TAP Vol 3 Issue 14 by Harborside Press LLC

Prostatectomy vs Observation

| End-of-life Care

33, 60

| Pioneers in Oncology

| Colorectal Cancer

VOLUME 3, ISSUE 14

55, 58

SEPTEMBER 15, 2012

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

Drug Development

Biomarker-driven Adaptive Trial Design Proving Informative in Non–Small Cell Lung Cancer By Caroline Helwick

iomarker-driven adaptive trial design is an accelerated strategy for targeted drug development that is proving informative in non–small cell lung cancer (NSCLC), according to Roy S. Herbst, MD, PhD, Chief of Medical Roy S. Herbst, MD, PhD Oncology and Associate Director of Translational Research at Yale Cancer Center, New Haven.1 At the Best of ASCO® ’12 meeting in Boston, Dr. Herbst described recent advances in drug development, drawing largely from his experience with the BATTLE (Biomarker-based Approaches of Targeted Therapy for Lung Cancer Elimination) drug development program at The University of Texas MD Ander-

son Cancer Center (prior to joining Yale). The new BATTLE-2 study is now open at Yale.

ASCOPost.com

Importance of Dermatologic Care for Patients with Cancer By Mario E. Lacouture, MD

As background, Dr. Herbst noted that the traditional approach to drug development required that many thousands of patients be treated before subset analyses reSee Page 81 vealed those most likely to respond. Gene sequencing and the discovery of mutations that drive tumor growth—yielding targets for inhibitors—changed the field and has led to good treatment outcomes in properly selected patients, but “the problem remains,” he said. “Still, no one is cured of metastatic lung cancer. Resistance to targeted agents occurs. The challenge continues.” “Tissue is the issue,” Dr. Herbst emphasized.

first became interested in treating skin issues associated with cancer about 10 years ago, during my dermatology residency training at the University of Chicago. Many of the agents under clinical development at the time, such as cetuximab (Erbitux) or sorafenib (Nexavar), were causing dose-limiting side effects. Consequently, patients with severe facial rashes or blisters on the hands and feet were referred to us. Desperate to have their skin issues resolved so they could remain on their anticancer regimens, patients would implore me to give them any medication available that would ease their side effects. Seeing this unmet need in patients with cancer made me realize that although we were mak-

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‘Tissue Is the Issue’

Immunology

Contagious Cancer and an Unexplained Phenomenon Might Inspire Future Therapies By Ronald Piana

Dr. Lacouture is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. He is an Associate Member at Memorial Sloan-Kettering Cancer Center, New York.

MORE IN THIS ISSUE

deadly contagious cancer known as devil facial tumor disease is pushing the world’s largest carnivorous marsupial, the Tasmanian devil (Sarcophilius harrisii), to the brink of extinction. The loss of an interesting creature aside, the plight of the Tasmanian devil raises provocative questions about the oncogenic process and the transmission of cancer. James S. Welsh, MD, a radiation oncologist with

the Northern Illinois University Neutron Therapy Facility at Fermilab, spoke with The ASCO Post about how immune responses to “contagious cancer” might someday play a principal role in oncology.

Underlying Mechanisms

What sparked your interest in contagious cancer? My interest in cancers spread among animals began quite some time ago, mainly as a zoology and ecology curiosity, but it Anyone who has seen the abscopal was evident that animal cancers could serve as a effect has got to be thinking that if model for human cancers. we could turn this response on at will, And the pioneering work the field of clinical oncology would be on oncogenic retroviruses that led to the discovery changed forever. of oncogenes set the stage —James S. Welsh, MD for our modern under-

Oncology Meetings Coverage Pan Pacific Lymphoma Conference �� 3 Best of ASCO® ’12 �� 6–8 ASCO Annual Meeting �� 38 Prostate Cancer �� 2, 15, 57 Letters to the Editor �� 2, 82, 83 Sexual Dysfunction in Cancer Survivors �� 24 Metronomic Chemotherapy in Myeloma �� 38 Direct from ASCO �� 47

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September is Prostate Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 15, 2012

PAGE 2

Letters to the Editor Genitourinary Oncology

More Thoughts on PSA Editorial Board James O. Armitage, MD Editor-in-Chief

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

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

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

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

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

Michael P. Link, MD Stanford University Medical Center

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

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

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

Harborside Press® Publishing Staff

n article that appeared in the August 15 issue of The ASCO Post (“Rethinking the Role of PSA Screening in Public Health”) contains false statements about the discovery of prostate-specific antigen (PSA) and its effectiveness as a test for early detection of prostate cancer. Contrary to what’s reported in this article, Richard Ablin, PhD, did not discover the PSA that forms the basis for the PSA test. Dr. Ablin discovered a “prostate-specific antigen” that appears in normal prostate tissue, but Roswell Park Cancer Institute (RPCI) researcher T. Ming Chu, PhD, DSc, and an extraordinary team of more than 20 researchers identified and purified another protein, initially called “prostatic antigen” and later renamed “prostate-specific antigen,” from normal, benign, and malignant human prostate tissue. This PSA was developed into the PSA blood test that is used today for the early detection of, and monitoring of treatment for, prostate cancer. A patent was issued in 1984 to the State of New York and RPCI, and the technology was transferred to the biomedical industry for preparing and marketing of testing kits. The PSA test received U.S. Food and Drug Administration approval in 1986 for monitor-

ing treatment response, and in 1994 for early detection of prostate cancer.

Novel Discoveries In the August 15 article, Dr. Ablin apparently refers to Dr. Chu and his RPCI colleagues when he See Page 81 suggests that “some other researchers rediscovered [his] work and subsequently developed what we know as the PSA test.” This statement is false. The findings made by Dr. Chu and his team were novel discoveries of a distinct molecule that has been fully characterized biochemically and biophysically, and bears no connection to the unknown antigen of the same name discovered by Dr. Ablin. The two antigens are different because Dr. Ablin’s antigen was found only in normal prostatic tissue, while Dr. Chu’s PSA is found not only in prostate tissue but in prostatic fluid and semen. This issue was resolved 27 years ago in a published interchange between Drs. Ablin and Chu.1,2 The Chu team’s efforts were documented in a series of articles published in major journals, such as Investigative Urology, Cancer Research, Journal of the National Cancer Insticontinued on page 82

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.

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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.

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

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

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

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 3

2012 Pan Pacific Lymphoma Conference Expert’s Corner

Predictors and Treatment for Transformed Lymphoma: Current Paradigms A Conversation with Richard I. Fisher, MD By Matthew Stenger and high β2 microglobulin, all at diagnosis. After initial treatment, patients not achieving a complete remission are more likely to have a transformation. To date, it is unclear whether early treatment vs a “watch and wait” strategy has any impact on the risk of transformation. Most studies suggest there is no change in risk. Some data suggest that initial treatment with rituximab (Rituxan) does lower the risk of transformation, although this has

No prior therapy or nonanthracycline therapy

Richard I. Fisher, MD

t the recent Pan Pacific Lymphoma Conference, held in Maui, Hawaii, Richard I. Fisher, MD, Chairman of the SWOG Lymphoma Committee and Vice-President for Strategic and Program Development at the University of Rochester Medical Center in New York, gave a presentation on the characteristics and treatment of transformed lymphoma. The ASCO Post subsequently spoke with Dr. Fisher about some of the topics he had addressed.

Transformation Predictors What factors are predictive of lymphoma transformation? I will define lymphoma transformation as the change in histology from a low-grade or indolent lymphoma to a more aggressive lymphoma, usually diffuse large B-cell lymphoma or Burkitt’s lymphoma. The diagnosis should always be made by a repeat biopsy. In that regard, there are certain clinical variables that have been shown to be predictive of transformation. They include advanced stage, high International Prognostic Index (IPI) or Follicular Lymphoma International Prognostic Index (FLIPI),

Now le b Availa

years. However, certain series have suggested that some patients will have a better outcome after transformation— these include patients who had limitedstage disease at diagnosis, have not been treated with chemotherapy, and have achieved a complete remission from their initial treatment. Patients who have transformed in a single site, as opposed to having disseminated disease, have an improved survival in almost all series.

R-CHOP CR

?? ASCT vs RIT

<PR

ASCT vs RIT

RIT or Salvage chemotherapy

ASCT

Fig. 1: Potential treatment approaches in patients with transformed lymphoma who have received no prior therapy or non–anthracycline-containing therapy. ASCT = autologous stem cell transplantation, CR = complete response, PR = partial response, RIT = radioimmunotherapy. Courtesy of Steven Bernstein, MD, and Richard I. Fisher, MD.

not been proven. Finally, overall transformation does increase with time from diagnosis, approaching 30% of all cases in most series.

Outcome Predictors What factors are predictive of outcome of transformed lymphoma? The outcome for patients with transformed lymphoma historically has been very poor. Multiple series suggest the median survival ranges from only 1 to 2

Treatment Options What are the best available treatments for transformed lymphoma, and what new options may become available in the near future? For many years, the standard of care has been to attempt to reinduce the patient into a very good response (either complete or partial remission) and then proceed to autologous stem cell transplantation. Results in selected series of patients treated in this manner have shown 5-year

progression-free survival in the range of 30% to 45%. Treatment with allogeneic transplantation and radioimmunotherapy has also been reported in selected series.

Treatment Recommendations How do you currently treat transformed lymphoma? If patients have not received chemotherapy prior to their transformation, I traditionally treat them with a course of R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]. Among patients achieving a complete response that is verified as being PET-negative, some may not need to have additional therapy—although this has not been proven convincingly. Other patients should be offered consolidation with autologous stem cell transplantation or radioimmunotherapy (Fig. 1). Patients who achieve only a partial response to R-CHOP should receive an autologous transplant or radioimmunotherapy. Patients who have not had a partial response may be considered for treatment with another salvage therapy followed by autologous transplantation or radioimmunotherapy. For patients who have a localized transformation, a course of R-CHOP followed by involved-field radiation seems reasonable. For patients who have had prior chemotherapy, I would consider a salvage therapy followed by autologous stem cell transplantation or radioimmunotherapy. It is hoped that new targeted therapies will also be able to impact disease at this stage, but this needs to be proven in future studies.

■

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

The ASCO Post’s webcast “Case Studies in Rare Lymphomas” moderated by James O. Armitage, MD, and featuring the following experts:

Joseph M. Connors, MD, on Hodgkin lymphoma following failure of autologous stem cell transplant

Andreas Engert, MD, on relapsed and refractory Hodgkin lymphoma

Steven M. Horwitz, MD, on systemic anaplastic large cell lymphoma following failure of one or more combination regimens

View this special webcast at www.ASCOPost.com/lymphomaweb/ Also, watch for your supplement on this presentation mailing with this issue of The ASCO Post. 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.

Indication VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

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

medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. • Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the randomized STS trial, in patients who had baseline and follow-up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT had congestive heart failure, which did not resolve in 1 patient. Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. • Hemorrhagic Events: Hemorrhagic events have occurred and can be fatal. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have occurred and can be fatal. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a

cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. • Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent

VOTRIENT for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitations of use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors (GIST) has not been demonstrated.

despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound healing. Interruption of therapy is recommended in patients undergoing surgical procedures. Treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. • Hypothyroidism: Hypothyroidism was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended. • Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Monitor urine protein. Interrupt treatment for 24-hour urine protein ≥3 grams and discontinue for repeat episodes despite dose reductions. • Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly. Consider discontinuation of VOTRIENT. • Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death.

• 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. • Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. • Pneumothorax: Pneumothorax has occurred (8/240 STS patients [3%] treated with VOTRIENT vs. 0% in the placebo group). • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases concentrations of VOTRIENT and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit juice. Concomitant use of strong CYP3A4 inducers (e.g., rifampin) should be avoided due to the potential to decrease concentrations of VOTRIENT. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of

concomitant administration of alternative statins and VOTRIENT. • Adverse Reactions in the Randomized STS Trial: Fifty-eight percent of patients on VOTRIENT required a dose interruption, 38% of patients on VOTRIENT had their dose reduced, and 14% of patients who received VOTRIENT discontinued therapy due to adverse reactions. The most common adverse reactions (≥20%) in patients who received VOTRIENT versus placebo were fatigue (65% vs. 48%), diarrhea (59% vs. 15%), nausea (56% vs. 22%), decreased weight (48% vs. 15%), hypertension (42% vs. 6%), decreased appetite (40% vs. 19%), hair color changes (39% vs. 2%), vomiting (33% vs. 11%), tumor pain (29% vs. 21%), dysgeusia (28% vs. 3%), headache (23% vs. 8%), musculoskeletal pain (23% vs. 20%), myalgia (23% vs. 9%), gastrointestinal pain (23% vs. 9%), dyspnea (20% vs. 17%). Laboratory abnormalities occurring in >10% of STS patients and more commonly (≥5%) in the VOTRIENT arm versus placebo included increases in AST (51% vs. 22%), ALT (46% vs. 18%), glucose (45% vs. 35%), alkaline phosphatase (32% vs. 23%), total bilirubin (29% vs. 7%), and potassium (16% vs. 11%); decreases in albumin (34% vs. 21%) and sodium (31% vs. 20%); and leukopenia (44% vs. 15%), lymphocytopenia (43% vs. 36%), thrombocytopenia (36% vs. 6%), and neutropenia (33% vs. 7%). Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages. Reference: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012.

VOTRIENT.com

The ASCO Post | SEPTEMBER 15, 2012

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B:11.75”

Best of ASCO® Annual Meeting ’12 Adaptive Trial Design continued from page 1

Tumor biopsies now not only guide treatment but are pivotal to drug development. While tissue is frequently obtained from stage�� III �� resected patients, it remains rare in the stage IV chemorefractory setting. Nevertheless, he said, biomarker-

driven drug development is accelerating and has changed the landscape of NSCLC from a disease with three major histologic types to, within adenocarcinoma alone, more than a dozen key recognized mutations (EGFR, KRAS, MAPK, P13K, ALK, INSR, FGFR, PDGFR, EPHA/B, HER2, VEGFR, AKT, BRAF) as well as am-

T:10.5” S:8.75”

plifications and fusions in a number of genes. Targeted agents for most of these abnormalities are available or in development. “With tissue, we can understand the biology and can develop agents to target it. And this brings hope, but there is much work to be done,” Dr. Herbst said.

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. Limitation of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In STS, a decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized STS trial, ALT >3 X ULN was reported in 18% and 5% of the VOTRIENT and placebo groups, respectively. ALT >8 X ULN was reported in 5% and 2% of the VOTRIENT and placebo groups, respectively. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (4/240) of patients on VOTRIENT and <1% (1/123) on placebo. Four-tenths percent (0.4%) of patients (1/240) in the randomized STS trial died of hepatic failure. 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. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the randomized STS trial, 0.2% (1/240) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. Post-baseline QT data were only collected in the STS trial if ECG abnormalities were reported as an adverse reaction. None of the 123 patients who received placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be

Challenges in Drug Development The discovery of druggable targets is one challenge. Equally daunting are the clinical trial process, long timeline, and huge expense in bringing drugs to market. To this end, there has been much discussion about “adaptive design.”

used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the randomized STS trial, myocardial dysfunction was defined as symptoms of cardiac dysfunction or ≥15% absolute decline in LVEF compared to baseline or a decline in LVEF of ≥10% compared to baseline that is also below the lower limit of normal. In patients who had baseline and follow up LVEF measurements, myocardial dysfunction occurred in 11% (16/142) of patients on VOTRIENT compared to 5% (2/40) of patients on placebo. One percent (3/240) of patients on VOTRIENT in the STS trial had congestive heart failure which did not resolve in one patient. Fourteen of the 16 patients with myocardial dysfunction treated with VOTRIENT in the STS trial had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) possibly by increasing cardiac afterload. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: There were no reports of fatal hemorrhage in the STS trials. In the randomized STS trial, 22% (53/240) of patients treated with VOTRIENT compared to 8% (10/123) treated with placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were epistaxis (8%), mouth hemorrhage (3%), and anal hemorrhage (2%). Grade 4 hemorrhagic events in the STS population occurred in 1% (3/240) patients and included intracranial hemorrhage, subarachnoid hemorrhage and peritoneal hemorrhage. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in no patients in the STS trials. In the randomized STS trial, 2% (4/240) of patients receiving VOTRIENT experienced a myocardial infarction or ischemia, 0.4% (1/240) had a cerebrovascular accident and there were no incidents of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized STS trial, venous thromboembolic events were reported in 5% of patients treated with VOTRIENT compared to 2% with placebo. Fatal pulmonary embolus occurred in 1% (2/240) of STS patients receiving VOTRIENT and in no patients receiving placebo. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the STS trials, gastrointestinal perforation or fistula occurred in 1% (4/382) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (1/382) of these patients. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 5% (11/240) of patients treated with VOTRIENT in the randomized STS trial. No patients on the placebo arm had hypothyroidism. In STS trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 5% (20/382) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized STS trial, proteinuria was reported as an adverse reaction in 1% (2/240) of patients, and nephrotic syndrome was reported in 1 patient, treated with VOTRIENT compared to none in patients receiving placebo. Treatment was withdrawn in the patient with nephrotic syndrome. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour

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Under an adaptive randomized design, a complex statistical process allows researchers an early glance at how patients with certain molecular signatures in their tumors are responding to various investigational agents. Researchers can then use these data to assign new participants to the treatments that appear likely to be most effective,

according to tumor profile. This is the approach taken in the BATTLE program at MD Anderson and Yale, a platform for integrated translational research that involves a clinical trial program, a novel trial design, and biomarker discovery. The hypotheses are that real-time biopsies are possible and they are accurate re-

urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection. Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

(N=240)

(N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 Adverse Reactions Fatigue Diarrhea Nausea Weight decreased Hypertension Appetite decreased Hair color changes Vomiting Tumor pain Dysgeusia Headache Musculoskeletal pain Myalgia Gastrointestinal pain Dyspnea Exfoliative rash Cough Peripheral edema Mucositis Alopecia Dizziness Skin disorder b Skin hypopigmentation Stomatitis Chest pain a b

65 59 56 48 42 40 39 33 29 28 23 23 23 23 20 18 17 14 12 12 11 11 11 11 10

13 5 3 4 7 6 0 3 8 0 1 2 2 3 5 <1 <1 2 2 0 1 2 0 <1 2

1 0 0 0 0 0 0 0 0 0 0 0 0 0 <1 0 0 0 0 0 0 0 0 0 0

48 15 22 15 6 19 2 11 21 3 8 20 9 9 17 9 12 9 2 1 4 1 0 3 6

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

1 0 0 0 0 0 0 0 2 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3. 27 of the 28 cases of skin disorder were palmar-plantar erythrodysesthesia.

