT Asthenia 14 3 0 8 0 0 and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT Abdominal pain 11 2 0 1 0 0 and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. Abdominal 11 2 0 patients 1 treated0with VOTRIENT 0 The most pain common hemorrhagic events in the Headache 10 0 0 5 0 0 The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), (2%), Headache 10 0 hemoptysis 0 5 and rectal 0 hemorrhage 0 were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage a National Cancer Institute Common Terminology Criteria for Adverse Events, (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic a National Institute Common Terminology for Adverse Events, and (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic version 3. eventsCancer experienced serious events including Criteria pulmonary, gastrointestinal, version 3. genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT events experienced serious events including pulmonary, gastrointestinal, and Other adverse reactions observed more commonly in patients treated with genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on with placebo. Other adverse reactions observed more commonly in (0%) patients treated VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.3).] Ininthe overall safety population in RCC VOTRIENT than placebo and that occurred <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% [See Warnings and Precautions (5.3).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), patients treated with(5% VOTRIENT. Hypothyroidism: In (1% a controlled clinical study (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) versus <1%), dyspepsia versus <1%), facial edema versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid(6% stimulating hormone palmar-plantar erythrodysesthesia (hand-foot syndrome) versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range(3% at any proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation versus 0%), and weight decreased (9% versus 3%). (TSH) within the normal range at baseline to above the normal range at any post-baseline visit indecreased VOTRIENT(9% compared versus 0%), and weight versus with 3%).the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in post-baseline visit in VOTRIENT compared with the placebo arm (27% compared Table 2 presents the most common laboratory abnormalities occurring in >10% presents(7%) the most common laboratory abnormalities occurring >10% arm. with 5%, respectively). Hypothyroidism was reported as an adverse reaction in treated with VOTRIENT and no patients (0%) in theinplacebo of patients who received VOTRIENT and more commonly (≥5%) in patients who Table192 patients 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. of patients who received VOTRIENT(5.8).] and more commonly (≥5%) in patients who [See Warnings and Precautions Diarrhea: Diarrhea occurred frequently received VOTRIENT versus placebo. received VOTRIENT versus placebo. and was predominantly mild to moderate in severity. Patients should be advised [See Warnings and Precautions (5.8).] Diarrhea: Diarrhea occurred frequently Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients how to manageLaboratory mild diarrhea and to notify their healthcare provider if moderate and was predominantly mild to moderate in severity. Patients should be advised Table 2. Selected Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who toReceived severe diarrhea occurs soMore appropriate management can be implemented to how to manage mild diarrhea and to notify their healthcare provider if moderate in Patients who who VOTRIENT and Commonly (≥5%) to severe diarrhea occurs so appropriate management can be implemented to Received VOTRIENT Versus Placebo minimize its impact. Proteinuria: Received VOTRIENT Versus PlaceboIn the controlled clinical study with VOTRIENT, minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated VOTRIENT Placebo with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with proteinuria has been reported as an adverse reaction in 27 patients (9%) treated Placebo In a single- with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with (N = 290) (N = 145) VOTRIENT. [See Warnings andVOTRIENT Precautions (5.9).] Lipase Elevations: (N = 145) arm clinical study, increases in(N = 290) lipase values were observed for 48/181 patients VOTRIENT. [See Warnings and Precautions (5.9).] Lipase Elevations: In a singleAll All All as an adverse reaction were All reported for 10 patients arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 (27%). Elevations in lipase as an adverse reaction were reported for 10 patients a Grade and 3 Grade Grade GradeRCC 4 (4%) and were Grade 3Grades for 6 apatients Grade44 Grades for 1 patient. In 3clinical (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC Parameters % % % % % % studies of VOTRIENT, clinical was Parameters % pancreatitis % % observed % in 4/586 % patients % (<1%). studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction Hematologic Hematologic (such as a decrease in ejection fraction and congestive heart failure) in patients Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction Leukopenia 37 0 0 6 0 0 with various cancer types, Leukopenia 37 including 0 RCC. In0the overall 6 safety 0population0 for RCC (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC Neutropenia 34 1 <1 6 0 0 (N = 586), cardiac dysfunction was1 observed Neutropenia 34 <1in 4/5866 patients0(<1%). 0 (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). Thrombocytopenia 32 <1 <1 5 0 <1 7 DRUG INTERACTIONS32 Thrombocytopenia <1 <1 5 0 <1 Lymphocytopenia 31 4 <1 24 1 0 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro 7 DRUG INTERACTIONS Lymphocytopenia 31 4 <1 24 1 0 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver Chemistry studies suggested that the oxidative metabolism of pazopanib in human liver Chemistry microsomes is mediated primarily by CYP3A4, with minor contributions from ALT increased 53 10 2 22 1 0 CYP1A2 and CYP2C8. Therefore, inhibitors and may0 alter microsomes is mediated primarily by CYP3A4, with minor contributions from ALT increased 53 10 2 inducers 22 of CYP3A4 1 AST increased 53 7 <1 19 <1 0 the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter AST 7 ketoconazole, <1 19 0 the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib withincreased strong inhibitors of 53 CYP3A4 (e.g., ritonavir,<1 clarithromycin) Glucose with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) 41 <1 0 33 1 0 Glucose may increase pazopanib41 concentrations. A dose increased <1 0 reduction 33 for VOTRIENT 1 0should may increase pazopanib concentrations. A dose reduction for VOTRIENT should increased be considered when it must be coadministered with strong CYP3A4 inhibitors Total bilirubin be considered when it must be coadministered with strong CYP3A4 inhibitors 36 3 <1 10 1 <1 [seebilirubin Dosage and Administration (2.2)]. Grapefruit juice should be avoided Total increased 36 and may 3 also <1 1 <1 [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity increase 10 plasma concentrations increased as it inhibits CYP3A4 activity and may also increase plasma concentrations Phosphorus of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may 34 4 0 11 0 0 Phosphorus of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decreased 34 concentrations. 4 0VOTRIENT 11 should0not be used 0 if decrease plasma pazopanib decreased decrease plasma pazopanib concentrations. VOTRIENT should not be used if Sodium chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and 31 4 1 24 4 0 Sodium chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and decreased Administration (2.2)]. 7.231 Effects of4 Pazopanib Results 1 on CYP 24 Substrates: 4 0 decreased from drug-drug interaction studies conducted in cancer patients suggest that Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results Magnesium from drug-drug interaction studies conducted in cancer patients suggest that 26 <1 1 14 0 0 Magnesium pazopanib is a weak inhibitor CYP2C8, and decreased 26 of CYP3A4, <1 1 14 CYP2D6 0 in vivo,0but pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but decreased had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology Glucose had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology 17 0 <1 3 0 0 (12.3) of full prescribing information]. Concomitant use of VOTRIENT with Glucose decreased 17 0 <1 are metabolized 3 0by CYP3A4, 0 (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that decreased a agents with narrow therapeutic windows that are metabolized by CYP3A4, National Cancer Institute Common Terminology Criteria for Adverse Events, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in a National Cancer Institute Common Terminology Criteria for Adverse Events, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in version 3. inhibition of the metabolism of these products and create the potential for version 3. inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT information.] 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Hepatic Toxicity:Across In a controlled clinical study with with VOTRIENT, VOTRIENT for Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and elevations. monotherapy studies ALTthe >3treatment X ULN was of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was

PAGE 86

Awards

The ASCO Post | MAY 15, 2012

B:12” T:10.5” S:8.75”

Oncology Practices continued from page 85

“The Conquer Cancer Foundation is pleased to recognize these community oncology practices that have been suc� cessful in performing oncology clinical trials in their communities. Clinical tri� als are a critical piece of the cancer care

delivery system and ultimately lead to improved patient outcomes and progress in cancer treatments,” said Martin J. Murphy, PhD, DMedSc, Chair of the Conquer Cancer Founda� tion Board of Directors. “We also hope that the State Affiliate grants will pro� vide much needed support for special

projects that contribute to improved oncology care in the states and com� munities supported by these affiliates.”

Clinical Trials Participation Award The Clinical Trials Participation Award recognizes practices that have Martin J. Murphy, PhD, DMedSc

reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

• Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. —yellowing of the skin or the whites of the eyes (jaundice), —unusual darkening of the urine, —unusual tiredness, —right upper stomach area pain.

The ASCO Post

• Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a registered trademark of GlaxoSmithKline.