Other adverse reactions observed more commonly in patients treated with VOTRIENT that occurred in ≥5% of patients and at an incidence of more than 2% difference from placebo included insomnia (9% versus 6%), hypothyroidism (8% versus 0), dysphonia (8% versus 2%), epistaxis (8% versus 2%), left ventricular dysfunction (8% versus 4%), dyspepsia (7% versus 2%), dry skin (6% versus <1%), chills (5% versus 1%), vision blurred (5% versus 2%), nail disorder (5% versus 0%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with STS who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=240)

Parameters

Placebo (N=123)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic Leukopenia Lymphocytopenia Thrombocytopenia Neutropenia Chemistry AST increased ALT increased Glucose increased

44 43 36 33

1 10 3 4

0 0 1 0

15 36 6 7

0 9 0 0

0 2 0 0

51 46 45

5 8 <1

3 2 0

22 18 35

2 2 2

0 1 0

Albumin decreased

Alkaline phosphatase increased Sodium decreased Total bilirubin increased Potassium increased a

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the STS clinical trial. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Pneumothorax: In the randomized trial of VOTRIENT for the treatment of STS, pneumothorax occurred in 3% (8/240) of patients treated with VOTRIENT and in no patients on the placebo arm. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)]. 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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ization, more patients are assigned to more effective therapies,” Dr. Herbst said. The study moves forward based on accumulating patient data. “We learn and update as we go,” he said. “Success is dependent on good biomarkers guiding assignments to good treatment options.”

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6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Soft Tissue Sarcoma: The safety of VOTRIENT has been evaluated in 382 patients with advanced soft tissue sarcoma, with a median duration of treatment of 3.6 months (range 0 to 53). The most commonly observed adverse reactions (≥20%) in the 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea and skin hypopigmentation. The data described below reflect the safety profile of VOTRIENT in 240 patients who participated in a randomized, double-blind, placebocontrolled trial [see Clinical Studies (14.2) of full prescribing information]. The median duration of treatment was 4.5 months (range 0 to 24) for patients who received VOTRIENT and 1.9 months (range 0 to 24) for the placebo arm. Fifty-eight percent of patients on VOTRIENT required a dose interruption. Thirty-eight percent of patients on VOTRIENT had their dose reduced. Fourteen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with STS who Received VOTRIENT

flections of aberrant signaling pathways in NSCLC, and that targeted agents matched to abnormal pathways will improve disease control. A single control arm is used for multiple experimental drugs, and each drug is evaluated for efficacy in multiple biomarkerdefined subgroups. “With Bayesian adaptive random-

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Adaptive Trial Design continued from page 7

Lessons of BATTLE-1 BATTLE-1 began 7 years ago and has since enrolled almost 350 patients with refractory, biopsy-amenable NSCLC. Patients undergo two biopsies and biomarker analysis, and are then randomly assigned to a targeted

agent (erlotinib [Tarceva], vandetanib [Caprelsa], erlotinib plus bexarotene [Targretin], or sorafenib [Nexavar]), depending on their tumor profile. The endpoint is disease control at 8 weeks. Some of the lessons learned from the BATTLE-1 experience are: ■■ Biomarker-based adaptive design is doable and is well received by

• 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 signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, or severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

■

Disclosure: Dr. Herbst has served as a consultant or in an advisory role for Biothera, Diatech, N-of-One, Roche/Genentech, and has research funding from Genentech and GlaxoSmithKline.

References 1. Herbst R: Developing a targeted therapy: Issues in the age of personalized medicine. Best of ASCO Boston. Education Session. Presented August 4, 2012. 2. Kim ES, Herbst RS, Wistuba II, et al: The BATTLE trial: Personalizing therapy for lung cancer. Cancer Discov 1(1):4453, 2011.

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

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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

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:

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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.

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.

ample, vandetanib improves disease control in patients with high VEGFR-2 expression. ■■ Eight-week disease control is an acceptable surrogate for efficacy in patients with pretreated lung cancer, as it predicts for overall survival; median overall survival was 11.3 months when patients achieved 8-week disease control vs 7.5 months when they did not (P = .002). ■■ Gene-expression signatures associated with response to EGFR tyrosine kinase inhibitors do exist in patients with wild-type EGFR. Now investigators are moving into the BATTLE-2 program, which builds on the experience of BATTLE-1, employs more specifically targeted drugs and drug combinations, avoids biomarker grouping, involves selection and validation of novel predictive biomarkers in real time, and unites multiple drug companies in a collaborative effort.

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)]. 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 preclinical 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 the STS trials, 24% (93/382) of patients were age ≥65 years. Patients ≥65 years had increased Grade 3 or 4 fatigue (19% versus 12% for <65), hypertension (10% versus 6%), decreased appetite (11% versus 2%) and ALT (3% versus 2%) or AST elevations (4% versus 1%). 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 C max and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 patients with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary.

clinicians and patients. ■■ Real-time biopsies are possible, and results can be obtained in 2 weeks. ■■ Adaptive randomization only works when effective drugs and predictive biomarkers are available. ■■ Matching targeted agents with abnormal pathways can improve disease control in NSCLC; for ex-

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 9

Perspective

Dermatologic Care continued from page 1

ing remarkable progress in developing agents that prolonged life, we were, to a great extent, overlooking the largest human organ: the skin. This realization was what motivated me to dedicate my career to treating patients with cancer. Many of the skin conditions that arise as side effects from cancer therapies appear unexpectedly and progress rapidly. Therefore, we need to see patients in a timely fashion, within days of the first symptom, or whenever the first sign of a rash or other skin issue alerts the oncologist. We’ve documented a decreased quality of life in patients with cancer who have dermatologic side effects; the patient often thinks that the skin disorder will result in their oncologist stopping their treatment. It is vital to medicate dermatologic conditions as soon as they arise.

Significant Advances Since beginning my career, there has been increasing awareness of the importance of dermatologic care in oncology. Consequently, we’ve seen a number of significant scientific advances. One is the use of antibiotics to prevent rashes associated with epidermal growth factor receptor (EGFR) inhibitors. We’ve demonstrated that prophylactic use of antibiotics (for example, clindamycin and mupirocin) reduces—by about 50%—the acne-like rashes associated with these agents. Another important discovery has been the impact of using cold gloves and socks on the hands and feet to diminish nail changes, including separation, and infections induced by the taxanes. A principal concept is that the majority of rashes are not allergic reactions, but

Contagious Cancer continued from page 1

standing of the molecular mechanisms of cancer. Recently, the discovery of contagious cancers, including the devil facial tumor disease, which might lead to extinction of the Tasmanian devil in the wild, has rekindled my curiosity. Eventually, I became convinced that underlying mechanisms in the transmission of animal-to-animal cancers might have value in clinical oncology, particularly in the area of immunotherapy.

Origin of Devil Facial Tumor Disease What kind of cancer is being transmit-

rather, a direct result of the agent’s mechanism of action. Understanding this, we can perform damage control, letting the patient remain on life-prolonging therapy while minimizing symptoms and enhancing cutaneous health. An advance that goes underutilized is the use of topical corticosteroids to

that comes with body image. Working with a dermatologist empowers patients to partner in their skin care, not only for cosmetic reasons, but also to be aware of painful or itchy dermatologic conditions that can affect activities of daily living or can result in lifethreatening infections.

We need to continue to press forward, making sure that dermatology is part of the continuum of cancer care for all of our patients. — Mario E. Lacouture, MD

prevent radiation dermatitis. In fact, about six randomized studies have demonstrated that prophylactic use of high-potency topical steroids minimizes the symptoms of radiation dermatitis, especially in breast and head and neck cancer. Despite our knowledge about dermatologic adverse events from cancer treatments, we still see a large number of patients who are reluctant to mention skin-related issues with their oncologists, often due to the aforementioned fear of being taken off treatment. Many patients also feel a sense of guilt, believing that if they complain about skin issues, this trivializes their doctor’s efforts to cure or control their disease. We need to show our patients that problematic dermatologic conditions can be managed in a way that allows them to have a good quality of life and maintain the healthy sense of “self ”

Psychosocial Perspective

ted among Tasmanian devils? Devil facial tumors are head and neck cancers. The cells are probably of neural crest origin, perhaps from Schwann cells. Similar to human head and neck cancers, they are locally destructive and they spread to regional lymph nodes, occasionally metastasizing to the lungs if the animal lives that long. We don’t know the origin of this tumor, but the first pathologically confirmed case of devil facial tumor disease was in 1997. We do know that these cancers are typically transmitted as an allograft when the face is bitten during territorial fights and courtship battles. Malignant cells are found

on the gums and teeth of affected animals and can be directly transplanted into the wound of another animal by a bite. A lot of people assume that devil facial tumor disease is a head and neck cancer that originally arose in that region, but I have my own hypothesis. This tumor might have arisen in a different organ in the index animal. We know that Tasmanian devils are prone to cannibalism, so it could be that one animal ate the index animal and tumor tissue got lodged in its teeth and gums. That tumor tissue developed into the cancer and was then transmitted to other animals during fighting. And that’s how I believe the disease became

Work in the psychosocial aspects of cancer has shown that one of the most problematic features of this disease is the patient’s feeling of a loss of control. One way for patients to strengthen the very important sense of self-determination that helps define us as individuals is by maintaining their appearance and sense of personhood. A patient’s skin care, which is essential to body image, needs to be addressed before, during, and after treatment. To that end, it is essential to provide patients with educational material that allows them to be actively engaged in their own cosmesis. For example, although various cosmetic options such as wigs, hats, scarves, powders, and sprays have helped many people cope with hair and eyelash loss, newer interventions such as minoxidil or bimatoprost (La-

tisse) may reduce the duration of hair and eyelash loss from chemotherapy. Similarly, supplements such as biotin and orthosilic acid have been shown to be effective in nail and hair health. Patients with cancer are often hesitant about using cosmetics, and some products on the market should be avoided. However, a growing number of cosmetic products are safe for patients with cancer and can be used to hide facial side effects associated with chemotherapy, such as rashes, scars, and discoloration. While we generally think cosmetics are for women, male patients may need this type of intervention as well. For example, men who never thought about using a concealing foundation are now offered an option that will hide facial rashes or discolorations, allowing them to be less conspicuous and self-conscious in the work place—a significant quality-of-life advance.

Continuum of Care Reducing or preventing dermatologic adverse events does not end at the physical level. Many patients have told me how skin intervention has improved their overall life, their interactions with friends and associates, their confidence, and most important, their ability to enjoy each and every day. Although participating in the care of skin, hair, and nails in people living with cancer is but one part of the challenging work that oncologists do, it is a valuable one. We need to continue to press forward, making sure that dermatology is part of the continuum of cancer care for all of our patients.

■

Disclosure: Dr. Lacouture is a consultant for Amgen, Roche, Bristol-Myers Squibb, AstraZeneca, Bayer, ImClone, and Genentech. He is the author of Dr. Lacouture’s Skin Care Guide for People Living With Cancer.

entrenched in the head and neck region of these animals. The locally aggressive malignancy often causes death within 6 months due to consequences of airway obstruction and inability to feed. It’s important to note that in little more than 10 years the cancer has spread so rapidly that the Tasmanian devil has been placed on the endangered species list, which is quite remarkable.

Other Contagious Cancers Are there other contagious cancers notable among animals? Several. One is among dogs, called canine transmissible venereal tumor, continued on page 10

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PAGE 10

Expert’s Corner

Contagious Cancer continued from page 9

also known as Sticker’s sarcoma. There are similarities between this cancer and devil facial tumor disease in that it is passed from animal to animal and is not caused by a virus or another infectious agent. But unlike devil facial tumor disease, which is rapidly progressive and fatal, the canine cancer progresses rapidly at first, then regresses, and is not usually fatal. We don’t know exactly why this cancer acts this way, but it is postulated that there might be an initial downmodulation of major histocompatibility complex (MHC) antigens, which reduces its initial visibility to the host’s immune system. Interestingly, the MHC class�� 2�� antigens are later reexpressed, and the dog’s immune system is alerted and rejects the tumor, which is a very different outcome from the cancer that has so far wiped out half of

the wild population of the Tasmanian devil.

Impact of Immunology Immunology receives mixed reviews in oncology. Do you believe there’s some potential there that we’re not yet seeing? I do, and a recent New England Journal of Medicine paper on the abscopal effect (ie, when local therapy directed at a tumor site is associated with regression of metastases elsewhere in the body) in a patient with melanoma further accelerated my interest and scientific belief in the underlying power of immune responses.1 I, and many radiation oncologists, have observed the abscopal phenomenon. For example, I was irradiating a bone metastasis in an end-stage patient to palliate his symptoms, and almost miraculously most of his metastatic disease disappeared. It left me scratching my head, wondering what had just happened.

What did happen? We know that the immune system somehow woke up, recognized the cancer as something that doesn’t belong in the body, and eradicated it in much the same way it would attack a transplanted organ. Unfortunately these abscopal responses happen infrequently, and when they do occur, they typically don’t last long, although sometimes the response is durable. Anyone who has seen the abscopal effect has got to be thinking that if we could turn this response on at will, the field of clinical oncology would be changed forever.

Pursuing the Mystery

Tasmanian devil

If we take the immune responses demonstrated in the abscopal effect and the canine cancer, is there a scientific clue that might lead to more extensive work in immunology? I’m not an immunologist, but I’ve come to believe that if we pursue this

intriguing biologic mystery, we’ll discover a critical sign that will allow us to switch on the abscopal effect that I and other radiation oncologists have seen firsthand. As mentioned, it leaves you in wonderment. continued on page 14

EXPERT POINT OF VIEW By Dan L. Longo, MD Professor, Department of Medicine, Harvard Medical School Senior Physician, Brigham and Women’s Hospital Boston, Massachusetts

Dan L. Longo, MD

he term “abscopal” is from Greek roots that mean “away from the target.” Coined by R.H. Mole in 1953, it was used to label observed effects of radiation at a distance from the volume irradiated. Mounting evidence suggests an immunologic basis for the effect, but it should also be remembered that blood-borne products of the tumor may be involved, given that some metastatic tumors (eg, renal cell cancer and neuroblastoma) can, rarely, regress with surgical resection of the primary tumor.

Tumor-induced Immunosuppression Tumors have a diverse repertoire

of tricks to elude detection and attack from the immune system. As cancers, in general, originate from one’s normal cells, they typically have few recognizable differences from self. They can stop expression of HLA molecules, making T cells blind to their presence. They can impair antigen presentation. They produce factors that can kill immune cells or paralyze immune responses. They also use the immune system’s safeguards against autodestruction to protect themselves by inducing the expansion of regulatory cell populations (myeloid cells, monocytes, T cells, B cells) that inhibit the immune response. As these factors (and others) contributing to tumor-induced immunosuppression have been elucidated, new interventions to overcome them are being brought to the clinic with impressive levels of success, including the mediation of abscopal effects. Antibodies to undo the tamping down of immune responses (eg, CTLA4, PD1) are showing meaningful response rates. Novel vaccine approaches are eliciting antitumor immunity. Immune stimulation (CD40 and OX40 activation) is making progress. And the strategy of arming and souping up T cells to kill tumors in adoptive transfer is joining graft-vs-tumor ef-

fects as an effective cell-based cancer treatment.

The Tasmanian Devil Mystery So why are Tasmanian devils being extinguished by a tumor they are passing to each other? Frankly, it is a surprise. Experiments conducted in the 1950s and 1960s on prisoners and chronically ill patients (tragically, without what we would consider informed consent) demonstrated that subcutaneous injection of live tumor cells from another person would not survive even in people with some immune compromise. Based on theories about the evolution of the immune system, the first mediator of cell-based immunity (the amebocyte of the sponge) arose to fight off another member of the same species competing for space on the same rock. A very large percentage of an animal’s or a person’s T cells are potently alloreactive— that is, they respond to and kill cells from another member of the same species. Yet xenogeneic responses (those against another species) are relatively weak. The rejection of a tumor from another member of one’s species is usually major histocompatibility complex (MHC)-based (involving either major or minor antigens or both) and similar to the

rejection of mismatched organs. The canine transmissible venereal tumor follows the predictions of the fate of an allogeneic tumor, namely to be ultimately rejected by the host. Why are Tasmanian devils dying before they can develop an effective immune response against their tumor? Unfortunately, we do not know enough about the devil immune system to draw a conclusion.

Ongoing Work Much interesting work is ongoing to sort out this mystery. Apparently only 20% of one population of devils (West Pencil Pine near Cradle Mountain) have developed the tumor, down from the 80% or more incidence among devils in the wild. Is the tumor changing or are the devils developing immunity? A decrease in the virulence of the tumor would be a welcome accompaniment to the gradual increase in scientific understanding that can combat this tragic disease. Thankfully, the killing of a tumor that originated in another person is not a major problem in humans. However, overcoming a cancer’s successful adaptation to life in a syngeneic host is becoming an achievable goal.

■

Disclosure: Dr. Longo is deputy editor of the New England Journal of Medicine.

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 11

FOR PATIENTS WITH ADVANCED BCC

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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. 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 Embryo-Fetal Death and Severe Birth Defects • 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

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea,

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 BCC1,3

Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

mBCC (n=33)

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

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

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 months (5.7-9.7)

7.6 months (5.6-NE)

ORR (95% CI)

Median response duration (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=confidence interval. NE=not estimable.

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. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012; 366:2171-2179.

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The ASCO Post | SEPTEMBER 15, 2012

PAGE 14

Expert’s Corner

Contagious Cancer

posite outcomes there might be a clue that will allow us to exploit our immune system’s ability to eradicate cancers.

continued from page 10

Moreover, the fact that Sticker’s sarcoma in canines disappears spontaneously after the immune system is alerted—as opposed to the Tasmanian devil cancer, which acts more like the cancers we see in humans—seems to indicate that in the space between the polar op-

Role of Vaccines We know that about 15% of cancers worldwide are caused by infectious etiologies. Do you see a greater role for vaccines moving forward?

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

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

Absolutely. The rise in head and neck cancers among a younger population that don’t have the classic carcinogenic risk factors is due to human papillomavirus infection. If that’s the case, there’s going to be a very important role for vaccination. And as we gain more knowledge in this area, I’m sure that vaccines will

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

prove effective in a growing number of virally transmitted cancers.

Valuable Clues Any last thoughts on contagious cancer and the immune system? The story of animal-to-animal transmission of malignancies is fascinating in that we see two starkly different outcomes—one that is rapidly fatal and one that is mediated by an immune response that makes the can-

The story of animalto-animal transmission of malignancies is fascinating in that we see two starkly different outcomes. —James S. Welsh, MD

cer completely regress. Then there’s the abscopal effect in humans, which further demonstrates the immune system’s uncanny ability to kill cancers. Also, as a clinician, I’ve been fascinated by the occasional mother-tofetus transmission of cancers such as lymphoma and leukemia. Even more rare is the transmission of cancers from donor to patient in organ transplants. Interestingly, if the donated organ is from a person with cancer, and the organ recipient subsequently develops cancer from that organ, sometimes when the immunosuppression is stopped and the donated organ is removed, the cancer will regress— even after metastasis. So that response is akin to dogs with Sticker’s sarcoma, in which the immune system wakes up and rejects the malignancy. In other words, if the immune system is not immunosuppressed to prevent it from rejecting the transplanted organ, it may also reject the transplanted cancer. Combining these various observations about transmission and immune response might someday provide valuable clues that can be translated into breakthroughs in the clinic.

■

Disclosure: Dr. Welsh is on the Advisory Committee for the Medical Use of Isotopes, United States Nuclear Regulatory Commission.

Reference 1. Postow MA, Callahan MK, Barker CA, et al: Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925-931, 2012.

ASCOPost.com | SEPTEMBER 15, 2012

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Journal Spotlight Genitourinary Oncology

No Survival Benefit of Radical Prostatectomy vs Observation for Localized Prostate Cancer Detected by PSA Testing By Matthew Stenger

he relative benefits of surgery or observation in men with prostate cancer detected by prostate-specific antigen (PSA) testing have not been defined. Randomized trials comparing radical prostatectomy with observation were conducted before widespread use of PSA testing and an observational study conducted during the PSA testing era suggested high 10-year survival rates among men treated conservatively. Recent studies of the effects of PSA screening on prostate cancer mortality have reached opposite conclusions: The Prostate, Lung, Colorectal, and Ovarian (PLCO)

Cancer Screening Trial on prostate cancer mortality found no benefit of PSA screening vs usual care; the 11-year follow-up of the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed a significant benefit of PSA screening vs control on prostate cancer mortality. In a recent article in The New England Journal of Medicine, Wilt and colleagues report findings of the Prostate Cancer Intervention Versus Observation Trial (PIVOT), 1 which enrolled patients during the early part of the PSA testing era. The results indicate a lack of survival benefit or reduction in

prostate cancer mortality of radical prostatectomy compared with observation in men with localized prostate cancer detected during the early PSA era.

PIVOT Details In the PIVOT trial, 731 men aged ≤ 75 years with localized prostate were randomly assigned to radical prostatectomy (n�� = �� 364) or observation (n�� = 367) between November 1994 and January 2002 and followed through January 2010. The primary endpoint was all-cause mortality. Patients had a median age of 67 years and a median PSA value of 7.8 ng/mL. Nearly one-third were

black, approximately 50% had stage T1c disease (nonpalpable, detected by PSA testing), and approximately 25% had histologic scores ≥ 7 on the Gleason scale. Tumors were low-risk in 40% of patients, intermediate-risk in 34%, and high-risk in 21%. On central pathology review, 48% of patients had Gleason scores ≥ 7 and 66% had intermediate- or high-risk tumors. Overall, 79% of the patients randomized to radical prostatectomy underwent an attempted procedure (at a median time from randomization of 35 days) and 85% of those received definitive therapy. Among those randomcontinued on pages 16 and 18

EXPERT POINT OF VIEW By Timothy Wilt, MD, MPH Professor of Medicine and Core Investigator Minneapolis VA Center for Chronic Disease Outcomes Research and the University of Minnesota School of Medicine, Minneapolis Chair, VA/NCI/AHRQ CSP#407: Prostate Cancer Intervention Versus Observation Trial (PIVOT)

Timothy Wilt, MD, MPH

IVOT is the largest and longest randomized trial conducted in men with early-stage prostate cancer detected during the era of widespread PSA testing. The trial enrolled 731 men and followed them for up to 15 years after randomization. PIVOT results demonstrate that compared to observation, radical prostatectomy did not result in a significant reduction in all-cause or prostate cancer mortality through at least 12 years among men with localized prostate cancer; absolute differences in mor-

tality rates were less than 3%. Results changed little after 8 years and additional follow-up is therefore unlikely to change these findings. Radical prostatectomy caused related harms within 30 days of surgery in 21% of men and urinary incontinence and erectile dysfunction through at least 2 years.

Other Key Findings PIVOT showed that prostate cancer mortality was infrequent among all men treated with observation (approximately 8%) and rare (3%) in men with PSA values ≤ 10 ng/mL or low-risk disease—important and reassuring findings for men, their families, and physicians. Noncancer death rates and surgical quality in PIVOT were similar to other studies enrolling men with early-stage prostate cancer. The mean age of 67 years, health status, and comorbidities for men in the trial were similar to most men diagnosed with prostate cancer and to patient populations in other trials. The effect of radical prostatectomy did not vary by patient age, race, health status, or presence of other medical conditions. As noted, death from prostate cancer was rare in men with low PSA (≤ 10 ng/mL) or low-risk disease treated with observation, and sur-

gery provided no reduction in overall or prostate cancer mortality or risk of bone metastases in such patients. Subgroup analyses indicate that surgery may reduce mortality and bone metastases in men with higher PSA or higher-risk disease. However, subgroup findings should be viewed with caution. Any positive results were based on multiple subgroup assessments, rarely met traditional levels of statistical significance, and often were sensitive to methods of analysis; thus, the findings may be due to chance.

Observation should be recommended as the preferred treatment option [in men with low-risk disease]. Implications of PIVOT Three-quarters of men with earlystage prostate cancer have low PSA or low-risk disease. Men diagnosed today and managed with observation likely have even a better prognosis than men enrolled in PIVOT because of increased detection of smaller, more indolent disease. Compared to active surveillance, informing men of the favorable long-term effects of observation on mortality, bone metasta-

ses, urinary and erectile function, and quality of life and increasing the use of observation may avert the harms of unnecessary biopsies and interventions while maintaining excellent long-term disease-specific survival. PIVOT results, combined with other data from randomized treatment and screening trials, indicate that observation should be the preferred treatment strategy for the majority of men currently diagnosed with early-stage prostate cancer. Such a strategy can help men live a similar length of life, avoid death from prostate cancer, and prevent treatmentrelated harms and costs. In conclusion, PIVOT demonstrated that surgery did not reduce overall or prostate cancer mortality compared to observation through at least 12 years. While surgery may reduce mortality in the minority of men with PSA greater than 10 ng/ mL or high-risk disease, it did not improve outcomes in men with PSA of ≤�� 10�� ng/mL or low-risk disease. Observation should be recommended as the preferred treatment option. Randomized controlled trials are needed to evaluate new, more effective, and safer screening and treatment approaches for men with aggressive prostate cancer.

■

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

The ASCO Post | SEPTEMBER 15, 2012

PAGE 16

Journal Spotlight

EXPERT POINT OF VIEW By Fritz H. Schröder, MD Professor of Urology Erasmus University Medical Centre Rotterdam, The Netherlands

Fritz H. Schröder, MD

am happy to accept the invitation by The ASCO Post to comment on the recent, long-awaited publication of the PIVOT study (Wilt et al: N Engl J Med 367:203-213, 2012) and the accompanying editorial by Thompson and Tangen (N Engl J Med 367:270-271, 2012). The editorial both points out weaknesses of the PIVOT report that limit its applicability to clinical practice and helps to clarify the confusion arising out of the contradictory findings of the PIVOT study and the recently published Scandinavian Prostate Group study 4 (SPG 4).1 The commentators strongly suggest that the PIVOT study is insufficiently powered to support the conclusion that radical prostatectomy does not reduce all-cause or prostate cancer mortality when compared with observation in men with clinically localized prostate cancer While I fully agree with the critical review of the original and revised power calculations in the editorial, the authors do not point out an underlying clinical factor that is likely to have affected the outcome of the study and that serves to further limit applicability of PIVOT results. The study included a large proportion of T1c Gleason 3+3 cancers, which are likely to be overdiagnosed, with most cases not expected to progress or become life-threatening during the patient’s lifetime. These tumors are part of the low-risk group described in the PIVOT article. The authors state: “About 50% of the men had stage T1c disease (not palpable, detected by means of [prostate-specific antigen (PSA)] testing) and about 25% had histologic scores of 7 or higher on the Gleason scale.” Although the

specific proportion of men with T1c cancers and Gleason scores of 6 or less is not available, these figures imply that somewhere around 75% of the men with T1c cancers had well-differentiated tumors classified as Gleason 6 or less and that somewhere around 37.5% of all patients had these characteristics.

A prospective study of active surveillance conducted at Johns Hopkins Medical Center included only T1c cases.8 No metastatic disease or prostate cancer deaths were encountered in 769 patients with a median follow-up of 2.7 years (range, 0.1–15.0 years).

Natural History of Prostate Cancer

Interpreting the Data

Knowledge about the natural history of well-differentiated T1c prostate cancer has developed only in recent years and was not available at the time PIVOT was initiated in 1994. About that time, the first evidence estimating the lead time of locally confined prostate cancer in relation to PSA levels became available.2,3 Estimates of lead time and overdiagnosis produced by PSA-driven screening were first published in 2003.4

What might the inclusion of 37.5% of participants with an almost zero chance of prostate cancer progression or mortality mean for the interpretation, understanding, and clinical application of the PIVOT data? Although I am not a statistician and unable to quantitatively judge the effect of including so many cancers that do not contribute to the endpoint of prostate cancer and all-cause mortality, I would venture to say that as the power of the study decreases further, its outcomes

How should we as clinicians understand and use the results of PIVOT? In dealing with prostate cancer, we need to apply current knowledge and either avoid the diagnosis of potentially overdiagnosed cancer altogether or, if such tumors are diagnosed, recommend active surveillance as the first option. An analysis of the effect of prognostic factors on these important predictors of the natural history of prostate cancer is about to be published.5 This analysis shows a rate of overdiagnosis of 30.5% for this lowest risk category. This estimate is in line with an analysis and risk classification of men who had chosen active surveillance in the Rotterdam screening study. The estimated rate of cancers defined as “indolent” in this report is 28.9%.6 Confirmative evidence of these classifications and of estimates that are based on modeling and on biopsy findings comes from the available active surveillance studies, which all have follow-up periods that—at this time—fall short of the lead-time estimates. Still, in a cooperative study in Finnish and Rotterdam European Randomized Study of Screening for Prostate Cancer (ERSPC) centers in 509 patients with a median follow-up of 7.4 years, a prostate cancer–specific survival of 99.1% was observed.7

become even less informative. Subgroup analyses in the PIVOT study show a significant effect of radical prostatectomy in men presenting with PSA ≥ 10 ng/mL (P = .04) and a borderline significance (P = .07) if the lowrisk group is compared to cancers with intermediate or high risk. What might the result have been if PIVOT had not included the 50% of T1c cancers? The study would have become very similar to the SPG 4 study and would probably have shown the same result.

Limited Options How then should we as clinicians understand and use the results of PIVOT? In dealing with prostate cancer, we need to apply current knowledge and either avoid the diagnosis of potentially overdiagnosed cancer altogether or, if such tumors are diagnosed, recommend active surveillance as the first option. Unfortunately, at present, the options to avoid prostatic biopsy in

men who harbor potentially overdiagnosed prostate cancers are limited. The only feasible option is the application of available risk calculators that consider routine clinical findings next to PSA. This has been shown to be effective in a study in the Rotterdam section of the ERSPC.9 In my view, the results of the SPG 4 study apply to prostate cancers that do not fall within the T1c Gleason 6 group. These men remain candidates for potentially curative forms of management such as radical prostatectomy or the different options offered by radiotherapy.

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

References 1. Bill-Axelson A, Holmberg L, Ruutu M, et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 364:1708-1717, 2011. 2. Stenman UH, Hakama M, Knekt P, et al: Serum concentrations of prostate specific antigen and its complex with alpha 1-antichymotrypsin before diagnosis of prostate cancer. Lancet 344:15941598, 1994. 3. Gann PH, Hennekens CH, Stampfer MJ: A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 273:289-294, 1995. 4. Draisma G, Boer R, Otto SJ, et al: Lead times and overdetection due to prostate-specific antigen screening: Estimates from the European Randomized study of Screening for Prostate Cancer. J Natl Cancer Inst 95:868-878, 2003. 5. Wever EM, Heijnsdijk EAM, Draisma G, et al: Treatment of PSA-detected prostate cancer: Benefits and harms by prognostic factors. Submitted, 2012. 6. Roemeling S, Roobol MJ, Postma R, et al: Management and survival of screen detected prostate cancer patients who might have been suitable for active surveillance. Eur Urol 50:475-482, 2006. 7. Bul M, van den Bergh RC, Zhu X, et al: Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer. BJU Int. August 29, 2012 (early release online). 8. Tosoian JJ, Trock BJ, Landis P, et al: Active surveillance program for prostate cancer: an update of the Johns Hopkins Experience. J Clin Oncol 29:2185-2190, 2011. 9. Roobol MJ, Steyerberg EW, Kranse R, et al: A risk-based strategy improves prostate-specific antigen-driven detection of prostate cancer. Eur Urol 57:7985, 2010.

NOW ENROLLING

ACUTE LYMPHOBLASTIC LEUKEMIA

INO-VATE ALL INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy A randomized, phase 3 trial in patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) This is a 2-armed, randomized, open-label, phase 3 study designed to evaluate the hematologic remission rate (CR + CRi) with inotuzumab ozogamicin compared with investigators’ choice of FLAG, cytarabine combined with mitoxantrone, or HIDAC.

Selected inclusion criteria • Relapsed or refractory CD22-positive ALL due to receive salvage 1 or salvage 2 therapy • Ph+ ALL patients must have failed treatment with at least 1 second-generation tyrosine kinase inhibitor • Bone marrow involvement with ≥5% lymphoblasts • Aged 18 years or older • ECOG performance status 0-2 • Adequate liver function

Selected exclusion criteria • Isolated extramedullary relapse, Burkitt’s lymphoma or mixed-lineage leukemia, or active central nervous system leukemia • Active heart disease • Prior chemotherapy ≤2 weeks prior to randomization and/or patients not recovered from acute toxicity • Prior treatment with monoclonal antibodies ≤6 weeks before randomization • Prior allogeneic hematopoietic stem cell transplant ≤4 months before randomization • Peripheral lymphoblasts >10,000/µL

Reference: ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01564784. Accessed April 3, 2012.

Inotuzumab ozogamicin is an investigational compound. This information is current as of August 14, 2012.

STW00067B

April 2012

Learn more about INO-VATE (B1931022) For more information about this trial, please visit www.clinicaltrials.gov (NCT01564784) or call: 1-877-369-9753 in the United States and Canada (toll-free) or +1-646-277-4066 outside the United States

The ASCO Post | SEPTEMBER 15, 2012

PAGE 18

Journal Spotlight

Prostatectomy vs Observation continued from page 15

ized to observation, 10% underwent attempted radical prostatectomy (at a median of 61 days) and 20% received definitive therapy.

All-cause Mortality Over a median follow-up of 10.0 years, all-cause mortality rates were 47.0% in the prostatectomy group and 49.9% in the observation group (HR = 0.88, 95% CI = 0.71–1.08, P = .22), a nonsignificant absolute 2.9% difference. Overall, 354 patients (48%) died from any cause, and 52 (7%) died from causes related to prostate cancer or its treatment (prostate cancer mortality). Median overall survival was 13.0 years in the prostatectomy group and 12.4 years in the observation group. At 12 years, 40.9% of the prostatectomy group and 43.9% of the observation group had died. The absolute reduction in mortality in the prostatectomy group was not significant at any time point and decreased over time from 4.6% at 4 years to 2.9% at 12 years. Subgroup analyses indicated no difference in mortality between the two groups according to age, Gleason histologic score, race, self-reported performance status, or Charlson comorbidity score, but showed a significant interaction between treatment group and baseline PSA level (P = .04) and a borderline interaction for = .07). Raditumor risk category (P �� cal prostatectomy was associated with an absolute 13.7% reduction in all-cause mortality among men with baseline PSA level > 10 ng/mL (HR = 0.67, 95% CI = 0.48–0.94), an absolute 12.6% reduction among those with intermediate-risk tumors (HR = 0.69, 95% CI = 0.49–0.98), and a nonsignificant absolute 6.7% reduction among those with high-risk tumors. Among patients with low-risk tumors, the prostatectomy group had a nonsignificant relative 15% increase in risk for mortality.

Prostate Cancer Mortality Rates of prostate cancer mortality (mortality due to prostate cancer or its treatment), a secondary end-

point of the study, were 5.8% in the prostatectomy group and 8.4% in the observation group (HR = 0.63, P = .09), a nonsignificant absolute 2.6% difference. Death considered to be definitely due to prostate cancer or its treatment occurred in 4.4% and 4.9% of patients, respectively. Rates of prostate cancer mortality in the two groups were identical at 4 years, with the prostatectomy group having a nonsignificant absolute 3.0% reduction at 12 years (4.4% vs 7.4%). Prostate cancer mortality rates were lower among patients in the prostatectomy group who had baseline PSA ≥ 10 ng/ mL (5.6% vs 12.8%, P = .02) or highrisk tumors (9.1% vs 17.5%, P = .04).

port observation for men with localized prostate cancer, especially those who have a low PSA value and those who have low-risk disease,” while “[s]ubgroup analyses suggested that surgery might reduce mortality among men with higher PSA values and possibly among men with higher-risk tumors.”

Do Studies Miss Benefit of Screening? In an accompanying editorial, Thompson and Tangen2 point out that prostate cancer mortality was reduced 44% between 1993 and 2009 and wonder how this can be if screening and treatment do not pro-

Prostatectomy vs Observation in Localized Prostate Cancer ■■ Through a maximum of 15 years of follow-up in the randomized PIVOT

trial, radical prostatectomy failed to significantly reduce mortality (vs observation) in men with localized prostate cancer detected during the early era of PSA testing.

■■ Results also did not differ among men with factors known to predict

longer life expectancy, including younger age, greater independence in activities, and fewer comorbidities.