Like us on

Facebook

©2012, GlaxoSmithKline. All rights reserved. Revised 03/2012 VTR:6BRS ©2012 The GlaxoSmithKline Group of Companies Companies All rights reserved. Printed in USA. VOT316R0 VOT219RO April April 2012 2012

facebook.com/TheASCOPost

T:13”

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following:

B:15”

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/ day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/ kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/ day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

S:12”

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/ kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/ kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin > 1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N = 11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin > 3 X ULN regardless of the ALT value) was 200 mg per day (N = 14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/ min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

established high-quality clinical cancer research programs. Oncology practices are selected based on several factors, in� cluding patient accrual rates, accrual of minority and underrepresented popu� lations, and innovative techniques in overcoming barriers to participation in clinical trials. The Conquer Cancer Foundation acknowledges the Coali� tion of Cancer Cooperative Groups for 10 years of continued support of the Clinical Trials Participation Award and for collaborating with the Founda� tion and ASCO to support access to clinical trials in communities. This year’s recipients include: ■■ Altru Cancer Center of Altru Health System, Grand Forks, North Dakota ■■ Billings Clinic, Billings, Montana ■■ Derrick L. Davis Forsyth Regional Cancer Center, Winston Salem, North Carolina ■■ LRGHealthcare-Lakes Region General Hospital, Laconia, New Hampshire ■■ Northwest Medical Specialties, Tacoma, Washington ■■ West Michigan Cancer Center, Kalamazoo, Michigan

ASCOPost.com | MAY 15, 2012

PAGE 87

Journal Spotlight Hematology

Oral Rivaroxaban Is Noninferior to Standard Anticoagulant Therapy in Acute Pulmonary Embolism By Matthew Stenger

hromboembolic disease is com� mon in patients with cancer and increases risk of mortality. Recent studies showed that the oral factor Xa inhibitor rivaroxaban (Xarelto) was as effective and safe as standard antico� agulant therapy in treating deep-vein thrombosis, with superior efficacy of rivaroxaban observed in a continuedtreatment cohort.1 Rivaroxaban may thus represent a simple, fixed-dose alternative to standard anticoagulant therapy that can be used without need for laboratory monitoring in treatment of deep-vein thrombosis. A more re� cent investigation (EINSTEIN-PE study) has assessed the effects of rivarox� aban in the treatment of acute symptomatic pulmonary embo� lism, finding that the See Page 89 agent had efficacy noninferior to standard therapy in ini� tial and continued treatment while of� fering a potential improvement in riskbenefit profile.2

Study Design In this open-label, noninferiority trial,2 4,832 patients with acute symp� tomatic pulmonary embolism with or without deep-vein thrombosis were randomly assigned to receive rivaroxa� ban (15 mg twice daily for 3 weeks fol� lowed by 20 mg once daily; n=2,420) or standard therapy consisting of enoxaparin followed by dose-adjusted vitamin K antagonist treatment (n = 2,413) for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous throm� boembolism, defined as a composite of fatal or nonfatal pulmonary embolism or deep-vein thrombosis. The primary safety outcome was major bleeding or clinically relevant nonmajor bleeding (the latter defined as bleeding requir� ing medical intervention, unsched� uled physician contact, interruption of study treatment, or impairment of activities of daily life). The rivaroxaban and standard ther� apy groups were similar with regard to mean age (58 years), gender (54%

and 52% male), proportion with con� current deep-vein thrombosis (25%), and proportion hospitalized (89%). Causes of pulmonary embolism in the two groups were unprovoked (65% and 64%), recent surgery/trauma (17% in both), immobilization (16% in both), estrogen therapy (9% in both), and active cancer (5% in both). Before randomization, almost all patients re� ceived low-molecular-weight heparin pending confirmation of a pulmonary embolism diagnosis. This therapy was limited to 1�� day in almost 60% of pa� tients, and less than 2% received more than 2 days of treatment. The intended duration of study treatment was 3 months in approxi� mately 5% of patents in both groups, 6 months in 57%, and 12 months in

95% CI = 0.75-1.68), with the differ� ence meeting the prespecified crite� rion for noninferiority of rivaroxaban (P = .003). Similar numbers of pa� tients in the rivaroxaban and standard therapy groups had fatal pulmonary embolism (2 vs 1), death in which pul� monary embolism could not be ruled out (8 vs 5), nonfatal pulmonary em� bolism (22 vs 19), recurrent deep-vein thrombosis plus pulmonary embo� lism (0 vs 2), and recurrent deep-vein thrombosis (18 vs 17). There was no difference between the rivaroxaban group and the stan� dard therapy group with regard to risk for the composite safety endpoint of major bleeding or clinically relevant nonmajor bleeding during treatment (10.3% vs 11.4%; HR = 0.90, 95% CI =

Rivaroxaban for Thrombosis and Pulmonary Embolism ■■ The oral factor Xa inhibitor rivaroxaban has proven to be a simple,

fixed-dose alternative to standard anticoagulant therapy that can be used without need for laboratory monitoring in treatment of deep-vein thrombosis.

■■ A more recent study has shown rivaroxaban to have efficacy noninferior to standard therapy in initial and continued treatment of acute symptomatic pulmonary embolism, while offering a potential improvement in riskbenefit profile.

37%. The mean study duration was 263 days in the rivaroxaban group and 268 days in the standard therapy group. Treatment was discontinued early in 11% of rivaroxaban patients and 12% of standard therapy patients, with the most common reasons being adverse events and withdrawal of consent. Pro� portions of patients lost to follow-up were similar in the two groups (0.3% and 0.4%). During study treatment, international normalized ratio (INR) was in the therapeutic range 62.7% of the time and exceeded 3.0 15.5% of the time in the standard therapy group.

Intent-to-treat Analysis On intent-to-treat analysis, symp� tomatic recurrent venous thromboem� bolism occurred in 2.1% of rivaroxa� ban patients, compared with 1.8% of standard therapy patients (HR = 1.12,

0.76-1.07). A significantly smaller pro� portion of rivaroxaban patients experi� enced a major bleeding event (1.1% vs 2.2%; HR = 0.49, 95% CI = 0.31-0.79, P = .003). Fatal major bleeding events occurred in two rivaroxaban patients and three standard therapy patients. Clinically relevant nonmajor bleed� ing occurred in 9.5% of rivaroxaban patients and 9.8% of standard therapy patients. A measure of net clinical benefit combined the number of patients with recurrent venous thromboembolism and the number of patients with ma� jor bleeding experienced during treat� ment or during the study period after treatment had stopped. The rate of this composite outcome was nonsignifi� cantly lower in the rivaroxaban group (3.4% vs 4.0%, HR = 0.85, 95% CI = 0.63-1.14).

Key Data The two treatments were similar with regard to adverse events. Any ad� verse event occurred in 80% of rivar� oxaban patients and 79% of standard therapy patients, with serious adverse events occurring in approximately 20% in each group, events resulting in dis� continuation of study drug occurring in 5% and 4%, and events leading to hospitalization occurring in 20% and 18%. Acute coronary events during treatment occurred in 0.6% and 0.9% of patients, respectively, with the rate during the 30-day poststudy treatment period being 0.1% in both groups. Overall, death occurred in 2.4% of rivaroxaban patients and 2.1% of stan� dard therapy patients. Causes of death in the two groups included pulmonary embolism or pulmonary embolism not ruled out in 11 and 7 patients and bleeding in 5 and 4 patients, respec� tively; fatal bleeding episodes occurred in 3 rivaroxaban patients and 1 stan� dard therapy patient when they were no longer taking study medication. Other causes of death included can� cer (20 and 23 patients), myocardial infarction (2 and 1 patient), ischemic stroke (2 and 1 patient), other cardiac disorder/respiratory failure (4 and 4 patients), and infectious disease/septi� cemia (10 and 6 patients). The notion that rivaroxaban can be administered at the same dose in all pa� tients without laboratory monitoring has raised concern. However, as stated by the investigators, subgroup analyses showed that rates of recurrent venous thromboembolism and bleeding were similar in the two study groups regard� less of age, sex, presence or absence of obesity, level of renal function, or ex� tent of pulmonary embolism.

■

References 1. The EINSTEIN Investigators: Oral rivaroxaban for symptomatic ve� nous thromboembolism. N Engl J Med 363:2499-2510, 2010. 2. The EINSTEIN-PE Investigators: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366:1287-1297, 2012.

The ASCO Post | MAY 15, 2012

PAGE 88

News

ASCO President Michael P. Link, MD, Makes Statement on Passage of FDA Safety and Innovation Act

SCO President Michael P. Link, MD, recently issued the following statement in response to the Senate Health, Education, La�

bor and Pensions Committee’s Pas� sage of the FDA’s Safety and Inno� vation Act: “ASCO commends the Senate

Health, Education, Labor and Pen� sions Committee for taking steps to address a crisis in cancer care through its reauthorization of pre�

AMG 386: Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-1: A Phase 3, Randomized, Double-Blind Trial of Weekly Paclitaxel Plus AMG 386 or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of AMG 386 With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Primary Endpoint: • Progression-free ee survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

■

Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

AMG 386 IV QW + Paclitaxel IV QW (3 on/1 off)

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + Paclitaxel IV QW (3 on/1 off)

R A N D O M I Z A T I O N

AMG 386 IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

AMG 386 IV QW Monotherapy

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

Primary

PFS

2:1 randomization

Placebo IV QW Monotherapy

Key Secondary

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

AMG 386 is an investigational agent that has not been approved by the FDA for the use under investigation for this trial.

For Additional Information:: • Amgen Call Center: (866) 57-AMGEN • www.AmgenTrials.com Trials.com (20090508) T • www.ClinicalTrials.gov Trials.gov (NCT01204749) T

scription drug user fee legislation. Drug shortages are continuing to strike hospitals and oncology prac� tices and threaten patient care throughout the country. In cancer care alone, 19 different therapies re� main in short supply.” Dr. Link added that “The legisla� tion’s creation of an interagency task force will help ensure that shortages are managed as efficiently as pos� sible. We are also pleased that the bill requires manufacturers to give the FDA six-months’ notice of an anticipated shortage of a life-saving therapy. However, fines or some oth� er type of enforcement mechanism are needed to ensure manufactur� ers comply with this requirement. ASCO hopes that this change may be added before final passage.” Further, Dr. Link said “We thank Senators Tom Harkin [D-Iowa] and Michael Enzi [R-Wyo.] for their lead� ership on the drafting and committee approval of this legislation. We urge the full Senate to pass the bill with the drug shortages provisions as quickly as possible.” For an in-depth interview with Dr. Link about the Oncology Drug Shortage and how to advise your patients who may have questions, see page 97 in this issue of The ASCO Post.

AMG 386 is an investigatio i tigational agent that at has not been approved ed by the FDA for the use se underr investigatio tigation forr this ttrrial.