■■ Subgroup analyses suggested that surgery might reduce mortality among men with higher PSA values or higher-risk tumors, but not among men with PSA levels ≤ 10 ng/mL or among men with low-risk tumors.

Bone metastases occurred in 4.7% of patients in the prostatectomy group compared with 10.6% of the observation group (HR = 0.40, P < .0001). Complications within 30 days after surgery, including 1 death, occurred in 21% of men in the prostatectomy group who underwent the procedure. Complications occurring in > 2% of these patients included urinary tract infection, surgical repair, bleeding requiring transfusion, and urinary catheterization more than 30 days after surgery. At 2 years, urinary incontinence and erectile dysfunction, but not bowel dysfunction, were significantly more common in the prostatectomy group. The investigators concluded, “[O]ur study showed that … radical prostatectomy did not significantly reduce all-cause or prostate cancer mortality through at least 12 years among men with clinically localized prostate cancer that had been diagnosed in the era of PSA testing.” They noted that their findings “sup-

vide benefit. They suggest that part of the problem may be flaws in the studies that have indicated lack of benefit, including the fact that in the PLCO study, more than half of the control group underwent PSA testing. With regard to the PIVOT trial, the commentators question whether statistical analysis of the trial was adequate to detect what might be meaningful differences in mortality. Due to slow enrollment, the target population of the trial had to be reduced from 2,000 to 740 patients. The statistical analysis was adjusted based on the estimate that an enrollment of 740 over a period of 7 years with 8 additional years of follow-up would provide 91% power to detect a 25% relative reduction in all-cause mortality on the assumption of a median survival of 10 years. The commentators noted that given the actual 12-year median survival in the study’s observation group, the patient sample would need to be

1,200 in order to detect a 25% relative reduction in mortality with 90% power and a twoSee Page 81 sided alpha level of 0.05. Given the actual enrollment of 731 patients, the study was underpowered to detect this relatively large clinical effect. The wide 95% confidence interval (0.71–1.08) for the hazard ratio for mortality in the treatment group illustrates this issue: A relative increase of up to 8% to a relative decrease of up to 29% in mortality in the prostatectomy group could not be excluded with 95% confidence. The commentators also note that while all-cause mortality is an important endpoint, only 15% of endpoints in the study (52 of 354 deaths) were prostate cancer–related (informative endpoints). The treatment effect in prostate cancer would have to be enormous to show an overall 25% difference in all-cause mortality when 85% of events were not informative endpoints. The commentators agree with the authors of the study that the finding of no benefit of prostatectomy in men with lower-risk disease argues for active surveillance in this population. They note that a rational approach to controlling prostate cancer is likely to include biopsy only for those with lethal cancer, treatment focused on such cancer, and individualized treatment approaches. Efforts under way to improve identification of patients with lethal cancer—including Early Detection Research Network studies of biomarker combinations and novel biomarkers—will help to achieve these objectives. For other perspectives on the PIVOT data, see pages 15 and 16.

■

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

References 1. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012. 2. Thompson IM Jr, Tangen CM: Prostate cancer—uncertainty and a way forward (editorial). N Engl J Med 367:270271, 2012.

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 19

FDA Update

FDA Approves New Orphan Drug for Chronic Myelogenous Leukemia

he FDA has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML). The drug is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome–positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec). The safety and effectiveness of Bosulif was evaluated in a single clinical trial that enrolled 546 adult patients with chronic, accelerated, or blast phase CML. All patients had disease that progressed after treatment with imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna), or who could not tolerate the side effects of prior therapy. Results showed 34% of patients with chronic phase CML who had been previously treated with imatinib achieved a major cytogenetic response after 24 weeks. Of the patients who achieved a major cytogenetic response at any time, 52.8% had their response last at least 18 months. Among patients previously treated with imatinib followed by dasatinib and/or nilotinib, about 27% achieved a major cytogenetic response within the first

24 weeks of treatment. Of those who achieved a major cytogenetic response at any time, 51.4% had their response last at least 9 months. In patients with accelerated CML previously treated with at least imatinib, 33% had blood counts return to

normal range (complete hematologic response) and 55% achieved normal blood counts with no evidence of leukemia (overall hematologic response) Bleed:7.875” within the first 48 weeks of treatment. Trim:7.625” Meanwhile, 15% and 28% of patients Live:7” with blast phase CML achieved com-

plete hematologic response and overall hematologic response, respectively. The most common side effects observed in those receiving bosutinib were diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

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NOW AVAILABLE ZALTRAP®, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatincontaining regimen. IMPORTANT SAFETY INFORMATION FOR ZALTRAP

First Drug for Children with Rare Brain Tumor Approved

he FDA approved a new pediatric dosage form of everolimus (Afinitor Disperz) to treat the rare brain tumor called subependymal giant cell astrocytoma (SEGA). This is the first approved pediatric-specific dosage form developed for the treatment of a pediatric tumor. Afinitor Disperz is recommended to treat patients aged 1 year and older with tuberous sclerosis complex who are diagnosed with SEGA that cannot be treated with surgery. Prior to approval of this new dosage form, everolimus was recommended for use only in patients aged 3 years and older. The drug was granted accelerated approval in 2010 to treat SEGA in patients with tuberous sclerosis complex.

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WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage. GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation. Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. WARNINGS AND PRECAUTIONS • Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events — Monitor patients for signs and symptoms of bleeding — Do not initiate ZALTRAP in patients with severe hemorrhage — Discontinue ZALTRAP in patients who develop severe hemorrhage Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent pages.

Visit www.ZALTRAP.com to learn more. For more information about ZALTRAP, call 1-855-ZALTRAP (1-855-925-8727).

FPO

The ASCO Post | SEPTEMBER 15, 2012

PAGE 20

FDA Update

FDA Issues New Safety Alert on Reumofan Plus and Reumofan Plus Premium

n August 21, the FDA issued a new warning to consumers about the potential health risks of two products marketed as natural dietary supplements for treating arthritis, muscle pain, osteoporosis, bone cancer, and other condi-

tions. The products, Reumofan Plus and Reumofan Plus Premium, contain potentially harmful active ingredients that are not listed on the product labels. The FDA received dozens of additional adverse event reports, including

death and stroke, associated with the use of Reumofan Plus after issuing its first warning about the product on June 1, Bleed:7.875” 2012. Other reports include liver injury, Trim:7.625” severe bleeding, sudden worsening of Live:7” glucose control, weight gain, swelling,

leg cramps, and adrenal suppression. Ongoing FDA laboratory analyses of these products found that they contain the prescription drug ingredients dexamethasone, diclofenac sodium, and methocarbamol.

NOW AVAILABLE

IMPORTANT SAFETY INFORMATION FOR ZALTRAP® (cont’d) • GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP — Monitor patients for signs and symptoms of GI perforation — Discontinue ZALTRAP in patients who experience GI perforation • Discontinue ZALTRAP in patients with compromised wound healing — Suspend ZALTRAP for at least 4 weeks prior to elective surgery — Do not initiate/resume ZALTRAP until at least 4 weeks after surgery and surgical wound is fully healed • Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Discontinue ZALTRAP therapy in patients who develop ﬁstula • An increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP — Monitor blood pressure every two weeks or more frequently and treat with appropriate anti-hypertensive therapy during treatment with ZALTRAP — Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles — Discontinue ZALTRAP in patients with hypertensive crisis • Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. Discontinue ZALTRAP in patients who experience an ATE • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP — Suspend ZALTRAP when proteinuria ×2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours — If recurrent, suspend until proteinuria <2 grams/24 hours and then reduce ZALTRAP dose to 2 mg/kg — Discontinue ZALTRAP if nephrotic syndrome or TMA develops • A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP — Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ×1.5 x 109/L • Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI — The incidence of diarrhea is increased in patients ×65 years of age. Monitor closely • Discontinue ZALTRAP in patients who develop reversible posterior leukoencephalopathy syndrome

ADVERSE REACTIONS • The most common adverse reactions (all grades, ×20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache • The most common Grade 3-4 adverse reactions (×5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia • Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection • In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI Please see accompanying Brief Summary of full Prescribing Information, including Boxed WARNING. In the U.S., ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 sanoﬁ-aventis U.S. LLC, a SANOFI company and Regeneron Pharmaceuticals, Inc.

US.AFL.12.07.046

8/12

Printed in U.S.A.

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 21

FDA Update

Manufactured in Mexico Reumofan Plus and Reumofan Plus Premium are labeled in Spanish. However, versions of these products may also exist with English labeling. The products are manufactured in Mexico by Riger Naturals and sold in the United States in some retail outlets, at flea markets, and on various popular Internet sites.

ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion

The hidden drug ingredients in Reumofan Plus and Reumofan Plus Premium may interact with other medications and result in serious adverse events. Health-care professionals are urged to ask their patients about use of ReumoBleed:7.875” fan Plus, Reumofan Plus Premium, and Trim:7.625” other similar products marketed as diLive:7” etary supplements when patients pres-

Rx Only

Brief Summary of Prescribing Information WARNING:

HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING Hemorrhage: Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. Gastrointestinal Perforation: Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. Compromised Wound Healing: Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Bleed:10.75”

Live:10”

Do not combine ZALTRAP with other drugs in the same infusion bag or intravenous line. Administer ZALTRAP using an infusion set made of one of the following materials: • PVC containing DEHP • DEHP free PVC containing trioctyl-trimellitate (TOTM) • polypropylene • polyethylene lined PVC • polyurethane 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hemorrhage Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/ hemorrhage (all grades) were reported in 38% of patients treated with ZALTRAP/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3–4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving ZALTRAP/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving ZALTRAP. Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage [see Dosage and Administration (2.2)]. 5.2 Gastrointestinal Perforation Gastrointestinal (GI) perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Across three Phase 3 placebo-controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with ZALTRAP and 0.3% for patients treated with placebo. Grade 3–4 GI perforation events occurred in 0.8% of patients treated with ZALTRAP and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP therapy in patients who experience GI perforation [see Dosage and Administration (2.2)]. 5.3 Compromised Wound Healing ZALTRAP impairs wound healing in animal models [see Nonclinical Toxicology (13.2) in the full prescribing information]. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI regimen and in none of the patients treated with placebo/ FOLFIRI regimen. Suspend ZALTRAP for at least 4 weeks prior to elective surgery. Do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed. Discontinue ZALTRAP in patients with compromised wound healing [see Dosage and Administration (2.2)]. 5.4 Fistula Formation Fistula formation involving gastrointestinal and non-gastrointestinal sites occurs at a higher incidence in patients treated with ZALTRAP. In patients with mCRC, fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 9 of 611 patients (1.5%) treated with ZALTRAP/FOLFIRI regimen and 3 of 605 patients (0.5%) treated with placebo/FOLFIRI regimen. Grade 3 GI fistula formation occurred in 2 patients treated with ZALTRAP (0.3%) and in 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula [see Dosage and Administration (2.2)]. 5.5 Hypertension ZALTRAP increases the risk of Grade 3–4 hypertension. There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti-hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% of patients treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Among those patients treated with ZALTRAP/FOLFIRI developing Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment. Monitor blood pressure every two weeks or more frequently as clinically indicated during treatment with ZALTRAP. Treat with appropriate anti-hypertensive therapy and continue monitoring blood pressure regularly. Temporarily suspend ZALTRAP in patients with uncontrolled hypertension until controlled, and permanently reduce ZALTRAP dose to 2 mg per kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy [see Dosage and Administration (2.2)]. 5.6 Arterial Thromboembolic Events Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. In patients with mCRC, ATE was reported in 2.6% of patients treated with ZALTRAP/FOLFIRI and 1.7% of patients treated with placebo/ FOLFIRI. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE [see Dosage and Administration (2.2)]. 5.7 Proteinuria Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP. In patients with mCRC,

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Trim:10.5”

Bleed:10.75”

Live:10”

1 INDICATIONS AND USAGE ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen [see Clinical Studies (14) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose and Schedule Administer ZALTRAP 4 mg per kg as an intravenous (IV) infusion over 1 hour every two weeks. Administer ZALTRAP prior to any component of the FOLFIRI regimen on the day of treatment [see Clinical Studies (14) in the full prescribing information]. Continue ZALTRAP until disease progression or unacceptable toxicity. 2.2 Dose Modification / Treatment Delay Recommendations Discontinue ZALTRAP for: • Severe hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised wound healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula formation [see Warnings and Precautions (5.4)] • Hypertensive crisis or hypertensive encephalopathy [see Warnings and Precautions (5.5)] • Arterial thromboembolic events [see Warnings and Precautions (5.6)] • Nephrotic syndrome or thrombotic microangiopathy (TMA) [see Warnings and Precautions (5.7)] • Reversible posterior leukoencephalopathy syndrome (RPLS) [see Warnings and Precautions (5.10)] Temporarily suspend ZALTRAP: • At least 4 weeks prior to elective surgery [see Warnings and Precautions (5.3)] • For recurrent or severe hypertension, until controlled. Upon resumption, permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.5)]. • For proteinuria of 2 grams per 24 hours. Resume when proteinuria is less than 2 grams per 24 hours. For recurrent proteinuria, suspend ZALTRAP until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg [see Warnings and Precautions (5.7)]. For toxicities related to irinotecan, 5-fluorouracil (5-FU), or leucovorin, refer to the current respective prescribing information. 2.3 Preparation for Administration Inspect vials visually prior to use. ZALTRAP is a clear, colorless to pale yellow solution. Do not use vial if the solution is discolored or cloudy or if the solution contains particles. Do not re-enter the vial after the initial puncture. Discard any unused portion left in the vial. Withdraw the prescribed dose of ZALTRAP and dilute in 0.9% sodium chloride solution, USP or 5% dextrose solution for injection, USP to achieve a final concentration of 0.6–8 mg/mL. Use polyvinyl chloride (PVC) infusion bags containing bis (2-ethylhexyl) phthalate (DEHP) or polyolefin infusion bags. Store diluted ZALTRAP at 2–8°C (36–46°F) for up to 4 hours. Discard any unused portion left in the infusion bag. 2.4 Administration Administer the diluted ZALTRAP solution as an intravenous infusion over 1 hour through a 0.2 micron polyethersulfone filter. Do not use filters made of polyvinylidene fluoride (PVDF) or nylon. Do not administer as an intravenous (IV) push or bolus.

ent with unexplained symptoms that suggest NSAID toxicity, psychiatric changes, or the use or abrupt discontinuation of corticosteroids.

Additionally, health-care professionals should evaluate patients who have used Reumofan Plus and/or Reumofan Plus Premium for drug and disease interactions involving diclofenac, methocarbamol, and corticosteroids, and consider whether a corticosteroid taper regimen may be appropriate.

The ASCO Post | SEPTEMBER 15, 2012

PAGE 22

FDA Update

NDA for Chemosaturation System to Treat Melanoma in the Liver

elcath Systems, Inc, announced that it has submitted a New Drug Application (NDA) to the FDA, seeking approval for its chemosaturation system (CHEMOSAT) for use with melphalan hydrochloride in the treatment of patients with unresectable

metastatic melanoma in the liver. The system is designed to administer highdose chemotherapy and other agents to diseased organs or regions of the body, while controlling the systemic exposure of those agents.. In a phase III clinical trial, patients

given chemosaturation therapy experienced a statistically significant extension in median hepatic progression-free survival of 5.4 months lonBleed:7.875” ger than patients treated with best alTrim:7.625” ternative care (P = .0001, HR = 0.39), Live:7” according to a blinded intent-to-treat

proteinuria was reported in 62% patients treated with ZALTRAP/FOLFIRI compared to 41% patients treated with placebo/FOLFIRI. Grade 3–4 proteinuria occurred in 8% of patients treated with ZALTRAP/FOLFIRI to 1% of patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies. Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria during ZALTRAP therapy. Obtain a 24-hour urine collection in patients with a UPCR greater than 1. Suspend ZALTRAP administration for proteinuria 2 grams per 24 hours or more, and resume when proteinuria is less than 2 grams per 24 hours. If recurrent, suspend until proteinuria is less than 2 grams per 24 hours and then permanently reduce the ZALTRAP dose to 2 mg per kg. Discontinue ZALTRAP in patients who develop nephrotic syndrome or TMA [see Dosage and Administration (2.2)]. 5.8 Neutropenia and Neutropenic Complications A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP. In patients with mCRC, Grade 3–4 neutropenia occurred in 37% of patients treated with ZALTRAP/FOLFIRI compared to 30% patients treated with placebo/FOLFIRI [see Adverse Reactions (6.1)]. Grade 3–4 febrile neutropenia occurred in 4% of patients treated with ZALTRAP/FOLFIRI compared to 2% of patients treated with placebo/FOLFIRI. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of patients treated with ZALTRAP/FOLFIRI and 1.2% of patients treated with placebo/FOLFIRI. Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay ZALTRAP/FOLFIRI until neutrophil count is at or above 1.5 × 109/L. 5.9 Diarrhea and Dehydration The incidence of severe diarrhea is increased in patients treated with ZALTRAP/FOLFIRI. In patients with mCRC, Grade 3–4 diarrhea was reported in 19% of patients treated with ZALTRAP/FOLFIRI compared to 8% of patients treated with placebo/FOLFIRI. Grade 3–4 dehydration was reported in 4% of patients treated with ZALTRAP/FOLFIRI compared to 1% of patients treated with placebo/ FOLFIRI [see Adverse Reactions (6.1)]. The incidence of diarrhea is increased in patients who are age 65 years or older as compared to patients younger than 65 years of age [see Geriatric Use (8.5)]. Monitor elderly patients closely for diarrhea. 5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Conﬁrm the diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death [see Dosage and Administration (2.2)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1)] • Gastrointestinal Perforation [see Boxed Warning, Warnings and Precautions (5.2)] • Compromised Wound Healing [see Boxed Warning, Warnings and Precautions (5.3)] • Fistula Formation [see Warnings and Precautions (5.4)] • Hypertension [see Warnings and Precautions (5.5)] • Arterial Thromboembolic Events [see Warnings and Precautions (5.6)] • Proteinuria [see Warnings and Precautions (5.7)] • Neutropenia and Neutropenic Complications [see Warnings and Precautions (5.8)] • Diarrhea and Dehydration [see Warnings and Precautions (5.9)] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.10)] 6.1 Clinical Trial Experience Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reﬂect the rates actually observed in clinical practice. The safety of ZALTRAP in combination with FOLFIRI was evaluated in 1216 previously treated patients with metastatic colorectal cancer (Study 1) who were treated with ZALTRAP 4 mg per kg intravenous (N=611) or placebo (N=605) every two weeks (one cycle) in a randomized (1:1), double-blind, placebo-controlled Phase 3 study. Patients received a median of 9 cycles of ZALTRAP/FOLFIRI or 8 cycles of placebo/FOLFIRI. The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm , in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache (see Table 1). The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between-arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia (see Table 1). The most frequent adverse reactions leading to permanent discontinuation in ≥1% of patients treated with ZALTRAP/FOLFIRI regimen were asthenia/fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.

analysis by an independent review committee. Previously reported investigator intent-to-treat analysis of these data showed an extension in hepatic progression-free survival of 6.4 months vs best alternative care (P < .0001, HR = 0.28).

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ZALTRAP® (ziv-aﬂibercept) Injection for Intravenous Infusion The ZALTRAP dose was reduced and/or omitted in 17% of patients compared to placebo-dose modiﬁcation in 5% of patients. Cycle delays >7 days occurred in 60% of patients treated with ZALTRAP/FOLFIRI compared with 43% of patients treated with placebo/FOLFIRI. The most common adverse reactions and laboratory abnormalities during study treatment in Study 1 where the incidence was ≥5% (all grades) in patients receiving ZALTRAP in combination with FOLFIRI and which occurred at ≥2% higher frequency in patients treated with ZALTRAP/FOLFIRI compared to placebo/FOLFIRI are shown in Table 1. Table 1 – Selected Adverse Reactions and Laboratory Findings in Study 1: Placebo/FOLFIRI ZALTRAP/FOLFIRI (N=605) (N=611) Primary System Organ Class All grades Grades All grades Grades Preferred Term (%) 3–4 3–4 Infections and infestations Urinary Tract Infection 6% 0.8% 9% 0.8% Blood and lymphatic system disorders Leukopenia 72% 12% 78% 16% Neutropenia 57% 30% 67% 37% Thrombocytopenia 35% 2% 48% 3% Metabolism and nutrition disorders Decreased Appetite 24% 2% 32% 3% Dehydration 3% 1% 9% 4% Nervous system disorders Headache 9% 0.3% 22% 2% Vascular disorders Hypertension 11% 1.5% 41% 19% Respiratory, thoracic and mediastinal disorders Epistaxis 7% 0 28% 0.2% Dysphonia 3% 0 25% 0.5% Dyspnea 9% 0.8% 12% 0.8% Oropharyngeal Pain 3% 0 8% 0.2% Rhinorrhea 2% 0 6% 0 Gastrointestinal disorders Diarrhea 57% 8% 69% 19% Stomatitis 33% 5% 50% 13% Abdominal Pain 24% 2% 27% 4% Abdominal Pain Upper 8% 1% 11% 1% Hemorrhoids 2% 0 6% 0 Rectal Hemorrhage 2% 0.5% 5% 0.7% Proctalgia 2% 0.3% 5% 0.3% Skin and subcutaneous tissue disorders Palmar-Plantar 4% 0.5% 11% 3% Erythrodysesthesia Syndrome Skin Hyperpigmentation 3% 0 8% 0 Renal and urinary disorders Proteinuria* 41% 1% 62% 8% Serum creatinine increased 19% 0.5% 23% 0 General disorders and administration site conditions Fatigue 39% 8% 48% 13% Asthenia 13% 3% 18% 5% Investigations AST increased 54% 2% 62% 3% ALT increased 39% 2% 50% 3% Weight decreased 14% 0.8% 32% 3% Note: Adverse Reactions are reported using MedDRA version MEDDRA13.1 and graded using NCI CTC version 3.0 *Compilation of clinical and laboratory data Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection. In patients with mCRC, severe hypersensitivity reactions have been reported with ZALTRAP/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%). In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 23

News

Anticancer Effect of Diabetes Drug Metformin By Matthew Stenger

etrospective analyses have indicated that the antidiabetic agent metformin may be associated with a quite substantial reduction in risk of cancers. There is evidence that the anticancer effects of metformin are related to inhibition of the

growth of certain cancers via activation of AMP kinase with secondary inhibition of protein synthesis or via an indirect mechaBleed:7.875” nism involving reduction in gluconeogenTrim:7.625” esis that leads to reduced proliferation of Live:7” insulin-responsive cancers.

ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion 8.8 Females and Males of Reproductive Potential Male and female reproductive function and fertility may be compromised during treatment with ZALTRAP, as suggested by findings in monkeys [see Nonclinical Toxicology (13.1) in the full prescribing information]. These animal findings were reversible within 18 weeks after cessation of treatment. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment. 10 OVERDOSAGE There have been no cases of overdose reported with ZALTRAP. There is no information on the safety of ZALTRAP given at doses exceeding 7 mg per kg every 2 weeks or 9 mg per kg every 3 weeks. Manufactured by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2012 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC ZIV-BPLR-SA-AUG12

Revised: August 2012

potential mechanism for this drug’s cancer-preventive activity.1 In studies involving mitochondrial toxins, these investigators first showed that metformin had no effect in attenuating exogenously (H2O2) induced reactive oxygen species and DNA damage, but reduced endogenous (paraquat-induced) reactive oxygen species and subsequent DNA damage and mutation.

Inhibition of Ras-related Damage

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To assess whether metformin could prevent these processes when induced by naturally occurring oncogenes, the investigators then introduced Ras into primary human fibroblasts, where it is known to induce production of reactive oxygen species, DNA damage, and cell senescence. See Page 81 Metformin attenuated the substantial increase in reactive oxygen species in the Ras-expressing cells, significantly reduced the number of DNA damage foci, and reduced cell proliferation, without having an effect on Ras signaling. As stated by the investigators, “While experimental investigation of the antineoplastic activity of metformin has documented growth inhibitory activity for established cancers, review of the epidemiologic data suggests that the dominant effect of metformin … may involve reduction in risk rather than improvement in prognosis, as the magnitude of the reported decline in mortality is similar to the magnitude of the decline in incidence.” They added “Our finding[s] that sequelae of the … mitochondrial actions of metformin include reduced endogenous reactive oxygen species production, reduced oxidative stress, reduced DNA damage, and reduced mutagenesis in normal somatic cells, or their variants expressing activated oncogenes, provide a novel mechanism to explain reduced cancer incidence associated with metformin therapy, and raise the possibility of novel applications in prevention of cancer and other diseases associated with cellular damage caused by mitochondrial reactive oxygen species production.”

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treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with ZALTRAP/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with ZALTRAP/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo. The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data. 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 ZALTRAP with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No dedicated drug-drug interaction studies have been conducted for ZALTRAP. No clinically important pharmacokinetic drug-drug interactions were found between ziv-aflibercept and irinotecan/SN-38 or 5-FU, based on cross-study comparisons and population pharmacokinetic analyses. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with ZALTRAP in pregnant women. ZALTRAP was embryotoxic and teratogenic in rabbits at exposure levels lower than human exposures at the recommended dose, with increased incidences of external, visceral, and skeletal fetal malformations. ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ziv-aflibercept produced embryo-fetal toxicity when administered every 3 days during organogenesis in pregnant rabbits at all intravenous doses tested, ≥ 3 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation losses and external (including anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (in the heart, great vessels, and arteries), and skeletal fetal malformations (including fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). Administration of the 3 mg per kg dose to rabbits resulted in systemic exposure (AUC) that was approximately 30% of the AUC in patients at the recommended dose. The incidence and severity of fetal anomalies increased with increasing dose. 8.3 Nursing Mothers It is not known whether ZALTRAP 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 ZALTRAP, 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 in pediatric patients have not been established. 8.5 Geriatric Use Of the 611 patients with mCRC, patients treated with ZALTRAP/FOLFIRI, 205 (34%) were 65 years or older, and 33 (5%) were 75 years or older. Elderly patients (≥65 years of age) experienced higher incidences (≥5%) of diarrhea, dizziness, asthenia, weight decrease, and dehydration when compared to younger patients. Monitor elderly patients more closely for diarrhea and dehydration [see Warnings and Precautions (5.9)]. The effect of ZALTRAP on overall survival was similar in patients <65 years old and ≥65 years old who received ZALTRAP/FOLFIRI. No dose adjustment of ZALTRAP is recommended for patients greater than or equal to 65 years of age. 8.6 Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild and moderate hepatic impairment were similar to those in patients with normal hepatic function [see Clinical Pharmacology (12.3) in the full prescribing information]. There are no data available for patients with severe hepatic impairment. 8.7 Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ziv-aflibercept. Based on a population PK analysis with data from 1507 patients, ziv-aflibercept exposure in patients with mild, moderate, and severe renal impairment were similar to those in patients with normal renal function [see Clinical Pharmacology (12.3) in the full prescribing information].

In recent in vitro studies, Algire and colleagues from McGill University in Quebec showed that metformin reduces endogenous reactive oxygen species synthesis and resultant DNA damage and mutations, thus identifying another

■

Reference 1. Algire C, Moiseeva O, Deschenes-Simard X, et al: Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 5:536-543, 2012.

The ASCO Post | SEPTEMBER 15, 2012

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Issues in Oncology Supportive Care

Sexual Dysfunction in Female Cancer Survivors Is Prevalent By Jo Cavallo

lthough medical experts put the proportion of female survivors facing some form of sexual dysfunction following a cancer diagnosis and treatment at nearly 100%, very few women raise sexual health concerns with their oncologist. In a study of 261 patients with gynecologic or breast cancer published last year in the journal Cancer,1 about 42% of respondents said they were interested in receiving medical care for sexual problems they were experiencing following their treatment, but only 7% asked for help. The study results showcase the extent of the unmet need for attention to the sexual health concerns of cancer survivors.

Barriers to Discussion Patients are not the only ones who are reluctant to broach the subject of sexual health. According to the study findings, 62% of vaginal and cervical cancer survivors reported that no doctor ever asked them about the sexual effects of their cancer or treatment. There are many reasons why both patients and doctors are hesitant to discuss sexual health. “Patients don’t want to embarrass their doctor or make anyone uncomfortable. They also understand that time is limited and that the primary job of their physician is to focus on saving lives. Although patients desperately want help, it is not clear

Sharon L. Bober, PhD

where they can turn,” said Sharon L. Bober, PhD, Assistant Professor, Department of Psychiatry at Harvard Medical School, and Director of the Sexual Health Program, Department of Psychosocial Oncology and Palliative Care at Dana-Farber

Cancer Institute. “Despite the fact that we live in such a highly sexualized culture, genuine conversation about sexual function is still quite taboo, even—or especially—in the physician consulting room,” Dr. Bober continued. “We also know from physician surveys we’ve conducted that most doctors feel they do not have the adequate preparation to address this issue with their patients.” Physicians may also be too embarrassed to initiate the conversation. “Oncologists may not be comfortable talking about sex. We are taught to treat and cure cancer, and the feeling may be that some of these continued on page 29

Differences in Male and Female Sexual Dysfunction

ike female cancer survivors, men experience high rates of sexual dysfunction following a cancer diagnosis and treatment, especially for prostate cancer, with as many as 90% of men reporting erectile dysfunction after radical prostatectomy and nearly as many suffering with the problem following external-beam radiation therapy, studies show.1-4 In addition to erectile dysfunction, men may also experience low libido and problems with arousal or the ability to reach orgasm. These sexual side effects are also common after treatment for bladder, colon, and rectal cancers and are also seen in men who have undergone a stem cell or bone marrow transplant.

Differing Rates of Therapeutic Improvements Although the rates of sexual dysfunction may be similar for men and women, advances to combat the problem in men are happening more rapidly than they are for women. Newer measures include a second generation of erectile dysfunction medications since the availability of sildenafil citrate (Viagra), other PDE5 (phosphodiesterase type 5) inhibitors (tadalafil, vardenafil) used before surgery to keep penile tissue healthy and preserve smooth muscles, and penile rehabilitation strategies (such as penile self-injection therapy) used after prostate cancer therapy.

“Men and women may be similar in terms of their biological and psychological determinants of sexual function. Yet how they express their sexuality may be different,” said Michael Krychman, MD, Executive Director of the Southern California Center for Sexual Health and Survivorship Medicine in Newport Beach. “We have a better understanding of

Michael Krychman, MD

the veins, arteries, and nerves that provide sexual function in men than we do in women. We understand the pathophysiology of erection and how we can impact it with medication.”

Long-term Effects of Prostate Cancer Treatment A recent study in the Journal of Clinical Oncology5 found that men treated for prostate cancer may suffer from sexual dysfunction and have more bladder control problems for up to 10 years after treatment. The

use of prediction models for earlystage prostate cancer—which include such variables as the patients’ sexual function and serum prostatespecific antigen levels prior to prostate cancer treatment, age, and treatment plan—may help physicians determine how quickly patients will recover from erectile dysfunction following prostatectomy, external radiotherapy, or brachytherapy. Such models also provide patients with information to help them decide which treatment options have the best chance of preserving potency and sexual function. In a study of prediction models, published last year in The Journal of the American Medical Association,6 researchers were able to accurately estimate erectile function probabilities 2 years after prostate cancer treatment “from as low as 10% to as high as 70% or greater, depending on the individual’s pretreatment patient characteristics and treatment details.” How sexually active men were before their cancer treatment may also impact their sexual function afterward. “If a patient is in a bad marriage [or relationship] and he was not connecting sexually before his cancer diagnosis, having cancer is not going to improve his overall intimate connection with his partner and his sexual function. But for patients who were doing well sexually before their

diagnosis, it is likely they will do well after their recovery, although they may have some changes in overall penile and sexual functioning,” said Dr. Krychman. Disclosure: Dr. Krychman reported no potential conflicts of interest.

References 1. Walsh PC, Epstein JI, Lowe FC: Potency following radical prostatectomy with wide unilateral excision of the neurovascular bundle. J Urol 138:823-827, 1987. 2. Talcott JA, Rieker P, Clark JA, et al: Patient-reported symptoms after primary therapy for early prostate cancer: Results of a prospective cohort study. J Clin Oncol 16:275-283, 1998. 3. Smith DS, Carvalhal GF, Schneider K, et al: Quality-of-life outcomes for men with prostate carcinoma detected by screening. Cancer 88:1454-1463, 2000. 4. Stanford JL, Feng Z, Hamilton AS, et al.: Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: The Prostate Cancer Outcomes Study. JAMA 283:354-360, 2000. 5. Taylor KL, Luta G, Miller AB, et al: Long-term disease-specific functioning among prostate cancer survivors and noncancer controls in the prostate, lung, colorectal and ovarian cancer screening trial. J Clin Oncol 30:2768-2775, 2012. 6. Alemozaffar M, Regan MM, Cooperberg MR, et al: Prediction of erectile function following treatment for prostate cancer. JAMA 306:1205-1214, 2011.

XGEVA速 (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA速 is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. Please see the following pages for Important Safety Information.

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

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

IMPORTANT SAFETY INFORMATION Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

www.XGEVA.com

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

PERCENTAGE OF PATIENTS WITHOUT SRE

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

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

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

0 0

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

STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

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

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

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

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

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identiﬁed.

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

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

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Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in SpeciďŹ c Populations). There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading. ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

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

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ÂŠ2012 Amgen Inc. All rights reserved. Printed in USA.

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T:13â&#x20AC;?

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor. NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk. 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information). Use in SpeciďŹ c Populations). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 29

Issues in Oncology

Sexual Dysfunction continued from page 24

problems are the inevitable side effects of treatment and part of the price patients pay for surviving their disease,” said Lidia Schapira, MD, Staff Oncologist, Gillette Center for

for causing long-term sexual problems, all cancers have the potential to shutdown sexual health. “We assume that [only] cancers involving breasts, ovaries, and the prostate have a major negative impact [on sexual function], but a wide range of treatments for other cancers, such as bone marrow transplant for blood cancers, also often result in profound changes,” said

solved quickly, crippling the longterm quality of life for many cancer survivors, said Dr. Bober.

Sexual Health Is Part of Quality of Life With nearly 14 million cancer survivors today, according to the latest figures from the American Cancer Society, and projections of more than 18 million by 2022, the need to

Resources on Sexual Health following Cancer and Its Treatment ■■ American Cancer Society: Lidia Schapira, MD

Breast Oncology at Massachusetts General Hospital; Assistant Professor of Medicine at Harvard Medical School; and Associate Editor of ASCO’s patient information website, Cancer.net. Also, physicians may feel that there are no sexual medical experts—or they may not know any— to refer patients to for treatment, said Dr. Schapira.

Components of Sexual Dysfunction Surgery, chemotherapy, hormonal therapy, and radiation therapy all contribute to sexual dysfunction in women. Problems may include both physical factors such as fatigue, the onset of chemically induced menopause—which can be more severe and less predictable than naturally occurring menopause—vaginal dryness, and dyspareunia, and psychological factors, including fear, changes in body image, depression, anxiety, reduced libido, and the inability to achieve arousal and orgasm. And while breast and gynecologic cancers tend to get the most attention

NOW ! LE AVAILAB

Sexuality for the Woman with Cancer—cancer.org/Treatment/ TreatmentsandSideEffects/PhysicalSideEffects/SexualSideEffectsinWomen/ SexualityfortheWoman/sexuality-for-women-with-cancer-cancer-sexsexuality; Sexuality for the Man with Cancer—cancer.org/Treatment/ TreatmentsandSideEffects/PhysicalSideEffects/SexualSideEffectsinMen/ SexualityfortheMan/sexuality-for-men-with-cancer-intro

■■ American Society of Clinical Oncology: Sexual Problems—cancer.net/allabout-cancer/treating-cancer/managing-side-effects/sexual-problems

■■ The Institute for Sexual Medicine: Sexual health issues and treatments for women and men—sexualmed.org

■■ Memorial Sloan-Kettering Cancer Center: Sexual health FAQs—mskcc. org/cancer-care/survivorship/sexual-health-faqs

■■ National Cancer Institute: Sexuality and Reproductive Issues—cancer.gov/ cancertopics/pdq/supportivecare/sexuality/Patient

Dr. Bober. “Vaginal graft-vs-host disease, which can cause vaginal discomfort and painful intercourse, is very common in these patients, and often doctors don’t relate the sexual side effects to the transplant and graft-vs-host disease.” Radiation therapy for colorectal and bladder cancers can also affect sexual health because it can cause fibrosis of the vaginal tissue, making sexual activity painful. Not only are problems with sexual functioning ubiquitous following cancer therapy, but they are also less likely to get re-

include sexual health as part of the overall survivorship quality-of-life clinical assessment is crucial, said Dr. Schapira. “Questions about sexual function should become part of the routine questions we ask patients about their health, in the same way we ask about problems with shortness of breath, tolerance to medication, or ability to eat,” she commented. “Just asking if a patient has any concerns about her sexual activity or whether she is sexually active can be a conversation starter. Even if the oncologist can’t

fix the problem, showing a willingness to listen and making a referral to a sexual health specialist [or a gynecologist who specializes in menopause issues] would help us make progress.” Having patient education material on the effects of cancer on female sexual health on hand to give patients or to have on display in See Page 81 office waiting rooms can help jump-start the conversation. They can also provide survivors with information on potential solutions, which can range from simple remedies such as vaginal moisturizers and lubricants to combat vaginal dryness to learning pelvic muscle awareness techniques to reduce vaginal pain during sexual activity (see sidebar on resources). “It is not reasonable to expect that oncologists are going to become sexual medicine experts,” said Dr. Bober. “However, it’s not only reasonable, but actually imperative for doctors to identify useful resources available either in their hospital or in the community. Many of the sexual problems that women struggle with, whether it is dyspareunia, menopausal symptoms, or low libido, can be made much better if not managed completely with some intervention. Now that so many patients live long after diagnosis and treatment, it is crucial that we start attending to this problem.”