For Additional Informat Information on: • Amgen Call Center: (866) 57-AMGEN • www w.Amgen .AmgenT Trials.com T rials.com (20101129) • www.ClinicalTrials.gov Trials.gov T rials.gov (NCT01493505)

Send Us Your

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

ASCOPost.com | MAY 15, 2012

PAGE 89

Lab Notes

Ongoing Molecular Research in the Science of Oncology Role of Myofibroblasts

GENE PROFILING Characteristics of Field Cancerization in Histologically Normal Tissue Adjacent to Breast Tumors It has been shown that a field of genetically altered but histologically normal tissue extends 1 cm or more from the margins of human breast tumors. The characteristics of this field are not fully understood, al� though it is clear that the molecular alterations in affected cells could provide mechanisms for increased replicative capacity, genomic insta� bility, and a microenvironment that supports tumor initiation and pro� gression. Trujillo and colleagues from the University of New Mexico, Albuquerque, and Johns Hopkins School of Medicine, Baltimore, recently identified a gene signa� ture that differentiated between patient-matched, tumor-adjacent histologically normal breast tissues located 1 cm from the margin of breast adenocarcinomas and those located 5 cm from the margin. The signature includes genes involved in extracellular matrix remodeling, wound healing, fibrosis, and epi� thelial to mesenchymal transition (EMT).

Myofibroblasts, which are media� tors of wound healing and fibrosis, and intralobular fibroblasts expressing MMP2, SPARC, TGF-β3, which are inducers of epithelial to mesenchy� mal transition, were both prevalent in tumor-adjacent histologically normal tissues 1 cm from the margin, sparse in tumor-adjacent histologically normal tissues 5 cm from the margin, and ab� sent in normal tissues (from reduction mammoplasty). In tumor-adjacent histologically normal tissues 1 cm from the margin, the epithelial-mes� enchymal transition markers S100A4 and vimentin were elevated in luminal epithelial and myoepithelial cells and the epithelial-mesenchymal transition markers α-smooth muscle actin and SNAIL were elevated in luminal epi� thelial cells. As stated by the investigators, “These results identify cellular pro� cesses that are differentially activated between [tumor-adjacent histologi� cally normal breast tissues 1 cm from the margin and those tissues 5 cm from the margin], implicate myofi� broblasts as likely mediators of these processes, provide evidence that [epi� thelial to mesenchymal transition] is occurring in histologically normal tissues within the affected field, and identify candidate biomarkers to in� vestigate whether or how field can�

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

cerization contributes to the develop� ment of primary or recurrent breast tumors.” Trujillo KA, et al: In t J Cancer 129:13101321, 2011.

TARGETED THERAPY Inhibition of IL-8 Receptor Reduces Colorectal Cancer Proliferation and Sensitizes the Disease to Oxaliplatin Recent studies have shown that interleukin-8 (IL-8) and its receptors CXCR1 and CXCR2 are significantly upregulated in colorectal cancer tu� mors and their microenvironment and act as regulators of proliferation, angiogenesis, and metastasis. Ning and colleagues from the University of Southern California, Los Ange� les, have evaluated the in vitro and in vivo effects of inhibition of CXCR2 in colorectal cancer. After showing that IL-8 overexpres� sion in colorectal cancer cells induces upregulation of the CXCR2-mediated proliferative pathway, these investiga� tors assessed whether a CXCR2 an� tagonist (SCH-527123) could inhibit colorectal cancer proliferation and sensitize colorectal cancer cells to ox� aliplatin. The antagonist suppressed CXCR2-mediated signal transduc� tion, as evidenced by decreased phos�

phorylation of the NF-κB/MAPK/ AKT pathway. Antagonist treat� ment of HCT116 See Page 89 and Caco2 colorec� tal cancer parental cell lines and their respective IL-8– overexpressing variants resulted in concentration-dependent antipro� liferative effects, decreased cell mi� gration and invasion, and increased apoptosis. Antagonist treatment in xenograft-bearing mice resulted in reduced tumor growth and microves� sel density compared with vehicletreated tumors. The combination of SCH-527123 and oxaliplatin resulted in greater reductions in cell prolifera� tion, tumor growth, and angiogenesis and a greater increase in apoptosis compared with treatment with either agent alone. As stated by the investigators, “Taken together, these findings sug� gest that targeting CXCR2 may block tumor proliferation, migration, in� vasion, and angiogenesis [and that] CXCR2 blockade may further sensi� tize [colorectal cancer] to oxaliplatin treatment.”

■

Ning Y, et al: Mol Cancer Ther. March 5, 2012 (early release online).

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

When you see a code that you would like to scan, start your code-reading application.

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.

The ASCO Post | MAY 15, 2012

PAGE 90

News

Brachytherapy Associated with Increased Complications Compared to Whole-breast Irradiation following Lumpectomy for Breast Cancer

mong older women with inva� sive breast cancer and treated with lumpectomy, brachytherapy compared with whole-breast irradiation was associ� ated with a decreased likelihood of longterm breast preservation and an increased likelihood of complications, but no dif� ference in overall survival, according to a study published recently in the Journal of the American Medical Association.1

breast irradiation. Brachytherapy was also associated with a higher risk of postop� erative complications; by 1 year, 1,126 pa� tients (16.20%) treated with brachythera�

py experienced skin or soft-tissue infection compared with 8,860 (10.33%) treated with whole-breast irradiation. “Similarly, by 1 year 1,132 patients (16.25%) treated

CD30-directed therapy

Although these results await validation in the prospective setting, they also prompt caution over widespread application of breast brachytherapy outside the study setting. Grace L. Smith, MD, PhD, MPH, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues conducted a study to compare breast brachytherapy vs whole-breast irradiation and the likelihood of long-term breast preservation, complications, and survival among older Medicare patients diagnosed with invasive breast cancer. According to the authors, “In recent years, use of breast brachytherapy after lumpectomy for early breast cancer has increased substantially despite a lack of randomized trial data comparing its effectiveness with standard whole-breast irradiation. Because results of long-term randomized trials will not be reported for years, detailed analysis of clinical outcomes in a nonrandomized setting is warranted.”

with brachytherapy experienced non� infectious postoperative, complications compared with 7,721 (9.00%) treated with whole-breast irradiation.”

CT SCANS confirmed responses in relapsed patients

120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/Lin:DCM/id:ID W:200 L25

512x512 B

Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9

A R

L Vp

Study Details The retrospective population-based study included 92,735 women ages 67 years or older with incident invasive breast cancer, diagnosed between 2003 and 2007 and followed up through 2008. After lumpectomy, 6,952 patients were treated with brachytherapy vs 85,783 with whole-breast irradiation. Breast brachytherapy was associated with a higher risk of subsequent mastec� tomy, with a 5-year cu� mulative incidence of 3.95% in patients treat� ed with brachytherapy vs 2.18% in patients See Page 89 treated with whole-

2011 August 19 Acq Tm: 14:05:52

855.4SEAGEN (855.473.2436) SeaGenSecure.com

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104d

ASCOPost.com | MAY 15, 2012

PAGE 91

News

Brachytherapy was generally associ� ated with higher risk of postradiation complications. “Specifically, 5-year cumu� lative incidence of breast pain was 14.55% in patients treated with brachytherapy vs 11.92% in patients treated with wholebreast irradiation; fat necrosis was 8.26% vs 4.05%; and rib fracture was 4.53% vs

3.62%,” the authors wrote. Five-year overall survival was 87.66% in patients treated with brachytherapy vs 87.04% in patients treated with whole-breast irradiation. At 5 years, an absolute 1.77% excess mastectomy risk in patients treated with brachytherapy compared with whole-

breast irradiation meant that, for every 56 women treated with breast brachy� therapy, 1 woman was harmed with unnecessary mastectomy. At 1 year, an absolute 10.64% excess postoperative complication risk in women treated with brachytherapy meant that for ev� ery 9 women treated with brachythera�

After multiple failures,

single-agent response Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

sALCL: 86% ORR (95% CI: 77%-95%)

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

Important Safety Information BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

py, 1 was harmed with an unnecessary postoperative complication.

■

Disclosure: The authors of the JAMA paper reported no potential conflicts of interest.

Reference 1. Smith GL, Xu Y, Buchholz TA, et al: JAMA 307:1827-1837, 2012.

The ASCO Post | MAY 15, 2012

PAGE 92

Issues in Oncology

Novel Initiative to Address Oncology Drug Crisis By Alice Goodman

uch has been written about the oncology drug shortage crisis in the United States. In the spirit of being part of the solution to that prob�

to find solutions to alleviate oncology drug shortages and to foster alternative drug discovery and development of drugs that are cheaper than and as safe

lem, a group of oncologists has formed the Citizen’s Oncology Foundation (COF). The goal of the start-up notfor-profit association is two-pronged:

Gabriel N. Hortobagyi, MD

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

General dosing information

Dose modification

Giving Back to the Cancer Community

Nursing mothers

It is not known whether brentuximab vedotin 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 ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

Laurence H. Baker, DO

Laurence H. Baker, DO, who is credited with the idea for the foun� dation, explained that COF is in the tradition of “social entrepreneurship,” which means an effort that benefits the greater community and also gen� erates a small profit (used toward selfpreservation, expansion, or to further social goals). In other words, Citizen’s Oncology Foundation will explore be� coming a successful business that pro� motes social good. Dr. Baker is Chair of the SWOG cancer research cooper� ative group and is Collegiate Professor in Cancer Developmental Therapeu� tics at University of Michigan Medical School, Ann Arbor.

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

and effective as those currently being used to treat many types of cancer. In the words of founding member Gabriel N. Hortobagyi, MD, the or� ganization was formed “when the stars, moon, and sun aligned in a way to favor good deeds.” Dr. Hortobagyi is Chair of Breast Medical Oncology at MD An� derson Cancer Center, Houston.