■

Disclosure: Drs. Bober and Schapira reported no potential conflicts of interest.

Reference 1. Hill EK, Sandbo S, Abramsohn E, et al: Assessing gynecologic and breast cancer survivors’ sexual health care needs. Cancer 117:2643-2651, 2011.

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The ASCO Post | SEPTEMBER 15, 2012

PAGE 30

Journal Spotlight Risk Factors

Physical Activity Benefits Breast Cancer Survivors, but Role in Reducing Breast Cancer Risk Is Less Clear By Charlotte Bath

reast cancer survivors who engage in moderate to high levels of physical activity have reduced mortality and improved quality of life, according to recent studies. In addition, exercise may play a role in lowering the risk of breast cancer. “Physical activity can hasten recovery from the immediate effects of treatment, prevent long-term effects, and may reduce the risk of recurrence and increase survival,” according to the latest report on cancer treatment and survivorship statistics, published in CA: A Cancer Journal for Clinicians.1 “In observational studies among breast cancer patients, moderate physical activity has been associated with a reduced risk of death from all causes (24%-67%) and breast cancer (50%-53%),” the report noted. The authors stated that intervention studies “have shown that exercise can improve fatigue, anxiety, depression, self-esteem, happiness, and quality of life in cancer patients.” They caution that exercise for survivors of cancer “should be individualized and tailored according to the disease site and stage and the survivor’s capabilities.”

associated with a reduction in breast cancer-specific mortality as well as allcause mortality; this risk reduction was statistically significant in nearly half of these studies, and there is evidence for a dose-response effect of decreasing mortality risk with increasing activity in roughly half of the studies.” The researchers noted that the evidence relates to physical activity before or after breast cancer diagnosis. The investigators added that the “next strongest evidence for an association between physical activity and disease outcomes for survivors of other cancer sites has been found for cancer-specific and all-cause mortality in colorectal cancer survivors.” The

‘Consistent Evidence’

Toll of Inactivity

A systematic review of 27 observational studies reporting associations between physical activity and cancerspecific outcomes or all-cause mortality found “consistent evidence” that physical activity is associated with reduced mortality from breast cancer, with weaker associations for reduced colon cancer–specific and all-cause mortality. “The strongest See Page 81 evidence for an association between physical activity and cancer outcomes comes from studies of breast cancer survivors,” reported researchers from the National Cancer Institute, Fred Hutchinson Cancer Research Center in Seattle, and the University of Alberta, Edmonton, and Alberta Health Services–Cancer Care, Calgary, in Canada. “Nearly all of the breast cancer studies report that physical activity is

The Lancet Physical Activity Series Working Group estimated that physical inactivity worldwide causes 10% of the burden of disease from breast cancer (range, 5.6%–14.1%) and colorectal cancer (range, 5.7%–13.8%).3 “For our analysis of burden of disease, we calculated population attributable fractions … associated with physical inactivity using conservative assumptions for each of the major noncommunicable diseases, by country, to estimate how much disease could be averted if physical inactivity were eliminated. We used life-table analysis to estimate gains in life expectancy of the population,” the working group explained. The estimated population attributable fractions, calculated with adjusted relative risks associated with physical activity for the United States are 12.4% (range, 5.8%–19.2%) for breast cancer and 12.0% (range, 6.7%– 17.4%) for colon cancer. “Worldwide, we estimated that

physical inactivity causes 6% to 10% of the major non-communicable diseases of coronary heart disease, type 2 diabetes, and breast and colon cancers. Furthermore, this unhealthy behavior causes 9% of premature mortality, or more than 5.3 million of the 57 million deaths in 2008,” the authors wrote. “With elimination of physical inactivity, life expectancy of the world’s population might be expected to increase by 0.68 years,” they continued. “These findings make inactivity similar to the established risk factors of smoking and obesity. The added years of life need to be interpreted correctly: they seem low because they represent gains in the whole population (includ-

With elimination of physical inactivity, life expectancy of the world’s population might be expected to increase by 0.68 years. These findings make inactivity similar to the established risk factors of smoking and obesity. study was published in the Journal of the National Cancer Institute.2

ing inactive and active people), rather than in inactive people who become active. Because all the gain accrues to people who move from inactive to active, the increase in life expectancy in the inactive group alone is greater. For perspective, other research done in the USA estimated that inactive people would gain 1.3 to 3.7 years from age 50 years by becoming active.”

Augmenting Weight Loss The Nutrition and Exercise for Women randomized controlled trial tested the independent and combined effects of three different 12-monthlong reduced-calorie weight loss and moderate to vigorous aerobic interventions on serum concentrations of estrogens, free testosterone, and other potential breast cancer biomarkers in overweight and obese postmenopausal women. Results from the 399 participants who completed physical examinations and provided blood samples at 12 months found that weight loss ≥ 5% was associated with significantly greater reductions in estradiol, free estradiol, and free testosterone and significantly

increased sex hormone–binding globulin, the researchers reported in the Journal of Clinical Oncology.4 Exercise interventions alone, however, “had little effect on sex hormones or the other potential breast cancer biomarkers.” The authors asserted that their findings taken together with those of other studies of dietary and exercise interventions among postmenopausal women “suggest that weight loss is the key factor linking alterations in diet or exercise to sex hormone changes.” They also pointed out that the “lack of effect of exercise alone does not agree with epidemiologic studies in which physical activity is associated with decreased risk of breast cancer. Therefore, exercise could play a role in reducing risk of postmenopausal breast cancer through different biologic mechanisms than were examined in this study. Exercise may also play a role in reducing breast cancer risk by augmenting dietary weight loss and maintenance, which will be critical for long-term risk reduction.”

■

Disclosure: Senior author of the study published in the Journal of Clinical Oncology, Dr. Anne McTiernan, has served as consultant or advisor for Merck, Metagenics, Novartis, Proctor & Gamble, and ZymoGenetics, owns stock in Merck, has received honoraria from Novartis and Wyeth, and has received research funding from Wyeth. All other authors of the studies discussed in this article reported no potential conflicts of interest.

References 1. Siegel R, DeSantis C, Virgo K, et al: Cancer treatment and survivorship statistics. CA Cancer J Clin 62:220-241, 2012. 2. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al: Physical activity, biomarkers, and disease outcomes in cancer survivors: A systematic review. J Nat Cancer Inst 104:815-840, 2012. 3. Lee I-M, Shiroma EJ, Lobelo F, et al: Effect of physical inactivity on major non-communicable diseases worldwide: An analysis of burden of disease and life expectancy. Lancet 380:219-229, 2012. 4. Campbell KL, Foster-Schubert KE, Alfano CM, et al: Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: Randomized controlled trial. J Clin Oncol 30:2314-2326, 2012.

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 31

News

Biomedical Research Faces Imminent $2.4 Billion Budget Cut Unless Congress Acts

he National Institutes of Health (NIH) faces a significant budget reduction in January 2013 due to automatic across-theboard cuts, known as sequestration, required under the federal Budget Control Act of 2011. The estimated $2.4 billion NIH cut could result in 700 to 2,300 fewer research grants funded and fewer jobs in every state across the country. The National Cancer Institute, in particular, would face a budget cut of almost $400 million

ASCO Calls on Congress to Prevent Cuts “Sustaining the nation’s investment in cancer research is critical to our future. We can’t afford to lose ground to a disease that touches nearly every American,” said ASCO PresiSee Page 81 dent Sandra M. Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center. “Congress must understand that cuts on the scale being discussed could significantly slow the pace of scientific discovery, hurt local economies and, most important, delay new cancer therapies for thousands of current and future patients.” Cancer survival rates have risen steadily in recent decades, and qual-

Sandra M. Swain, MD

ity of life for patients has improved dramatically. Much of this progress, detailed on ASCO’s interactive CancerProgress.Net website, is due to critical NIH-funded research. Federal funding also plays a vital economic role by supporting research at cancer centers and universities throughout the United States. According to a recent report by U.S.

Senator Tom Harkin (D-Iowa), Chairman of the Appropriations Subcommittee on Labor, Health and Human Services and Education, and Related Agencies, every

$1 in NIH funding generates $2.21 in local economic growth, and in Fiscal Year 2011, NIH-funded research supported 432,000 jobs in the United States.1

■

Reference 1. Harkin T: Under threat: Sequestration’s impact on nondefense jobs and services. July 25, 2012. Available at http://1.usa. gov/OqaPDx. Accessed August 28, 2012.

The ASCO Post | SEPTEMBER 15, 2012

PAGE 32

News

EMILIA Study: T-DM1 Significantly Improves Overall Survival in HER2-positive Metastatic Breast Cancer

pdated results from the phase III EMILIA study showed that trastuzumab emtansine (T-DM1) significantly improved overall survival of people with HER2-positive metastatic breast cancer

compared to the combination of lapatinib and capecitabine (Xeloda). The new data were reported in a press release issued by Genentech on August 26, 2012.

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

Primary Endpoints Met The EMILIA study in patients with HER2-positive metastatic breast cancer who had previously received trastuzumab (Herceptin) and

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.

taxane chemotherapy has now met both coprimary efficacy endpoints of significant improvements in overall survival and progression-free survival. These data will be presented at an upcoming medical meeting, according to the press release. Based on these updated overall survival results, people in the lapatinib and capecitabine arm of EMILIA will be offered the option to receive trastuzumab emtansine. Trastuzumab emtansine is an antibody-drug conjugate being studied in HER2-positive cancers. It is comprised of the antibody trastuzumab and the chemotherapy DM1 attached together using a stable linker. Trastuzumab emtansine is designed to target and inhibit HER2 signaling and deliver the chemotherapy DM1 directly inside HER2-positive cancer cells.

Previously Presented EMILIA Results A previous interim analysis of overall survival demonstrated a trend towards improved overall survival in people receiving trastuzumab emtansine compared to those who received lapatinib plus capecitabine. However, the data were not considered statistically significant at that time.

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PAGE 33

Journal Spotlight End-of-life Care

Dying Patients with Cancer Who Avoid Aggressive Care but Stay Connected with an Oncologist Have Better Quality of Life By Jo Cavallo

ying patients with cancer who avoided hospitalizations and life-prolonging measures, who worried less, prayed or meditated, were visited by a pastor, and maintained a therapeutic alliance with their oncologist had the highest quality of life at the end of life, according to a study recently published in Archives of Internal Medicine.1 Called Coping With Cancer, the multisite prospective study followed nearly 400 patients with advanced cancer from the time of enrollment until their death about 4 months later to identify factors that promoted a higher quality of life in their remaining weeks of life.

Study Details Patients were asked a series of questions about their sociodemographic characteristics such as age, sex, race, ethnicity, and religious faith; their physical and psychological status; treatment preferences; and support structures. After the patient’s death, caregivers were interviewed about the types of care received in the last week of life, the location of the patient’s death, and any physical and psychological distress the patient suffered during the last week of life. Nine factors were identified as explaining the most variance in patients’ quality of life at the end of life. The main factors that contributed negatively to the patients’ final week of life included admittance into the intensive care unit, placement of a feeding tube, and the administration of chemotherapy. The mean age of the study participants was 58.7 years; most were white, belonged to a Christian religion, and had health insurance. Younger patients had a worse quality of life at the end than older patients in the study. Previous Coping With Cancer studies—as well as other investigations— have examined patients’ quality of life at the end of life. This new research, however, is the first to examine predictors of quality of life in the patient’s last week of life. MoreSee Page 81 over, it is thought to be the first to simultaneously examine the vast array of experiences dying patients with cancer face, from their medical care to the so-

Holly Prigerson, PhD

cial and spiritual support they receive, to determine those predictive factors. “We really know very little about what the most important factors are that influence a patient’s quality of life in their final days. And this study was an attempt to understand the factors that most contribute to it,” said Holly Prigerson, PhD, Associate Professor, Department of Psychiatry, Harvard Medical School; Director of Psychosocial Epidemiology and Outcomes Research at Dana-Farber Cancer Institute; and principal investigator of the NCI-funded Coping With Cancer study. “Surprisingly, after you factor in all of the aggressive care that is negatively associated with quality of life, the positive factors included psychospiritual aspects—being visited by a pastor in the hospital or clinic—and maintaining human connections, particularly with oncologists.” Another revealing finding, said Dr. Prigerson, was the impact that worry and anxiety had on the quality of life of dying patients, which also influenced how well the caregivers coped. “How worried the patients were when they entered the study predicted how worried they felt much later on. We also found that the caregivers who met the criteria for generalized anxiety disorder were associated with patients who had a worse quality of life at the end,” said Dr. Prigerson.

Maintaining the Oncologist– Patient Connection The study findings, according to Dr. Prigerson, may help physicians, patients, and family members focus on what matters most to ensure a high quality of life at the end of life. “The results suggest the benefits that patients reap when oncologists attend to patient worries and fears. The clinical implications of the study highlight

the need to incorporate psychosocial support into the care of patients with advanced cancer.” Having oncologists maintain a connection with their patients after they leave active therapy and are transferred into hospice care can also help dying patients have a more peaceful end, according to the study results. “Therapeutic alliance matters tremendously to the quality of life of dying patients. Oncologists often tell me that there is little they can do for patients who are that far along in their illness, but these results suggest that that’s not the case, and that patients want the sense that they still matter to their oncologist and that they will work together to the very end. It’s somewhat surprisingly one of the most important influences on outcomes of care at the end of life,” said Dr. Prigerson. “In another report that we are finalizing, one of the most important predictors of whether adolescent and young adult patients with advanced cancer want to kill themselves or not is their therapeutic alliance with their

George Sledge, MD

Coping With Cancer study. Those results highlighted that patients who discussed with their oncologists the care that they would want to receive if they were dying did not have significantly higher rates of depression or anxiety than those who avoided those discussions. Moreover, patients who discussed end-of-life matters with their physicians were more likely to engage in advance care planning, die receiving less intensive care, and were more likely to enroll in hospice. According to Dr. Prigerson, the study findings from the present report extend these results to suggest that when an oncologist invites and answers the dying pa-

At the simplest level, a patient should know if he has an incurable disease, and the conversation should be done in a kind but honest manner. —George Sledge, MD

oncologist, rather than their relationship with their psychiatrist or family member,” she added. “I think it’s very easy for patients to feel abandoned if their doctor, who has been taking care of them for 2 or 3 years, no longer talks to them once they’ve been referred to palliative or hospice care,” said George Sledge, MD, Ballvé-Lantero Professor of Oncology at Indiana University at Indianapolis and Past President of ASCO. “It is a difficult issue for busy physicians, of course, who have to go on to take care of the next 25 patients they have waiting in their office that day.”

Initiating End-oflife Discussions The importance of effective communication between the oncologist and the patient with advanced cancer was evaluated in prior reports of the

tient’s questions and concerns, this has the capacity to improve the patient’s quality of life. To help oncologists’ initiate candid discussions with these patients, last year ASCO issued a set of recommendations to reduce barriers to such conversations. Included among the recommendations are making quality of life an explicit priority throughout the course of advanced cancer care; helping patients fully understand their prognosis; discussing the potential risks and benefits of available cancer treatments; and when active treatment is no longer likely to extend survival, raising palliative care as a concurrent or alternative therapy. According to ASCO, conversations along these lines currently happen with fewer than 40% of patients with advanced cancer. “At the simplest level, a patient continued on page 34

The ASCO Post | SEPTEMBER 15, 2012

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Journal Spotlight

Quality of Life continued from page 33

should know if he has an incurable disease, and the conversation should be done in a kind but honest manner,” said Dr. Sledge. “But it’s a very uncomfortable conversation to have with your patients. There are some physicians who avoid having these discussions, and there are some patients who don’t want to have that discussion as well.” To help patients with advanced cancer broach the subject of their end-oflife care with their physicians, ASCO also released a guide to Advanced Cancer Care Planning (www.cancer.net), which includes information on treatment options; palliative and hospice care; steps to take to finalize legal, financial, and business affairs; and how

to find religious and spiritual support.

Integrating Palliative Care into Standard Oncology Care A phase III study of patients with metastatic non–small cell lung cancer (NSCLC) showed strong evidence of a survival benefit when palliative care is offered along with standard therapy at initial diagnosis.2 Based on these findings, ASCO published a provisional clinical opinion (PCO) earlier this year in the Journal of Clinical Oncology to encourage integration of palliative care services into standard oncology practice at the time a person is diagnosed with any type of metastatic cancer.3 According to the PCO, the goal of palliative care is to provide “patients with relief from the symptoms, pain,

and stress of a serious illness—whatever the diagnosis … and improve quality of life for both the patient and the family.” “I don’t think there is anything special about NSCLC in terms of the survival findings in the study,” said Dr. Sledge. “If there is a survival benefit in NSCLC, it is likely to be true in other cancers as well. It’s ethically appropriate for all patients to have their symptoms palliated and, therefore, it is an important part of the oncologist’s training. ASCO has recognized that for a long time.” Because end-of-life care discussions are so difficult for physicians, said Dr. Sledge, ASCO’s PCO and its recommendations for improving communication with patients gives oncologists

tools to individualize care and improve patients’ quality of life throughout the course of their illness.

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

References 1. Zhang B, Nilsson ME, Prigerson HG: Factors important to patients’ quality of life at the end of life. Arch Intern Med. July 9, 2012 (early release online). 2. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010. 3. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol. February 6, 2012 (early release online).

Study Finds HPV Testing Can Predict Risk of Cervical Cancer for Up to 18 Years

ew results from a major prospective study indicate that HPV testing can predict which women will develop cervical “precancers” for 10 to 18 years after the test is conducted. The study found that, while both a positive HPV test and an abnormal Pap test predicted which women would develop precancers within 2 years of testing, the positive HPV test continued to predict which women were at risk for the entire 18year follow-up of the study. An initial negative HPV test, on the other hand, provided greater reassurance against cervical precancer and cancer over 18 years than a one-time normal Pap test. The results were published in the July 30 issue of the Journal of Clinical Oncology.1 “While we knew that testing for high-risk HPV can predict cervical cancer risk for a few years, it’s remarkable that this predictive effect lasts for almost two decades,” said senior study author Philip E. Castle, PhD, MPH, of the American Society for Clinical Pathology. “Our findings strongly reinforce the value of HPV testing as a routine part of care, in line with recent guidelines.”

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The findings support cervical cancer screening guidelines, issued by the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology in 2012, which call for combining high-risk HPV testing with Pap testing every 5 years for women 30 to 65 years old. Their conclusion also supports an alternative strategy to HPV/Pap co-testing for women in this age group: HPV testing first to rule out cervical disease, followed by Pap testing only in HPV positive women to identify those who are at immediate risk of cervical precancer or cancer.

Study Details The new study enrolled 20,000 women receiving routine Pap screening at Kaiser Permanente in Portland, Oregon. The women underwent baseline Pap as part of routine care and high-risk HPV testing for research purposes and were then followed up by conventional Pap testing for up to 18 years. Researchers calculated cumulative incidence for two different outcomes, CIN2 or the more severe (CIN2+), and CIN3 or

more severe diagnoses (CIN3+). A U.S. Food and Drug Administration-approved molecular test, which screens for a pool of 13 highrisk HPV types, was used for baseline HPV testing. Those women who tested positive on the pooled test were also tested for HPV16 and HPV18 separately, using a prototype clinical assay. These two high-risk types are known to account for approximately 55% and 15% of all cervical cancers, respectively.

Results Among study participants older than 30 years, 8.7% tested HPV-positive and 4.3% had an abnormal Pap test result at initial testing. More cases of CIN3 and cervical cancer occurred after a baseline HPV-positive result versus abnormal Pap over the 18-year period (112 vs 65). Furthermore, HPV-positive women were more likely to have precancer at 10 to 18 years than HPV-negative women, regardless of the result of their initial Pap test. Thus, positive HPV test results were better at forecasting long-term cervical cancer risk than abnormal Pap results. Over the 18-year follow-up, the

JCO Spotlight

incidence of CIN3 and cervical cancer was lower after a one-time negative HPV test than after See Page 81 one normal Pap test (0.9% vs 1.27%), suggesting that HPV testing is a stronger predictor of not developing cervical precancer years later. And finally, the study showed that, among women older than 30 years who had negative HPV and normal Pap tests, increasing the screening interval from 3 years to 5 years did not substantially increase the CIN3 and cervical cancer risk (0.08% vs 0.16%). The researchers also found that, over an 18-year period, HPV16- and HPV-18 positive women with normal Pap results were at elevated risk of developing CIN2, CIN3, and cervical cancer compared with other HPV-positive women with normal Pap.

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Reference 1. Castle PE, Glass AG, Rush BB, et al: Clinical human Papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up. J Clin Oncol July 30, 2012 (early release online).

website at ASCOPost.com

NOW

APPRO ED For Patients With Advanced HR+ BC AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

Important Safety Information

There have been reports of non-infectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR® (everolimus), some with fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared to patients <65 years of age. Oral ulceration is the most frequently occurring adverse event and occurred at an incidence ranging from 44% to 86% of AFINITOR-treated patients across the clinical trials experience. Most of these events were Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 4%-8% of patients. Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported; monitoring of laboratory tests is recommended. The use of live vaccines and close contact with those who have received live vaccines should be avoided. AFINITOR can cause fetal harm when administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Please see Brief Summary of Prescribing Information on adjacent pages. For more information, please visit www.AFINITOR.com.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

7/12

AFB-1039129

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] . Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

T:14”

B:14.25”

S:13”

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use AFINITOR is recommended for use only in patients with SEGA who are aged ≥ 3 years. A prospective, open-label, single-arm trial was conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA associated with TSC. In total, 28 patients received treatment with AFINITOR; median age was 11 years (range 3-34). AFINITOR has not been studied in patients with SEGA < 3 years of age. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITORtreated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For SEGA patients with severe hepatic impairment (Child-Pugh class C), AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however, subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2012-132 July 2012

The ASCO Post | SEPTEMBER 15, 2012

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News Hematology

Is There a Role for Metronomic Chemotherapy in Patients with Highly Refractory Multiple Myeloma? By Caroline Helwick

etronomic chemotherapy using a multidrug regimen appears beneficial and fairly well tolerated in patients with multiple myeloma that is highly refractory to previous treatments, investigators from the Myeloma Institute for Research and Therapy in Little Rock, Arkansas, reported. 1 Their results were presented at this year’s ASCO Annual Meeting.

Xenofon Papanikolaou, MD

Metronomic chemotherapy entails the use of repetitive low doses of chemotherapeutic agents, with regimens designed to minimize toxicity and target the endothelium or tumor stroma as opposed to targeting the tumor. “Multirelapse and multirefractory myeloma represents a great challenge in myeloma therapy. Based on the concept that low-dose continuous application of certain cytotoxic drugs can inhibit tumor progression, we developed a treatment schema of metronomically scheduled ther-

Metronomic Chemotherapy for Refractory Myeloma ■■ According to a recent

187-patient study, metronomically scheduled therapy is an effective salvage treatment strategy in relapsed/ refractory multiple myeloma, producing a high overall response rate and a favorable toxicity profile.

■■ The overall response rate was 65%, median overall survival was 1.1 year, and median progression-free survival was 3.7 months.

EXPERT POINT OF VIEW

apy for myeloma,” said Xenofon Papanikolaou, MD.

Study Design The study included 187 patients who received at least one cycle of metronomically scheduled therapy. Their median number of prior therapies was 14 (but ranged up to 51); 79% had prior stem cell transplant, usually multiple transplants, as is the custom at this cancer center. Treatment was as follows: ■■ Bortezomib (Velcade), 1 mg/m2 on days 1, 4, 7, 10, 13 and 16 ■■ Thalidomide (Thalomid), 200 mg on days 1 to 16 ■■ Dexamethasone, 20–40 mg on days 1, 4, 7, 10, 13 and 16 ■■ Doxorubicin, 3 mg/m2 by continuous infusion on days 1 to 16 ■■ Cisplatin, 1.5–3 mg/m2 continuous infusion on days 1 to 16 ■■ Sirolimus (Rapamune), 3 mg on day 1, then 1 mg days 2 to 16 (depending on renal function) These were the most common dosages (80% of cases). Variations included thalidomide, 50–200 mg on days 1 to 16, and doxorubicin, 1–3 mg/m2 by continuous infusion on days 1 to 16.

Key Results The overall response rate was 65%, which included complete responses (6%), very good partial responses (7%), partial responses (36%), and minor responses (16%). Stable disease was achieved by 15% of the patients. The median time to best response was 27 days (range of 6 to 203), the investigators reported. Interestingly, according to PET scans, 73% of patients with extramedullary disease had a response. No parameters appeared to be predictive of a response to treatment. The median overall survival was 1.1 year, and median progression-free survival was 3.7 months. Hematologic toxicities occurred in most patients, including grade�� 4 leukopenia (74%), anemia (17%), and thrombocytopenia (89%). “The true effect of metronomic therapy regard-

ergio Giralt, MD, Chief of Adult Bone Marrow Transplant Service at Memorial SloanKettering Cancer Center, New York, commented on the findings by Papanikolaou et al presented at the 2012 ASCO Annual Meeting. “To put this trial into context, in a recent study of 283 double-refractory multiple myeloma patients, Kumar et al1 demonstrated a median event-free survival of 5 months and median overall survival of 9 months [after disease Sergio Giralt, MD proved refractory to bortezomib (Velcade) and patients relapsed following, proved refractory to, or were ineligible to receive an immunomodulatory drug],” Dr. Giralt noted. “The findings from that study are somewhere in the ballpark of what we get with metronomic chemotherapy.” The Kumar study aimed to elucidate the natural history of patients who become refractory to bortezomib and thalidomide (Thalomid) or lenalidomide (Revlimid) and undergo no further treatment. The study concluded that event-free survival and overall survival are poor in dualrefractory disease.

Relative Benefit “So the question is, should we be doing this [metronomic chemotherapy] in our practices for patients who have failed all prior treatments? Probably not,” Dr. Giralt concluded. “Metronomic chemotherapy seems interesting. It can work in heavily pretreated patients. The question is whether it is better than giving palliative care or enrolling patients on phase I/II trials of new agents and strategies, which we should be encouraging,” he maintained. Dr. Giralt felt, however, that metronomic chemotherapy is worthy of further study. In particular, he continued, investigators need to determine whether it has value earlier in the disease course and as compared with traditional schedules.

■

Disclosure: Dr. Giralt has received honoraria from Millennium and Celgene for consulting and speaker’s bureau activities.

Reference 1. Kumar SK, Lee JH, Lahuerta JJ, et al: Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter International Myeloma Working Group study. Leukemia 26:149-157, 2012.

ing hematologic toxicity [in these patients] is difficult to determine due to the presence of cytopenias prior to the initiation of metronomic therapy,” Dr. Papanikolaou noted. No grade 5 hematologic toxicities were reported, and the incidence of grade 4 neutropenic fever was only 1%. Nonhematologic toxicities were manageable. Paresthesia and numbness were the most common com-

plaints and were transient.

■

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

Reference 1. Papanikolaou X, Szymonifka J, Mitchell A, et al: Metronomic therapy for heavily pretreated relapsed/refractory multiple myeloma. 2012 ASCO Annual Meeting. Abstract 8041. Presented June 2, 2012.

ASCOPost.com | SEPTEMBER 15, 2012

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News

Lack of Sleep Found to Be Risk Factor for Aggressive Breast Cancers

ack of sleep is linked to more aggressive breast cancers, according to new findings published in the August issue of Breast Cancer Research and Treatment by physician-scientists from University Hospitals Case Medical Center’s Seidman Cancer Center and Case Comprehensive Cancer Center at Case Western Reserve University, Cleveland.1 Led by Cheryl Thompson, PhD, the study is the first-of-its-kind to show an association between insufficient sleep and biologically more aggressive tumors as well as likelihood of cancer recurrence.

duration of sleep and improve quality of sleep could be an underappreciated avenue for reducing the risk of developing more aggressive breast cancers and recurrence,” said Li Li, MD, PhD, study coauthor and family medicine physician in the Department of Family

Medicine at UH Case Medical Center and Associate Professor of Family Medicine, Epidemiology and Biostatistics at Case Western Reserve University School of Medicine. The study was supported by NCI grants to Case Western Reserve Uni-

versity School of Medicine.

■

Reference 1. Thompson CL, Li L: Association of sleep duration and breast cancer Oncotype DX recurrence score. Br Cancer Res Treat 134:1291-1295, 2012.

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

THE OTHER SIDE OF RCC

Study Design The research team analyzed medical records and survey responses from 412 postmenopausal breast cancer patients treated at UH Case Medical Center. All patients were recruited at diagnosis and asked about average sleep duration in the past 2 years. Researchers found that women who reported 6 hours or less of sleep per night on average before breast cancer diagnosis had higher Oncotype DX tumor recurrence scores (which are based on the expression level of a combination of 21 genes). “This is the first study to suggest that women who routinely sleep fewer hours may develop more aggressive breast cancers compared with women who sleep longer hours,” said Dr. Thompson, who is Assistant Professor at Case Western Reserve University School of Medicine and lead author. “We found a strong correlation between fewer hours of sleep per night and worse recurrence scores, specifically in postmenopausal breast cancer patients. This suggests that lack of sufficient sleep may cause more aggressive tumors, but more research will need to be done to verify this finding and understand the causes of this association.”

Pre- vs Postmenopausal Women The authors point out that while the correlation of sleep duration and recurrence score was strong in postmenopausal women, there was no correlation in premenopausal women. It is well known that there are different mechanisms underlying premenopausal and postmenopausal breast cancers. The data suggest that sleep may affect carcinogenic pathway(s) specifically involved in the development of postmenopausal breast cancer, but not premenopausal cancer. “Effective intervention to increase

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown.2 The American Cancer Society estimates that there will be 64,770 new cases and 13,570 deaths in 2012.3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations.3,6,7 In the Phase III trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.5 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living.3,6

Is good enough, enough? Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical.1 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.2,3

Furthermore, in addition to dose modifications deemed necessary by a physician, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy, among other factors.6

There may be opportunities to improve patient care

Therapy for advanced RCC has evolved, but…

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives.3,6

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.4 Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.5,6

Go behind the scenes to learn more at www.WhyCompromiseRCC.com.

AVEO and Astellas are uncompromising in their commitment to RCC patients References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012. 4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30. 6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin N Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y.

An Uncompromising Commitment to RCC

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The ASCO Post | SEPTEMBER 15, 2012

Pioneers in Oncology A Leading Light in Cancer Advances, Mary Lasker Used Wealth and Connections to Increase Funding for Medical Research By Jo Cavallo

orn in Watertown, Wisconsin, in 1900, Mary Woodard Lasker was introduced to the ravages of cancer when she was just 3 or 4 years old and went with her mother to visit the family’s laundress, Mrs. Belter, who had just undergone surgery for breast cancer. On the way over to Mrs. Belter’s home, Ms. Lasker’s mother explained that the laundress had had both her breasts removed. The experience left an indelible memory. “I thought, this shouldn’t happen to anybody,” Ms. Lasker told an interviewer in 1965. “And when I stood in the room and [saw] this miserable sight with her children crowding around her, I was absolutely infuriated, indignant, that this woman should suffer so and that there should be no help for her. I was encouraged, however, by the fact that Mrs. Belter survived, and I recall noticing that cancer didn’t have to be fatal even though it was very cruel. And I’ll never forget my anger at hearing about this disease that caused such suffering and mutilation and my thinking that something should be done about this.” Four decades later, in 1942, Ms. Lasker and her husband Albert, owner of the largest advertising agency in the United States (Lord and Thomas), established the Albert and Mary Lasker Foundation. Still in place today, the Foundation was set up to reward scientists and physicians for their contributions in basic and translational research in cancer as well as other diseases. The couple also used their wealth and social connections to garner federal funding for medical research in cancer, heart disease, arthritis, hypertension, and mental health.

researchers were largely ousted from the organization and replaced by a lay group of businessmen, movie producers, admen, and friends of the Laskers (dubbed the “Laskerites” by the media). The couple reorganized the ACS using a business model that incorporated advertising and publicity strategies to raise funds, increase the public’s faith in medical science, and promote the idea that research could find a “cure” for cancer. Four years later, the ACS raised $14 million, one-quarter of which was devoted to research grants. Called the “fairy godmother of medical research” by BusinessWeek magazine, Ms. Lasker used her political skills and contacts to lobby Congress to increase federal expenditures for medical research. Mary Woodard Lasker. Library of Congress, Prints and Photographs She helped raise the Division, reproduction number LC-USZ62-11493. budget of the National to advance cancer research. She was Institutes of Health (NIH) from just $2 million in 1945 to over $5 billion appalled by the small size of the opin 1985. eration and its meager annual budget of about $250,000. Utilizing Albert Partnering with Sidney Farber Lasker’s business skills—his advertisRecognizing the need for a sciening campaigns in the 1920s boosted tific strategist who could be her ally in sales of Lucky Strike cigarettes among fundraising but also have impeccable women with the words, “Light a credentials in cancer research, Ms. Lucky and you’ll never miss sweets Lasker teamed up with Sidney Farber, MD—who in 1947 used antifolates Called the ‘fairy godmother of medical research’ by to induce remissions in children with leukemia—to expedite the discovery BusinessWeek magazine, Ms. Lasker helped raise the of approaches to cancer prevention budget of the National Institutes of Health (NIH) from and cure. According to The Emperor just $2 million in 1945 to over $5 billion in 1985. of All Maladies: A Biography of Cancer by Siddhartha Mukherjee, MD, “The idea of chemotherapy—a chemical Takeover of the ASCC that make you fat”—and Mary’s sothat could cure cancer outright—fasIn 1943, Mary Lasker met with cial connections, the couple took over cinated Lasker.”1 That fascination was coupled with Dr. Clarence Cook Little, Director of the ASCC’s board of directors and, in a new sense of urgency to find effecthe American Society for the Control 1944, renamed the organization the tive treatments for cancer when Alof Cancer (ASCC) in New York, to American Cancer Society (ACS). bert Lasker was diagnosed with colon learn what the organization was doing At this point, doctors and medical

cancer in 1951 and died the following year. However, Ms. Lasker’s impatience to speed laboratory discoveries and bring new chemotherapies to market put her increasingly at odds with scientists and lawmakers. They resented her intrusion into their territory with her lobbying efforts for more cancer funding and insistence on separating NIH institutes by disease category rather than by scientific discipline, which she thought was slowing progress. Such a complete restructuring of the NIH, argued officials and scientists, would prohibit essential interaction among its researchers and undermine the quality of basic research across the NIH. Academic researchers, who were dependent on federal funding, also opposed decentralizing the NIH over fears that it would cost them their share of biomedical research grants.

Lasting Legacy Ms. Lasker’s efforts helped gain passage of the National Cancer Act of 1971, which provided the unprecedented sum of $1.59 billion for cancer research over a 3-year period. By the end of the decade, however, her influence on the “War on Cancer” began to decline, as new cures for the disease failed to materialize and the public’s skepticism of impending scientific breakthroughs in cancer research and treatment grew. Nevertheless, Mary Lasker’s contribution to the advancement of cancer awareness and fundraising for research provided the groundwork for unprecedented progress in cancer treatment over the past 40 years—but not the cure that she had hoped for. By the time she died of heart failure in 1994, Mary Lasker rarely spoke “about the achievements (or disappointments) of the War on Cancer,” wrote Dr. Mukherjee. “The complexity, the tenacity—the sheer magisterial force of cancer—had made even its most committed and resolute opponent seem circumspect and humbled.”