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150b

Drs. Baker and Hortobagyi said that they are at a point in their careers where they want to use their influence to give back to the cancer community by addressing major challenges related to access to oncology drugs. Dr. Baker said that the seed for COF was planted when he received a university-wide e-mail notifying the faculty of a doxo�

ASCOPost.com | MAY 15, 2012

PAGE 93

Issues in Oncology

rubicin shortage, with no suggestions about what other drugs might be good substitutes. “At SWOG, when a drug is in shortage, we try to advise physicians about alternatives. I was in the pro� cess of writing an angry e-mail to the leadership and faculty at my institu� tion, when I realized that writing yet another e-mail was not going to ad� dress the problem. That was the ‘aha’ moment, and I decided that action was needed.” Over the years, Dr. Baker had had conversations with similar-minded colleagues, and together they found� ed Citizen’s Oncology Foundation. These colleagues are: Lowell E. Schnipper, MD, Chief of Oncology at Beth Israel Hospital, Boston; Mark J. Ratain, MD, Leon O. Jacobson Professor of Medicine and Associ� ate Director for Clinical Sciences at the Cancer Research Center at Uni� versity of Chicago; Frederick R. Appelbaum, MD, Executive Director of the Seattle Cancer Care Alliance at the Fred Hutchinson Cancer Center, Seattle; Michael P. Link, MD, cur� rent President of ASCO and Profes� sor of Pediatrics at Stanford Univer� sity School of Medicine, California; and George F. Tidmarsh, MD, a pe� diatric oncologist who has spent most of his career as a businessman in the pharmaceutical industry and an ex� pert on delivery of generic drugs.

Two-pronged Mission The first part of COF’s mission is to ensure the continuing availability of ge� neric oncology drugs to all Americans. Some possible strategies to address this, according to Dr. Baker, are for

Citizen’s Oncology Foundation to (1) go into business as a generic drug com� pany, (2) lobby Congress for changes that will encourage generic drug com� panies to continue to produce oncolo� gy drugs, especially injectables, and (3) coordinate efforts with other powerful groups invested in the same goal. The second, and equally important mission of COF is to serve as an al� ternative pathway to drug discovery, development, and delivery. Elabo�

ed to exemestane more than doubled progression-free survival in metastat� ic breast cancer.1 “This is the first time that we were able to show extended progres� sion-free survival with hormonal therapy,” he said. Although an ef� fect on overall survival remains to be shown for the combination of evero� limus and exemestane, the authors hypothesized that they could get a similar benefit from substituting ra�

Citizen’s Oncology Foundation Sets Goals ■■ Citizens’ Oncology Foundation is a new not-for-profit group founded by

oncologists to seek solutions to oncology drug shortages and provide an alternative pathway for drug discovery, design, and development.

■■ The mission of the Citizen’s Oncology Foundation is twofold: to ensure

availability of generic oncology drugs for all Americans; and to serve as an alternative pathway to drug discovery, development, and delivery.

■■ The foundation is collaborating with business experts to develop a sound model for social entrepreneurship.

rating on this goal, Dr. Hortobagyi explained that there is a disconnect between the research that he and his colleagues believe is needed and the research they are actually able to do, mainly because of shrinking support from NCI and the growing influence of Pharma. “Much of the research that we think is important does not interest the NCI or Pharma,” Dr. Hortobagyi said. An example is the potential use of rapamycin (sirolimus, Rapamune) as a replacement for everolimus (Afini� tor) in the treatment of metastatic breast cancer. At the 2011 San Anto� nio Breast Cancer Symposium, Dr. Hortobagyi and colleagues presented a study showing that everolimus add�

pamycin, the parent compound for everolimus, which would be much cheaper. First, a noninferiority study comparing rapamycin vs everolimus would be needed. “We could save the health-care sys� tem billions of dollars if this proves to be true,” Dr. Hortobagyi said. Another example of a much less ex� pensive, but possibly equally safe and effective therapy might be to replace tamoxifen with its active metabolite, endoxifen. At present, neither Pharma nor the NCI would support a study to demonstrate endoxifen’s equivalence with tamoxifen, even though—once again—billions could be saved each year. This is exactly the type of research that COF wants to engage in.

Sound Business Model Citizen’s Oncology Foundation has filed for approval as a 501.3c (taxexempt) corporation. The founders are in the process of developing a sound business model in conjunction with the University of Michigan’s Ross School of Business and the Tech Transfer group of the School of Medicine. Also, Dr. Baker and other COF members are ex� ploring relationships with benefactors who believe in social entrepreneurship and exploring potential partnerships with other professional societies. Thus far, the response has been enthusiastic, Dr. Baker said. “In the next few months, we will meet with consultants and have busi� ness models based on solid business practices compatible with social entre� preneurship,” Dr. Baker said. “The founders of Citizen’s Oncol� ogy Foundation are passionate about this. We want to make this a viable entity. The initiative itself is great news and will be the first tangible ser� vice to the oncology community,” Dr. Hortobagyi stated.

■

Disclosure: Dr. Hortobagyi serves as a consultant to Allergan, Genentech, Merck, Novartis, and sanofi-aventis and receives research support for a multicenter clinical trial from Novartis. Dr. Baker receives grant support from the National Institutes of Health and Hyatt Corporation and he’s on the advisory board of The Hope Foundation, Merck, BioMed Valley, Inc, and CytRx DSMB.

Reference 1. Hortobagyi GN, Piccart M, Rugo H, et al: Everolimus for postmenopausal women with advanced breast cancer: Up� dated results of the BOLERO-2 phase III trial. San Antonio Breast Cancer Sympo� sium. Abstract S3-7. Presented December 8, 2011.

Visit The ASCO Post at the ASCO Annual Meeting

June 2012, Chicago

The ASCO Post – BOOTH 6068

Harborside Press – BOOTH 6069

The ASCO Post | MAY 15, 2012

PAGE 94

News

Fellows of the American Society of Clinical Oncology: 2012 Recipients Will be Honored at ASCO Annual Meeting

ormerly called the ASCO Statesman Award, which launched in 2007, the new distinction of Fellow of the American Society of Clinical Oncology

(FASCO) is designed to honor ASCO’s B:8.375” most active volunteer members. T:7.875” “The FASCO status represents rec� S:7” ognition for the most dedicated volun�

teer members inside the organization,” said ASCO CEO Allen Lichter, MD. “These are people who have given of themselves tirelessly over a long period

of time. They represent the very best of our organization.”

Recipients in 2012 include:

Visit Booth #10027 at ASCO for more information

Harold J. Burstein, MD, PhD

Nora Janjan, MD, MPSA, MBA

Bruce E. Johnson, MD

Karen Kelly, MD

David Khayat, MD

B:11.125”

S:10”

angiogenesis than VEGF-A?

T:10.5”

Is there more to

Barnett S. Kramer, MD, MPH

Mark N. Levine, MD

VEGF-A DOES NOT ACT ALONE As tumors grow, other angiogenic factors such as VEGF-B and placental growth factor (PlGF) can also contribute to angiogenesis.1-3

Thomas A. Marsland, MD

Inhibiting additional angiogenic factors beyond VEGF-A has become an important area of oncology research. For additional information about the role of VEGF-A, VEGF-B, and PlGF in angiogenesis, go to www.VEGFandBeyond.com.

William C. Penley, MD

Sanofi and Regeneron are investigating the potential impact of broad blockade of angiogenic growth factors, including VEGF-A, VEGF-B, and PlGF. Richard L. Schilsky, MD

References: 1. Zhang F, Tang Z, Hou X, et al. VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis. PNAS. 2009;106:6152-6157. 2. Taylor AP, Rodriguez M, Adams K, et al. Altered tumor vessel maturation and proliferation in placenta growth factor-producing tumors: potential relationship to post-therapy tumor angiogenesis and recurrence. Int J Cancer. 2003;105:158-164. 3. Fischer C, Jonckx B, Mazzone M, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131:463-475. US.AFL.12.04.006 4/12 Printed in U.S.A. © 2012 sano-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

Deborah Schrag, MD, MPH

ASCOPost.com | MAY 15, 2012

PAGE 95

News

Oncology Professionals and Leaders to be Honored at ASCO Annual Meeting

SCO is recognizing researchers, patient advocates, and leaders of the global oncology community through its Special Awards Program at this year’s Annual Meeting in Chi� cago. Recipients of ASCO’s special awards collectively represent signifi� cant strides in cancer treatment and leadership in the oncology commu� nity. George Sledge, MD, ASCO im� mediate Past President and Chair of the Special Awards Selection Commit� tee, said “We are honored to commend their contributions and accomplish� ments in the field of oncology with ASCO’s most prestigious awards.”

Among the 2012 ASCO Special Awards Honorees Distinguished Achievement Award

Robert F. Ozols, MD, PhD

Robert F. Ozols, MD, PhD, an in� ternationally known expert in ovarian cancer and a leader in advancing che� motherapy research, is the recipient of the 2012 Distinguished Achievement Award for his extraordinary leadership in the field of oncology. Dr. Ozols was the first Audrey Weg Schaus and Geof� frey Alan Weg Chair in Medical Sci� ence at Fox Chase Cancer Center, and also served as senior vice president and chief clinical officer at Fox Chase Cancer Center until his retirement in 2008 following two decades of service at the institution. His research has

Visit

focused on how cancer cells develop drug resistance and on strategies for overcoming resistance.

Special Recognition Award

David Satcher, MD, PhD

David Satcher, MD, PhD, is the recipient of the 2012 Special Recogni� tion Award for his leadership as a pub� lic health administrator and, in par� ticular, for his contribution to cancer awareness and prevention. Dr. Satcher is director of the Satcher Health Lead� ership Institute at Morehouse School of Medicine, and has served as the 16th Surgeon General of the United States, Assistant Secretary for Health, and Director of the Centers for Dis� ease Control and Prevention. He has received over 40 honorary degrees and numerous distinguished honors in� cluding top awards from the National Medical Association and the Symbol of H.O.P.E. Award for health promotion and disease prevention. Dr. Satcher has an established record of leadership, research, and community engagement in many areas of health policy includ� ing childhood obesity and disparities in health.

Humanitarian Award Edith Peterson Mitchell, MD, clinical professor in the Departments of Medicine and Medical Oncology and program leader of Gastrointes� tinal Oncology at Jefferson Medical College of Thomas Jefferson Uni� versity, is the 2012 recipient of the

Humanitarian Award. Dr. Mitchell has spent her medical career helping individuals in medically underserved areas to realize that simple changes in lifestyle can have a dramatic im� pact on cancer care. Through her work, she has demonstrated the im� portance of community service and outreach, especially to those individ� uals who may not have the means to seek out more conventional medical advice. ASCO is pleased to present Dr. Mitchell with the Humanitarian Award for her personification of the Society’s mission and values, and for going above and beyond the call of duty in providing outstanding pa� tient care.

ing Hall of Fame. ASCO is pleased to honor Ms. Thomas for her dedicated efforts to increase public awareness of childhood cancer and for her support of cancer research and care.

Partners in Progress Award

Nancy G. Brinker is the 2012 re� cipient of the Public Service Award for her commitment to breast can� cer awareness, fundraising efforts, and legislation in support of cancer research, treatment, and care as well as her tireless efforts on behalf of patients with breast cancer, survi� vors, and their families. As founder and CEO of Susan G. Komen for the Cure®, she is regarded as the leader of the global breast cancer move� ment. From 2001 to 2003, she served as U.S. Ambassador to the Republic of Hungary, and from 2007 to 2009 she served as U.S. Chief of Protocol, where she was responsible for over� seeing all protocol matters for visit� ing heads of state and presidential travel abroad. In 2009, she was named Goodwill Ambassador for Cancer Control by the World Health Organi� zation. Ambassador Brinker’s global leadership in the breast cancer move� ment has led to increased government research funding and has been key to making cancer care and research a pri� ority for policy makers. For information on other notable awardees, see the April 15 issue of The ASCO Post or visit ASCOPost.com.

Marlo Thomas

Marlo Thomas, an award-winning actress, author, and activist, is the re� cipient of the 2012 Partners in Prog� ress Award. Ms. Thomas is the Na� tional Outreach Director for St. Jude Children’s Research Hospital and is the driving force behind countless public awareness efforts to educate the public about the life-saving work being done at St. Jude that impacts the lives of children in communi� ties across America and around the world. As an actress, she conceived, produced, and starred in television’s That Girl, has been honored with four Emmy Awards, the Peabody, a Golden Globe, and a Grammy, and has been inducted into the Broadcast�

Public Service Award

Nancy G. Brinker

website at ASCOPost.com

■

The ASCO Post | MAY 15, 2012

PAGE 96

News

Scott M. Lippman, MD, Named New Director of UC San Diego Moores Cancer Center

cott M. Lippman, MD, has been named Director of Moores Cancer Center at the University of California, San Diego, effective May 1, 2012. Dr.

Lippman was previously Chair of Tho� racic/Head and Neck Medical Oncol� ogy at The University of Texas MD Anderson Cancer Center, in Houston.

“As the new director, Dr. Lippman will implement strong initiatives for ramping up the research-driven cancer therapy and prevention programs and

Experience our world at ASCO Booth 10115

clinical trials of the Moores Cancer Center,” said David A. Brenner, MD, vice chancellor for Health Sciences and dean of the School of Medicine at UC San Diego. “His ultimate goal, and ours, is to facilitate the translation of novel discoveries from our worldclass laboratories into personalized therapies. I am confident that under Dr. Lippman’s leadership, research at Moores Cancer Center will benefit our patients and change standards of care for decades to come.”

Scott M. Lippman, MD

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives. We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

This is our pledge. This is GSK Oncology. Learn more at the new GSKoncology.com

04/12

Dr. Lippman received his medi� cal degree from Johns Hopkins Uni� versity School of Medicine, and per� formed his internship and residency training at Johns Hopkins Hospital and Harbor-UCLA Medical Center. Dr. Lippman received hematology/ medical oncology training at Stanford University and the University of Ari� zona. He is board-certified in internal medicine, hematology and medical oncology. Dr. Lippman’s major fields of re� search are translational/molecular studies of cancer risk, molecular-tar� geted drug development and personal� ized therapy, with a long-standing re� cord of funding from the NCI in these research areas, including recently as principal investigator of two program project (P01) grants and a Special� ized Program of Research Excellence (SPORE). He is also leader of the Lung Cancer Program of the MD An� derson Cancer Center Support Grant and is co-investigator on the Ameri� can Association for Cancer Research (AACR) Stand Up to Cancer (SU2C) project involving molecular studies of lung cancer. The University of California, San Diego, Moores Cancer Center is a Na� tional Cancer Institute (NCI)-desig� nated comprehensive cancer centers and it is part of the UC San Diego Health System.

■

ASCOPost.com | MAY 15, 2012

PAGE 97

In the News

Update on Oncology Drug Shortage: Better for Now, But Permanent Solutions Must Address Underlying Issues By Charlotte Bath

Michael P. Link, MD

Many other drugs remain in shortage, and we need permanent solutions,” Dr. Link stated at an FDA news brief� ing in February. The briefing was held to announce the approval of a new manufacturer of a preservative-free formulation of methotrexate and tem� porary importation of the liposomal doxorubicin Lipodox as a replace� ment for Doxil.1 The announcement put the issue of drug shortages in the news once again, including several reports quoting Dr. Link on the need for permanent solutions that address the root causes of the drug shortages.

ver the past few years, drug shortages in the United States Economic Underpinnings have been on the rise, involving hun� “Many of us believe that economics dreds of agents, many of which are in some way underpins this,” Dr. Link lifesaving medications for patients told The ASCO Post. The economic is� with cancer. In recent months, the sues include the relatively low price FDA has taken steps to alleviate some of generics and the resulting lack of of the most critical oncology drug incentives for companies to produce shortages. drugs for little or no profit. “If you are “We should absolutely be grateful not making much money on a drug to the FDA for their efforts in solving and you have problems producing it, the methotrexate shortage, which there is very little incentive to fix the was really a crisis for children with cancer,” ASCO President Michael problem, especially if fixing the prob� P. Link, MD, said in an interview lem costs a lot of money, which it usu� with The ASCO ally does,” Dr. Link Post. “They have said. If you are not making used leverage and Some who as� much money on a drug they have used sert that the prices their knowledge of generic drugs and you have problems to prevent a cri� in this country are producing it, there is very too low point to sis. On the other hand, there is no the example of Eu� little incentive to fix the reason to believe ropean countries problem, especially if that there won’t where the prices of be another drug generics are higher fixing the problem costs in short supply and the drugs are a lot of money, which it in the very near not in short sup� future, because ply. “That is sort usually does. we have not ad� of circumstantial —Michael P. Link, MD dressed the fun� evidence, but it is damental issues compelling,” Dr. that caused the shortage in the first Link said. place.” Dr. Link is Professor of Pedi� At the FDA briefing, Dr. Link called atrics, Division of Pediatric Hema� on Congress to appoint a bipartisan panel to develop legislation that would tology/Oncology, at Stanford Uni� versity School of Medicine in Palo result in permanent solutions, and out� Alto, California. lined three specific actions advocated “FDA, our pharmacists, physi� by ASCO. Two of these measures ad� cians, and manufac� dress economic issues—providing turers have cobbled economic incentives to companies to together patches, but ensure continued availability of drugs, we cannot continue and expanding FDA’s authority to col� to practice medicine lect user fees from generic drug manu� See Page 89 from crisis to crisis. facturers as part of the regulatory ap�

Drug Development in the Era of Personalized Medicine

dvances in understanding cancer on a molecular level and the identifica� tion of subgroups of cancer patients with rare diseases are expected to have an effect on drug development and supply. “The vision of what cancer care will be like in the future is this very pre� cise personalized care, where the patient’s tumor genome and germline ge� nome will tell the doctor the specific agents that the patient will need. They will need two or three targeted agents from among several possibilities, and the oncologist will choose these based on how patients metabolize drugs, and what drugs are likely to cause them specific toxicities,” ASCO Presi� dent Michael P. Link, MD, explained. “When you think this through, it becomes very clear that each therapy will be individualized. In fact, it will be so individualized, the question will become, is there sufficient incentive for industry to develop drugs that are only going to be used in a limited number of patients?” he noted.

Lessons from Pediatric Oncology “What was learned in pediatric oncology is that we are treating patients with relatively rare tumors,” Dr. Link said, and therefore very few drug compa� nies have been manufacturing drugs specifically for pediatric cancers. “There usually needs to be some sort of signal that the drugs are going to be useful in an adult cancer first,” he said. “A good example is crizotinib [Xalkori],” he said. “The target of that drug was cloned from a child with non-Hodgkin lymphoma a relatively long time ago. We hadn’t seen much activity in developing drugs for that target, because it is a relatively rare tumor. It turned out that it is also pres� ent in a couple of other rare tumors. Once it became evident that the ALK tyrosine kinase receptor was a target in a subset of lung cancer,” he added, “there was an incentive to develop a drug for that.” (Crizotinib was ap� proved by the FDA for the treatment of patients with locally advanced or metastatic non–small cell lung cancer that is ALK-positive as detected by an FDA-approved test.) “As a sideline, crizotinib actually also works for that rare lymphoma, and it works with a couple of the other rare tumors where ALK is an important driver,” Dr. Link added. “But it is not clear that anybody would have developed the drug just for the rare cancers that could be targeted.”

■

proval process. “These fees should be used to ensure that FDA has the resources to quickly review applications for generic drugs either in or at risk of shortage, and speed the availability of these medicines to patients,” said Dr. Link. “The fees would also pro� vide flexibility for FDA to incentivize production of key drugs, for example, by charging reduced fees for compa� nies that demonstrate adequate con� tingency plans for manufacturing dis� ruptions,” according to ASCO. The other measure advocated by ASCO is to require manufacturers to notify the FDA about “market with� drawals or manufacturing interrup� tions 6 months in advance or as soon

as such problems become known.” (The ASCO priorities were reported in the April 15 issue of The ASCO Post.2 Reasons and potential solutions to chemotherapy drug shortages were de� scribed in an article coauthored by Dr. Link in the March 1 issue of the Journal of Clinical Oncology.3) Previous ASCO recommendations to ease drug shortages included poten� tially extending the expiration date of a drug in short supply and clarifying the definition of “medically necessary,” the term that triggers notifying the FDA about drug shortages. The FDA has been extending expiration dates of drugs when they are still safe and ef� fective to use, but “that’s just a mecha� continued on page 98

The ASCO Post | MAY 15, 2012

PAGE 98

In the News

Oncology Drug Shortage continued from page 97

nism that FDA can use in the very, very short term. That is not a long-term so� lution,” Dr. Link said. “Extending the definition of what is medically neces� sary and early notification came out as part of the executive order,” he added, referring to Executive Order 13588, issued by President Barack Obama on October 31, 2011.4 A recent article in The New York Times noted that while the executive order directs the FDA and the De� partment of Justice to take actions to prevent drug shortages, “the steps re� main voluntary for drug companies,” because Congress has not passed legislation enforcing these require� ments.5

Cures and Collaborations For many pediatric cancers, as well as some adult cancers—certain early-stage breast cancers, testicular cancer, adult lymphomas, and adult leukemias—cura� tive therapies are known, Dr. Link noted, but these regimens are “based all or in part on older drugs that are now gener�

ics. Virtually all of those drugs, which are the foundation of curative therapy for those diseases, have at one time or an� other been in short supply.” These include preservative-free methotrexate, as discussed at the February FDA briefing. Doxorubi� cin, “which is a mainstay of therapy for lymphoma, and for sarcomas in adults and young adults, has been in short supply on and off,” Dr. Link said. “Cisplatin, which is a major drug for the treatment of many can� cers and for the curative therapy of testicular cancer in young men, has been in short supply,” he added. “When you know the recipe for cura� tive treatment and yet the ingredients are not available, that is pretty heart� breaking.”

■

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

References 1. FDA acts to bolster supply of criti� cally needed cancer drugs. FDA News Re� lease, February 21, 2012. 2. ASCO advocates for solutions to the oncology drug shortage crisis. The ASCO

Expect Questions from Your Patients

hile the process of finding permanent solutions to the shortage of oncol� ogy drugs continues, physicians and patients may still face difficult situ� ations when certain drugs, possibly part of curative regimens, are not available. “The key thing is that we urge patients to have discussions with their physicians in terms of whether they are even affected,” ASCO President Michael P. Link, MD, advised. Specifically, physicians should discuss with their patients the following issues: ■■ Does the regimen that the patient is on include a drug that has ever been in short supply? ■■ Is that drug in short supply where the patient is being treated? “Sometimes a drug is in short supply nationally or we know it is in short supply in different places, but not particularly where the patient is being treat� ed,” Dr. Link said. “Even if it is in short supply, for some of these cancers there is a very appropriate workaround—an alternative drug that isn’t in short sup� ply—and therefore, the patient need not worry.” For patients, the message should be “not to get stressed out at a time when you are already very stressed out,” Dr. Link counseled. “Try to discuss these issues with your oncologist to see how it affects individuals, if at all.”

■

Post 3(6):44, 2012. 3. Link MP, Hagerty K, Kantarjian HM: Chemotherapy drug shortages in the United States: Genesis and poten� tial solutions. J Clin Oncol 30:692-694, 2012. 4. Executive Order 13588—Reducing

Prescription Drug Shortages. The White House Office of the Press Secretary, Oc� tober 31, 2011. Available at www.white� house.gov. Accessed April 4, 2012. 5. Savage C: Shift on executive power lets Obama bypass rivals. New York Times, April 22, 2012.

Collaborating to Conquer Cancer, Theme of 2012 ASCO Annual Meeting

eveloping curative regimens and other advances in pediatric on� cology have demonstrated "what can be accomplished through collabora� tion, through the understanding of multidisciplinary care," said Michael P. Link, MD, ASCO President. Dr. Link commented to The ASCO Post about the theme for this year's ASCO Annual Meeting "Collaborating to Conquer Cancer." Dr. Link said "We learned long ago in pediatric leukemia that this is really a complex heterogeneous collection of diseases, all of which are different and with different responses to therapy. The implications are that we can't just treat leukemia; we have to treat it de� pending on the specific molecular ab� normality that puts you in a favorablerisk group or a high-risk group and ultimately will put you in a group that will be amenable to a targeted therapy." With smaller subgroups of cancer patients, conducting robust clinical trials becomes more challenging. "So you have to collaborate very broad� ly," Dr. Link said. "Single institutions aren't going to be able to do the kinds of studies that we used to do, even in common cancers, because it turns out

that what we thought were common cancers really are a series of relatively rare cancers under one rubric, like lung cancer."

the theme of the 2012 ASCO Annual Meeting, is basically "the model of what has been done in pediatric on�

cology, and now those lessons are rel� evant to medical oncology generally as well," Dr. Link said.

■

Developing curative regimens and other advances in pediatric oncology have demonstrated ‘what can be accomplished through collaboration, through the understanding of multidisciplinary care.’ —Michael P. Link, MD

Physicians and others involved in conducting clinical trials in pediatric oncology, Dr. Link said, 'learned to collaborate a long time ago, in part because we had no choice. None of us had enough patients, so we had to pool our efforts in order to do this." "Collaborating to Conquer Cancer,"

Chicago–The 2012 ASCO Annual Meeting is being held June 1 to 5 at McCormick Place. Watch future issues of The ASCO Post for comprehensive coverage of the meeting.

Explore our latest research at BioOncology.com/research

Exploring uncharted territories — bringing advances in oncology to light

At Genentech BioOncology, we’re transforming the way cancer is treated by gaining a broad understanding of cancer biology and following a comprehensive approach to drug discovery. A robust pipeline — We currently have more than 40 new molecules in clinical development across a range of pathways, from angiogenesis to apoptosis. Innovative molecules — Our new molecular entities target the fundamental mechanisms of cancer growth and include antibody-drug conjugates, a HER2 dimerization inhibitor, a type II glycoengineered anti-CD20 antibody, and a one-arm antibody targeting Met. Extensive clinical trial program — We and our partners are currently enrolling patients in over 600 ongoing trials for both postapproval and pipeline products in more than a dozen tumor types. Our goal is to fundamentally change the way that cancer is treated — not just with incremental advances, but with new standards of care.

The ASCO Post | MAY 15, 2012

PAGE 100

In the Literature

Emerging Clinical Data on Cancer Management HODKGIN LYMPHOMA Two Cycles of Chemotherapy plus Involved-field Radiation Improves Tumor Control in Early Unfavorable Disease Final analysis of the German Hodgkin Study Group (GHSG) HD14 trial concluded that intensi� fied chemotherapy with two cycles of escalated BEACOPP (bleomycin, et� oposide, doxorubicin, cyclophospha� mide, vincristine, procarbazine [Mat� ulane], and prednisone) followed by two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacar� bazine) and 30 Gy involved-field radiotherapy (IFRT) significantly improved tumor control in patients with early unfavorable Hodgkin lym� phoma. The BEACOPP plus ABVD (2+2) regimen demonstrated supe� rior freedom from treatment failure compared with four cycles of ABVD. At 5 years, there were differences of 7.2% in freedom from treatment fail� ure and 6.2% in progression-free sur� vival, both favoring the 2+2 regimen over the ABVD regimen. “The intensified 2+2 arm was clear� ly superior in terms of [freedom from treatment failure] and [progressionfree survival], despite moderately higher acute toxicity,” investigators re� ported in the Journal of Clinical Oncology. There were no overall differences in treatment-related mortality or sec� ondary malignancies.

Key Data “Patients were recruited and treated in 407 hospitals and practices in Ger� many, Switzerland, the Netherlands, the Czech Republic, and Austria,” the authors reported. Of the 1,528 qualified patients, more than 95% had stage II disease and the remainder had stage I disease. The median age was 32, with 9.4% older than 50 years. “There was significantly more se� vere (WHO grades 3 to 4) hemato� logic toxicity with 2+2 (87.1%) as compared with four cycles of ABVD (50.7%); acute treatment-related mor� tality in the 2+2 arm was 0.52%. The more pronounced acute toxicity of 2+2 is counterbalanced by fewer re� lapses and fewer patients with progres� sive disease,” the investigators stated. Despite the higher rate of relapse/ progression in the ABVD arm, overall survival was not significantly different, because “more than 50% of relapsed or progressing patients in both arms underwent successful salvage therapy,” the authors noted. “The regimen of 2+2 plus 30 Gy [involved-field radio� therapy] is the new GHSG standard for patients with early unfavorable [Hodgkin lymphoma] age 60 years or younger,” the researchers concluded.

Both Options Reasonable In an editorial accompanying the article, Anas Younes, MD, of MD Anderson Cancer Center in Houston, noted that “in North America, patients with bulky mediastinal stage I/II dis�

ease are typically treated with six to eight cycles of ABVD plus 36 Gy” of involved-field radiation therapy. “The HD14 study provides another option for these patients,” Dr. Younes added. “An obvious advantage for the 2+2 regimen is the shorter number of che� motherapy cycles and the use of lower doses of radiation. At the present time, there are no data to demonstrate that one approach is better than the other, and therefore, both options seem to be reasonable. It is clear that four cycles of ABVD plus 30 Gy of [involved-field radiotherapy] is not an optimal regi� men for patients with bulky stage I/II disease.” von Tresckow B, et al: J Clin Oncol 30:907-913, 2012. Younes A: J Clin Oncol 30:895-896, 2012.

BREAST CANCER Concepts about Effects of Menopausal Hormone Therapy on Breast Cancer Continue to Change In 2002, it was thought that meno� pausal hormone therapy using estro� gen alone increases breast cancer risk, although not as quickly as combined estrogen plus progestin. Current thinking about estrogen alone is that it reduces breast cancer risk. This is just one example of changing concepts about menopausal hormone therapy and breast cancer outlined in an article the Journal of the National Cancer Institute by Rowan T. Chlebowski, MD, PhD, of the Los Angeles Biomedical Research Institute at Harbor, Univer� sity of California Los Angeles Medi� cal Center in Torrance, and Garnet L. Anderson, PhD, of the Fred Hutchin� son Cancer Research Center in Seattle. “Recent results from large prospec� tive cohort studies and the Women’s Health Initiative randomized placebocontrolled hormone therapy trials have substantially changed concepts regard� ing how estrogen alone and estrogen plus progestin influence breast cancer,” Drs. Chlebowski and Anderson stated. “In the [Women’s Health Initiative] trials, fewer breast cancers were seen in postmenopausal women with a previ� ous hysterectomy who were receiving estrogen alone. In contrast, estrogen plus progestin statistically significantly increased breast cancer incidence and

breast cancer mor� tality,” they noted. “Although the ab� solute risk of death due to breast cancer SEE PAGE 89 associated with es� trogen plus progestin use is relatively modest, from a public health perspec� tive, a near doubling of breast cancer deaths with estrogen plus progestin represents a considerable concern,” they wrote. In addition, the risks of developing breast cancer continue to increase the longer the hormones are used. The authors caution that “findings are lim� ited to the duration of intervention and adherence achieved in the tri� als; cancer effects of longer duration hormone therapy cannot be inferred from these data.” They also noted that “the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely under� stood.”

Cheblowski RT, Anderson JL: J Natl Cancer Inst 104:517-527, 2012.

Women Treated with Breastconserving Surgery More Likely to Have Diagnostic and Invasive Procedures over Time Women with ductal carcinoma in situ (DCIS) treated with breastconserving surgery “continue to have diagnostic and invasive breast proce� dures in the conserved breast over an extended period,” according to a study reported in the Journal of the National Cancer Institute. “The estimated 10year cumulative risk of having at least one diagnostic mammogram after ini� tial DCIS excision was 41.0%,” the in� vestigators reported. The cumulative risk of having at least one invasive pro� cedure was 65.7%. “The fact that women undergoing BCS are likely to have diagnostic and invasive breast procedures in the con� served breast over an extended period of time is important and needs to be in� cluded in discussions about treatment options. The frequency of ongoing diagnostic breast evaluations should be included in discussions about treat� ment,” the authors concluded. The study involved 2,948 women with DCIS who were treated with breast-conserving surgery from 1990 to 2001 and followed for up to 10 years at three integrated health-care delivery systems that are part the NCI-funded

ASCOPost.com | MAY 15, 2012

PAGE 101

In the Literature

Cancer Research Network. The mean age of the women was 58.2 years.

Study Data “Approximately 42% (n = 1,247) were treated with [breast-conserving surgery] alone, 42% (n = 1,243) with adjuvant radiation, 11% (n = 328) with both adjuvant radiation and tamoxi� fen, and 4% (n = 130) with tamoxifen alone,” the researchers reported. “Elev� en percent (n = 325) of the women had a local recurrence, 173 ipsilateral DCIS, and 152 ipsilateral invasive breast can� cer.” During the 10-year follow-up, 907 women (30.8%) had 1,422 diagnostic mammograms and 1,813 (61.5%) had 2,305 ipsilateral invasive procedures. Diagnostic mammograms occurred in 7.3% of women in the first 6 months and continued at a median annual rate of 4.3%. Ipsilateral invasive procedures occurred in 51.5% of women in the first 6 months and continued at a me� dian annual rate of 3.1%,” the investiga� tors stated. While breast-conserving surgery “has become the most common treat� ment for women with DCIS,” accord� ing to the authors, “recent data show that mastectomy rates have again be� gun to increase.” The reasons for this are unclear, but women’s preferences “appear to have a role in the deci� sion for [breast-conserving surgery] vs mastectomy; a recent study found that after women were informed about mortality, treatment, and recurrences after [breast-conserving surgery] and mastectomy, 35% chose mastectomy.”

Informed Decision-making Women who choose breast-con� serving surgery “may be embarking on a more extended journey than antici� pated—a journey replete with diagnos� tic testing that can span many years,” according to an editorial accompany� ing the article. Women need to un� derstand the implications of screening and treatment options, but informed decision-making is hampered by in� complete information, the editorialists noted. “To reduce the uncertainties surrounding DCIS, we need to learn how to avoid overdiagnosis by calling back fewer women for additional test� ing after screening mammography; we also need better prognostic biomarkers to minimize overtreatment of lesions that are unlikely to progress to invasive cancer,” they commented. “In the meantime, we urgently need to assist women in making the best

treatment decisions for themselves. Carefully constructed decision aids have been shown to assist patients in understanding medical evidence as well as areas of uncertainty,” the edi� torialists wrote, and the new data re� ported should be incorporated into decision aids.

“As the science of DCIS progresses, informed decision-making should re� main a motivating priority for clini� cians,” the editorialists concluded. “In� formed patients feel better about the decision process, and their decisions are more likely to reflect their prefer� ences, values, and concerns. Informed

patients are more likely to adhere to treatment and report better self-rated health than less-informed patients.” Nekhlyudov L, et al: J Natl Cancer Instit 104:614-621,2012. Elmore JG, Fenton JJ: J Natl Cancer Instit 104:569-571,2012. continued on page 102

Clarient Insight®Dx Mammostrat® Reduce your patient’s anxiety with test results available in days… not weeks. Clarient’s InsightDx Mammostrat provides important information independent of proliferation and grade to aid physicians in making appropriate and earlier treatment decisions in order to determine which patients are most likely to recur from breast cancer. Results you can trust. Mammostrat has been studied in more than 4,500 women, including cohorts from NSABP B14 and B20 trials. Learn more about Clarient, a GE Healthcare Company and our world-class anatomic and molecular pathology laboratory services. Learn more. Visit us at ASCO, booth #24083. Together, we help you find the difference that makes the difference.

www.clarient.com

The ASCO Post | MAY 15, 2012

PAGE 102

In the Literature

Emerging Clinical Data continued from page 101

RETINOBLASTOMA Younger Patients Treated with Systemic Carboplatin at Higher Risk of Ototoxicity Patients younger than 6 months at the start of systemic carboplatin treat� ment for retinoblastoma have a sig� nificant risk of developing hearing loss, according to a study in the Journal of Clinical Oncology. A review of audio� logic test results of 60 patients with ret� inoblastoma who received front-line treatment with systemic carboplatin and vincristine found that 12 patients had hearing loss at some time after treatment, 10 with sustained hearing loss. Of those 10, 9 were less than 6 months of age when treatment began. “Age at the start of chemotherapy was the only risk factor identified as a significant predictor of sustained hear� ing loss,” the investigators reported. “The 10-year cumulative incidence of hearing loss was 39.0% ± 10.6% for patients younger than 6 months of age vs only 8.3% ± 4.7% for patients 6 months of age and older at the start of treatment (P =.004),” the researchers wrote. “Most ototoxicity was grade 3 or 4 (90%) and bilateral (90%), which underscored its potential impact on quality of life,” the investigators noted. “Because damage to either hearing or vision reduces quality of life, partial or total loss of both senses could syner� gistically impair development, cogni� tion, and rehabilitation, especially in young children. Hence, ototoxicity is a crucial issue in patients with bilateral retinoblastoma.”

Task Force Recommendations The authors noted that carboplatin “is the principal agent in all retinoblas� toma chemotherapy protocols report� ed to date.” Although considerably less toxic than cisplatin, carboplatin “has been linked to sensorineural hearing loss.” They also pointed out that the Children’s Oncology Group (COG) published recommendations for evalu� ating and managing pediatric patients at risk for hearing loss due to disease or its treatment. “The COG task force recommended that childhood cancer survivors should receive at least yearly hearing tests. More frequent testing is required if any change is noticed or if hearing loss is suspected,” the authors stated.

Of the 60 patients whose records were reviewed, 23 had been treated according to the Retinoblastoma-3 (RTE-3) protocol at St. Jude Chil� dren’s Research Hospital in Mem� phis. That protocol consisted of eight cycles of vincristine and carboplatin administered at 3-week intervals. Af� ter the RET-3 protocol closed, pa� tients were treated off-protocol ac� cording to best clinical management, with 31 receiving carboplatin and vincristine, 5 also receiving etopo� side, and 1 also receiving topetecan. The median number of audiologic evaluations was five per patient. Ototoxicity was evaluated by three different grading systems, which, the authors noted, “showed good overall agreement in the identification of pa� tients with ototoxicity.” Qaddoumi I, et al: J Clin Oncol 30:1034104, 2012.

ACUTE MYELOID LEUKEMIA Integrated Genetic Profiling Can Identify Predictors of Outcome and Improve Risk Stratification in AML Patients A mutational analysis of 18 genes in 398 patients with acute myeloid leuke� mia (AML) found at least one somatic alteration in 97.3% of the patients and identified genetic predictors of out� come that improved risk stratification among patients with AML, indepen� dent of age, white-cell count, induction dose, and postremission therapy. The mutational analysis was performed with diagnostic samples obtained from patients in the Eastern Cooperative Oncology Group (ECOG) E1900 trial who had AML and were randomly as� signed to receive induction therapy with high-dose or standard-dose dau� norubicin. The prognostic findings were validated in an independent set of 104 patients. “Previous studies have suggested that mutational analysis of CEBPA, NPM1, and FLT3-ITD can be used to stratify risk among patients with intermediate-risk. Using data from a large cohort of patients treated in a single clinical trial, we found that more extensive mutational analysis can bet� ter discriminate patients with AML into various prognostic groups,” the authors wrote. “Taken together, these data show that mutational analysis of a larger set of genetic alterations than that current� ly used in the clinic setting could be

used to retrospectively classify patients with AML into more precise sub� groups with favorable-risk, intermedi� ate-risk, or unfavorable-risk profiles, with marked differences in the overall outcome. This approach could be used to identify an additional subgroup of patients who would have a mutation� ally defined favorable outcome with induction and consolidation therapy alone and a subgroup of patients with mutationally defined unfavorable risk who would potentially be candidates for allogeneic stem-cell transplanta� tion or participation in a clinical trial, given the prediction of a poor outcome with standard AML therapy,” the au� thors stated. “The challenge,” they concluded, “is to provide genetic information in a timely and affordable way and show that this information could prospec� tively influence treatment decisions.” Patel JP, et al: N Engl J Med 366:10791089, 2012.

KIDNEY CANCER Partial Nephrectomy Can Optimize Survival in Patients with Early-stage Disease Following recent clinical trial data from the European Organisation for Research and Treatment (EORTC) showing a survival benefit for patients with small kidney cancers treated with radical vs partial nephrectomy, an analysis using linked Surveillance, Epi� demiology and End Results (SEER) and Medicare data found that treat� ment with partial rather than radi� cal nephrectomy was associated with improved survival. Researchers at the University of Michigan in Ann Arbor noted that the EORTC study “had several notable limitations,” includ� ing accrual difficulties and premature closure, and “occurred in an era when most surgeons rarely performed par� tial nephrectomy. As such, many argue that the EORTC trial is not generaliz� able to contemporary practice.” The Michigan researchers used “an instrumental variable approach to account for measured and unmea� sured differences between treatment groups,” they reported. “By applying this technique to a population-based patient cohort, we can clarify the com� parative effectiveness of partial vs radi� cal nephrectomy in the treatment of patients with early-stage kidney can� cer,” they wrote in Journal of the American Medical Association.

Key Findings The study included 7,138 Medi� care beneficiaries with clinical stage T1a kidney cancer treated from 1992 through 2007, 27% with partial and 73% with radical nephrectomy. “Pa� tients treated with partial nephrec� tomy were younger, more often men, and resided in census tracts with high� er levels of average income and educa� tion than those treated with radical ne� phrectomy,” the authors noted. At a median follow-up of 62 months, 487 of the 1,925 (25.3%) of patients who had partial nephrectomy died, compared to 2,164 of the 5,213 (41.5%) of patients who had radi� cal nephrectomy. “Kidney cancer was identified as the cause of death for 37 patients (1.9%) treated with partial nephrectomy and 222 patients (4.3%) treated with radical nephrectomy,” the researchers reported. “Based on a predicted survival difference of 15.5 percentage points at 8-year follow-up, 1 life would be saved for every 7 pa� tients treated with partial rather than radical nephrectomy. Accordingly, our findings support partial nephrectomy as the preferred treatment option for the ever-expanding pool of patients with kidney tumors measuring 4 cm or smaller,” the researchers stated.

Study Limitations The authors noted that their own study also has limitations, such as being restricted to Medicare beneficiaries and the smallest kidney tumors (≤ 4 cm), so the findings may not be generalizable to younger patients and those with larger masses. They also pointed out that “par� tial nephrectomy remains a technically challenging operation with potentially significant complications (eg, hemor� rhage, urinary fistula) that are seen less frequently with radical nephrectomy. This concern cannot be ignored when making treatment decisions,” they wrote. “Indeed, the benefits of partial ne� phrectomy must always be weighed against the risk of acute surgical morbid� ity. In certain scenarios, some patients may be better served with an uncom� plicated radical nephrectomy. Likewise, alternative treatment options, including active surveillance and ablative thera� pies, may be particularly prudent for patients in whom the benefits of surgical removal are less apparent.”

■

Tan HT, et al: JAMA. 307:1629-1635, 2012. Compiled by Charlotte Bath for The ASCO Post.

To confront the threat of angiogenesis in first-line metastatic non-squamous NSCLC…

Think Avastin

Because survival matters most

Percentage Surviving

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991 100

1-year survival: 51% vs 44%2

2-year survival: 23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

OS (Months) Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68– 0.94], P=0.013).1 Clinically meaningful 1- and 2-year survival rates were demonstrated with Avastin plus PC (51% and 23%, respectively, vs 44% and 15% with PC alone).2

Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; OS=overall survival; HR=hazard ratio; CI=confidence interval.

Indication

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%)

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. Avastin Prescribing Information. Genentech, Inc. September 2011. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

AVA0000400601

Printed in USA.

(11/11)

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age

73586ha_a 2

AVASTIN® (bevacizumab)

greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 3795 patients with CRC, non‑squamous NSCLC, MBC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, and 7) or uncontrolled, single arm (Study 5) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] Data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, an indication for which Avastin is not approved. The population was aged 18‑88 years (median 59), 43.2% male and 85.3% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 5, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

AVASTIN® (bevacizumab) Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).] Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 5, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3‑5 infection was 10%. Proteinuria Grade 3‑4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 7. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 7, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 7). [See Warnings and Precautions (5.8).] Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer MBC, an indication for which Avastin is not approved, the incidence of Grade 3–4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test)was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84 or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1 IFL ++ Placebo (n = 396) 74%

Arm 2 IFL ++ Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence ( ≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 5 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 7. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 7 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

55% 55% 19%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 );

2/28/12 11:51 PM

ASCOPost.com | MAY 15, 2012 AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected. Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

y battle with cancer started with a simple sore throat in June 2005. Despite two rounds of an anti� biotic to clear up the problem, within 2 months my throat hurt so much I couldn’t swallow, and a mysterious lump had suddenly appeared on my tongue. By the end of August, I was diagnosed with stage IIIB squamous cell carcinoma of the tongue that had metastasized to the lymph nodes in my neck.

What’s more troublesome, how� ever, is how the treatment has affected my speech. Even though I pride myself in my ability to communicate, I’m no longer always clearly understood when I speak, especially by strangers, and I sometimes have to preface a conversa� tion by explaining that I’m not drunk or mentally challenged.

Living with the Fear of Recurrence

Although the treatment for my head and neck cancer was successful, I was admitted to the hospital a nagging cough brought me back to for 2 weeks of tests to determine my primary care physician in 2007 if I was healthy enough to with� for a checkup. Because of my history stand the gruel� as a smoker and ing treatment that cancer survivor, CT and PET scans lay ahead and to of my chest were also wean me off performed, which my two primary showed a shotgun vices: smoking pattern of tumors and drinking. The in both lungs. I was first stage of my told I might have treatment proto� just 10 months to col required 15 live. hours of surgery It turned out to remove half that most of what my tongue and Despite permanent appeared to be replace it with masses were actu� tissue from my aftereffects and the fear ally the remnants left arm, a nerve of recurrence, surviving of a lung infec� transplant from tion I’d had. How� my left wrist to cancer has given me ever, there was my left elbow, and a greater appreciation one mass in my a radical neck dis� lower right lobe section to remove of life. that looked sus� the malignant —Joe Alvey picious enough lymph nodes. The for my doctor to surgery was so recommend biopsying. The tumor extensive, when my father saw the was malignant, and although it was black lines my doctor had drawn on squamous cell carcinoma, it couldn’t my face and arms indicating where be determined whether this was a he was going to make his incisions, new cancer or a metastasis, and the he cried. After the surgery, I was put lobe was removed. Because I wanted into an induced coma for 4 days to to be as aggressive as I could to stay give my wounds time to heal and cancer-free, I opted for adjuvant che� then released from the hospital motherapy, which consisted of many 2 weeks later. rounds of carboplatin and paclitaxel. What followed were months of cis� platin chemotherapy and 33 rounds Celebrating Life of radiation therapy. The therapy, The past 7 years have been dif� along with my surgery, rendered me ficult, but I’ve gotten through them unable to eat and required the place� ment of a PEG tube so I could get nu� with hope and humor. Did smoking and drinking cause my cancer? May� trition. Although the tube, thankfully, be. Or maybe it happened because I has been removed, I can’t say that I have a strong family history of can� can eat normally. But I am able to eat, cer. Maybe it’s both. The reason why and I’ve managed to regain 5 of the 85 continued on page 106 lb I’ve lost.

Grueling Treatment

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

73586ha_a 3

I Refuse to Let Cancer Win

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/ carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/ carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 7, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

Patient's Corner

By Joe Alvey, as told to Jo Cavallo

6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis,Anastomotic ulceration Hemic and lymphatic: Pancytopenia Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

PAGE 105

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

2/28/12 11:51 PM

The ASCO Post | MAY 15, 2012

PAGE 106

Patient’s Corner

I Refuse to Let Cancer Win continued from page 105

I got cancer isn’t as important to me as what I’m doing now as a result of having the disease, and that’s cel� ebrating life. If I can make one per� son laugh, provide for my family, and spend time with my loved ones and

friends, I’ve had a good day. Today, I’m cancer-free, but I know that that could change at any moment. Every little cough or hiccup leads me to wonder, is this a cancer recurrence? But I refuse to be overcome with fear and let the cancer win. The common thread throughout

my diagnoses and treatments has been my oncologist, who has been a critical part of my team from the very start and who continues to monitor my health and point me in the right direction for help if and when anom� alies are reported. Cancer has given me an aware�

The best time to

ness about the preciousness of life that perhaps others don’t have. That awareness is helping me live the best life I can have while I’m still here.

■

Joe Alvey is a website designer/developer living in Virginia Beach, Virginia.

Visit

JOIN ASCO

is NOW

Already registered? Join & get a PARTIAL REFUND of your nonmember registration.

ASCOPost.com