■

Reference 1. Mukherjee S: The Emperor of All Maladies: A Biography of Cancer. New York, Scribner, 2010.

Take part

in ground-breaking national

oncology census The National Oncology Census, sponsored by the American Society of Clinical Oncology (ASCO), represents an unprecedented effort to gain in-depth understanding about the practice of oncology in the United States and how it is faring under current economic, legislative, and regulatory pressures. ASCO plans to use the census results on Capitol Hill and elsewhere to advocate on behalf of cancer patients and providers for improvements in the U.S. cancer care delivery system.

â&#x20AC;&#x153;It is critically important that we fully understand the impact our demanding healthcare landscape is having on cancer patients and the oncologists who serve them. Lives depend on it.â&#x20AC;? ASCO President Sandra M. Swain, MD Medical Director, Washington Cancer Institute at MedStar Washington Hospital Center

B e Co u n t e d. Learn how at www.asco.org/census.

ASC121313 Census 95x13 Ad.indd 1

8/22/12 2:52 PM

The ASCO Post | SEPTEMBER 15, 2012

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Lab Notes

Ongoing Molecular Research in the Science of Oncology OUTCOME PREDICTORS Predictive Markers for Outcome with Pazopanib in Metastatic Renal Cell Cancer Several targeted drugs are approved for treatment of metastatic renal cell cancer, but no validated biomarkers are available for prediction of clinical outcome of treatment with these agents. In a recent study, Tran and colleagues from The University of Texas MD Anderson Cancer Center in Houston, GlaxoSmithKline in Research Triangle Park, North Carolina, and Collegeville, Pennsylvania, Cedars-Sinai Medical Center in Los Angeles, California, Baylor-Sammons/Texas Oncology in Dallas, and San Carrillo and Forlanini Hospitals in Rome identified baseline cytokine and angiogenic factors that predicted outcome in patients receiving pazopanib (Votrient) in clinical trials. Screening of 17 cytokine and angiogenic factors in 129 patients with greatest and least tumor shrinkage in a phase II trial yielded the candidate markers interleukin (IL)-6, IL-8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analysis in the same population identified IL-6, IL-8, VEGF, osteopontin, E-selectin, and HGF as having an association with continuous tumor shrinkage or progression-free survival. In the validation study in samples from 344 patients enrolled in a phase�� III trial, pazopanib-treated patients with high concentrations (relative to median) of IL-8 (P = .006), osteopontin (P = .0004), HGF (P = .010), and TIMP-1 (P = .006) had shorter progression-free survival than did those with low levels of these markers. In placebo-treated patients, high concentrations of IL-6 (P < .0001), IL-8 (P = .002), and < .0001) were assoosteopontin (P �� ciated with shorter progression-free survival. These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High IL-6 was associated with greater relative progression-free survival benefit from pazopanib vs placebo (P = .009 for

the interaction), whereas standard clinical classifications did not predict progression-free survival benefit. As stated by the investigators, “[Cytokine and angiogenic factor] profiles could provide prognostic information

beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal cell carcinoma. Further studies of the predictive effects of these markers in different pop-

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%),

ulations and with different drugs (eg, mTOR inhibitors) are warranted.” Funding for the study was provided by GlaxoSmithKline.

Tran HT, et al: Lancet Oncol 13:827837, 2012.

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.

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OUTCOME PREDICTORS Metastasis Promoted by Cleaving and Inhibiting Proapoptotic Effect of von Willebrand Factor Mochizuki and colleagues from Keio University in Tokyo, the Che-

mo-Sero-Therapeutic Research Institute in Kumamoto, and RIKEN in Saitama have shown that von Willebrand factor has proapoptotic effects and that a disintegrin and metalloproteinase 28 (ADAM28) promotes metastasis by cleaving and inactivating von Willebrand factor and thus enhancing cancer cell survival in the

circulation. These researchers had previously shown that increased tumor and serum levels of ADAM28 correlated with poor prognosis and metastasis in patients with breast and non–small cell lung cancer, and proposed that ADAM28 promotes tumor growth via selective digestion of insulin-like growth factor bind-

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.

ing protein 3 and connective tissue growth factor. In their study of the potential role of ADAM28 in metastasis, screening of a human lung cDNA library for substrates of ADAM28 using a yeast twohybrid system yielded von Willebrand factor as a candidate binding protein. continued on page 44

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Ongoing Molecular Research continued from page 43

ADAM28 was found to bind and cleave native von Willebrand factor. Cells with low ADAM28 expression—breast carcinoma MCF-7, renal carcinoma 769P, and hepatocellular carcinoma HepG2 cells—were

susceptible to von Willebrand factor– induced apoptosis. In contrast, cells with high ADAM28 expression— lung carcinoma PC9 and Calu-3, breast carcinoma MDA-MB231, and renal cell carcinoma Caki-2 cells— were resistant to von Willebrand factor–induced apoptosis. Further, von Willebrand factor–induced apoptosis

was shown to involve the αVβ3 integrin and activation of a mitochondrial cell death pathway. In a mouse model of lung metastasis, knockdown of ADAM28 expression in PC-9 and MDA-MB231 cells using short hairpin RNAs (shRNAs) resulted in increased carcinoma cell apoptosis, which oc-

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

curred mainly in lung blood vessels and was associated with decreased von Willebrand factor degradation in the blood. In vivo imaging showed a significant decrease in lung metastasis at week 3 after injection in ADAM28-shRNA knockdown mice compared with control mice (mean counts of 37 vs 198 × 106 photons/s

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

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Lab Notes

for PC-9 ADAM28-shRNA, P < .001). Similar inhibition of lung metastasis was observed with ADAM28 knockdown using small interfering RNAs (siRNAs) and with inhibition of ADAM28 activity via an anti-ADAM28 neutralizing antibody. As summarized by the investigators, “ADAM28 cleaves and inacti-

vates proapoptotic [von Willebrand factor] in carcinoma cells and enhances lung metastasis probably by promoting carcinoma cell survival within the blood vessels.” Mochizuki S, et al: J Natl Cancer Inst 104:906-922, 2012. Zucker S, Cao J: J Natl Cancer Inst 104:887-888, 2012.

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

GENE PROFILING Evolutionary Pathways in BRCA1-associated Breast Tumors BRCA1 germline mutations are associated with elevated risk of breast and ovarian cancers, and somatic loss

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

of the wild-type BRCA1 allele has been thought to be a rate-limiting initiating step in tumor development. BRCA1-associated breast tumors acquire additional somatic alterations during progression, with mutations of PTEN and TP53 frequently being found in this setting. However, it also continued on page 46

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Lab Notes

Ongoing Molecular Research continued from page 45

has been observed that normal cells do not survive acute loss of BRCA1, suggesting that the loss of wild-type BRCA1 may not be the initiating step in tumorigenesis. Further, loss of

wild-type BRCA2 appears to occur relatively late in pancreatic tumor development in BRCA2 mutation carriers, and evidence suggests that loss of wild-type BRCA1 might occur only in preexisting TP53 mutant foci in ovarian cancer. In a recent study, Martins and col-

(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.

leagues from Dana-Farber Cancer Institute in Boston, Massachusetts, analyzed BRCA1, p53, and PTEN at the single cell level in BRCA1associated breast tumors and used computational methods to identify the relative order of somatic events on the basis of the frequency of cells

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.

with single or combined alterations. Evaluation of 55 BRCA1-associated breast tumors showed no single obligatory order of events, but suggested distinct evolutionary pathways. Loss of PTEN was the most common first event and was followed by TP53 mutation or BRCA1 loss of heterozygosity with approximately equal frequency. TP53 mutation was the second-most common first event and was almost always followed by BRCA1 loss of heterozygosity. BRCA1 loss of heterozygosity was the least common first event, and the majority of such cases exhibited mutant p53 as the only other alteration. The order of events was strongly associated with tumor type. PTEN loss (evolutionary path 1) was almost always the first event in triple-negative (basal-like) tumors, whereas TP53 mutation or BRCA1 loss of heterozygosity was the first event in luminal tumors (path 2). PIK3CA mutation, which is associated with the luminal subtype in sporadic breast tumors, was infrequent in the BRCA1associated tumors. Further, loss of wild-type BRCA1 was not consistent among tumor cells within a single tumor, and increased cell proliferation and centrosome amplification were observed in normal breast epithelium of BRCA1 mutation carriers.

Implications As concluded by the investigators, “Our combined experimental and computational approach reveals that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors.… Our results [may] have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.” Among the potential clinical implications of these findings cited by the investigators are that agents such as PARP inhibitors, which have a synthetic lethal interaction in cells lacking wild-type BRCA–associated DNA repair function, may have reduced activity in some BRCA1 mutation carriers. They also note that AKT pathway inhibitors and agents targeting p53 mutant tumor cells may have promise for prevention and treatment of breast tumors in a subset of such carriers.

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.

Martins FC, et al: Cancer Discov 2:503511, 2012. More ‘Lab Notes’ on page 65 Cosmos Communications 718.482.1800

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Direct from ASCO

Genitourinary Cancers Symposium Still Intimate Despite Record Growth

espite its exponential growth since launching in 2007—from 1,450 attendees then to a record 2,530 last year—the Genitourinary (GU) Cancers Symposium remains an inviting meeting that feels small, accessible, and comfortable. And that’s the perfect blend for networking, said Jeff Michalski, MD, Chair of the meeting’s Program Committee and Vice Chair and Director of Clinical Programs in the Department of Radiation Oncology at Washington University School of Medicine. “The GU Cancers Symposium allows a more intimate setting for the practicing oncologist,” Dr. Michalski said. “It gives you the opportunity to interact not just with colleagues that you might encounter in your own practice, but also with professionals and researchers who are working in an area that has interest to you but with whom you might not otherwise have an opportunity to speak to oneon-one.”

Talking with the Experts This is especially useful for earlycareer providers interested in expanding into research, Dr. Michalski said, pointing to the Fellows, Residents, and Junior Faculty Network-

ing Luncheon specifically. This event, on day 2 of the symposium, allows junior faculty, fellows, and residents to meet with more seasoned faculty, oncologists, and investigators in a group setting. “This gives them the opportunity to talk about how to advance one’s career,” said Dr. Michalski. “How do you start a lab? How do you start, manage, and conduct a clinical trial? Then also, how do you actually introduce some of these new advances into your own clinical care?”

Truly Multidisciplinary The 3-day meeting, which will take place February 14–16, 2013, in Orlando, Florida, is open to all members of the cancer care community interested in the prevention, screening, evaluation, and management of GU cancer, including medical oncologists, urologists, radiation oncologists, radiologists, pathologists, epidemiologists, pharmacologists, and translational-oriented laboratory scientists. In the early days of the GU Cancers Symposium, prostate cancer was the focus, but since then the meeting has greatly expanded its scope. It now also provides the latest strategies in

prevention, screening, diagnosis, and treatment of bladder and kidney cancer, as well as some of the less common cancers such as those of the penis and testes.

Poster Sessions Offer Unique Opportunity This year, the symposium will again offer the popular Best of Journals session, where top leaders discuss recent groundbreaking articles, and Translational Science General Sessions, where the latest translational research is applied to clinical practice. In addition to the educational sessions, the poster sessions represent another tremendous learning opportunity where attendees can talk to the researchers one-on-one, said Dr. Michalski. “These offer a very nice opportunity to meet the investigators and have detailed conversations about what went into their research [and] to ask, what are some of the details about their patient population? How might those results apply to your clinical practice?” he said.

Fully Connected Just as last year, many of the symposium’s sessions will be interac-

Jeff Michalski, MD

tive, with attendees encouraged to submit questions online or via text or tweet. In addition, 12 hours after select sessions, attendees will be able to access the presentation on their handheld devices or computers, searchable by title, presenter, or track. Attendees will again receive an eTote, a USB device that contains proceedings content in digital format, including meeting abstracts, education articles, and links to the symposium’s daily news. The deadline for abstract submission is October 16, 2012, at 11:59 PM EST. To learn more about the GU Cancers Symposium and to register, go to www.gucasym.org.

■

All Oncology Care Practices Urged to ‘Be Counted’ in Groundbreaking Census

he National Oncology Census, sponsored by the American Society of Clinical Oncology (ASCO), represents the first-ever attempt to capture comprehensive, real-time data on the state of oncology practice in the United States. ASCO is urging all U.S. oncology practices—representing oncologists in private practice and in academic and hospital settings—to be counted in this landmark initiative. “This census is a rare opportunity to understand how oncology is being practiced in this country,” said ASCO President Sandra M. Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center. “This

is an unprecedented effort to gain seminal knowledge of our national cancer care delivery system to help us accurately represent, advocate for, and serve the oncology community.” The ASCO census, conducted in partnership with the Center for Health Workforce Studies at the State University of New York, will gather information on current practice settings, oncology care specialties and services, patient volume, technology use, and payer mix, including the number of practices serving Medicare patients. Information on how oncologists are faring in the current economic, legislative, and regulatory environment will also be collected. “It is

critically important that we fully understand the impact our demanding health-care landscape is having on cancer patients and the oncologists who serve them,” said Dr. Swain. “Lives depend on it.” The census will examine whether high costs, drug shortages, competitive forces, payer restrictions, and other pressures in oncology practice threaten cancer patients’ access to care. October 1, 2012, is the deadline to respond to the confidential survey, which takes approximately 10 to 15 minutes to complete. Each practice has been assigned a username and password, which are needed to access the online survey. Only one individual per practice (whether a pri-

vate practice or academic/hospital setting) should complete the survey on behalf of the entire practice. To participate in The National Oncology Census: ■■ E-mail workforce@asco.org to receive your practice’s username, password, and direct link to the online census survey. (Include practice site name, address, and email address of practice contact.) ■■ For participants who already have their assigned username and password, visit www.asco.org/census and click on the “Start Census” link.

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The ASCO Post | SEPTEMBER 15, 2012

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Direct from ASCO

Philanthropy Spotlight

Kidney Cancer Association Works with Conquer Cancer Foundation to Stimulate Breakthrough Research

or any nonprofit cancer organization, a key challenge is how to balance the enormous task of supporting cancer patients with the latest information about current treatments while helping to advance the search for new breakthroughs in therapeutic options. For the past 6 years, the Kidney Cancer Association (KCA) has addressed this challenge by working with the Conquer Cancer Foundation of ASCO to leverage the strengths of both organizations.

Leveraging Strengths to Advance Clinical Research KCA was founded in 1990 by a small group of patients, including Eugene P. Schonfeld, PhD, and medical doctors in Chicago, with the mission of not only educating and advocating on behalf of kidney cancer patients, but also funding breakthrough research in the field of kidney cancer. Since 2006, KCA has collaborated with the Conquer Cancer Foundation to sponsor eight Young Investigator Awards, the Foundation’s research grants for early-career physician scientists. “We partnered with the Conquer Cancer Foundation to award an annual Young Investigator Award because of the expertise resident in the organization, because of the difference in scale—we knew that they would receive more and betterquality proposals—and because of the efficiency of the process, which relieves our small organization of the financial and logistic burden of reviewing proposals,” said Bill Bro,

[KCA’s] consistent support of earlycareer research in kidney cancer is creating a pipeline of research talent that will enrich the field for years to come, building momentum with every project they support. — Nancy R. Daly, MS, MPH

KCA Chief Executive Officer. “We’re very pleased with our collaboration. It’s an extremely effective synergy.” Over 60,000 people in the United States are diagnosed with kidney cancer each year, and each year over 13,000 people lose their battle with this disease. Kidney cancer is the sixth most common cancer for men and the eighth most common cause of cancer for women. KCA has sponsored more kidney cancer research projects than any organization of its size in the world. In its most recent fiscal year, KCA invested more than $650,000 in research-related program activities. In 2011, KCA supported a Young Investigator Award for Thai Ho, MD, PhD, a physician-scientist from The University of Texas MD Anderson Cancer Center, researching the role of the histone methyltransferase SETD2 in the development of renal cell carcinoma. Dr. Ho’s preliminary results were presented at the 10th International VHL Medical Symposium and the 2012 ASCO Genitourinary

■■ Henk Verheul, MD, PhD (2006)

■■ Stephen Keefe, MD (2009)

■■ Patricia Tang, MD (2007)

■■ Aditya Bardia, MBBS, MPH (2010)

Princess Margaret Hospital

■■ Kevin Courtney, MD, PhD (2008) University of Texas Southwestern Medical Center

■■ Aymen Elfiky, MD (2008)

Dana-Farber Cancer Institute

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

Recent Progress

Young Investigator Award Recipients Supported by Kidney Cancer Association (2006-2012) VU University Medical Center

Cancers Symposium. He will present an update of his work at the upcoming 11th International Kidney Cancer Symposium, sponsored by KCA.

University of Pennsylvania

Massachusetts General Hospital

■■ Martin Voss, MD (2012)

Memorial Sloan-Kettering Cancer Center

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

What’s Hot in

JCO

JCO.org easons Why Physicians Do Not Have Discussions About R Poor Prognosis, Why It Matters, and What Can Be Improved

Reversing Hormone Resistance: Have We Found the Golden Key?

Prostate Cancer Screening: Facts, Statistics, and Interpretation in Response to the US Preventive Services Task Force Review

Metformin: A Diabetes Drug for Cancer, or a Cancer Drug for Diabetics?

■■ Thai Ho, MD, PhD (2011)

The University of Texas MD Anderson Cancer Center

“We’re grateful to Dr. Ho and the many brilliant young researchers who have entered the field of kidney cancer research as the result of KCA’s funding of Young Investigator Awards, made collaboratively with the Conquer Cancer Foundation of ASCO Grants & Awards Program and AUA Foundation Research Scholars Program,” said Carrie Konosky, KCA Vice President for Public Affairs. The latest KCA-funded Young Investigator Award recipient, Martin Voss, MD, from Memorial SloanKettering Cancer Center, just be-

My First Patient

ASCOPost.com | SEPTEMBER 15, 2012

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Direct from ASCO

gan his project “Predictive Tissue Biomarkers for mTOR Inhibitors in Advanced Renal Cell Carcinoma (RCC),” and the Conquer Cancer Foundation and KCA are excited to see continued productive results.

Upcoming Projects KCA will also be supporting a 2013 Young Investigator Award that will be presented at the 2013 ASCO Annual Meeting. The Conquer Cancer Foundation is currently accepting applications and encourages applications in the field of kidney cancer. “We encourage those who are interested in kidney cancer research to apply for research grants,” continued Mr. Bro. “By working with the world’s most respected foundations, we are able to attract some of the best and brightest minds to this area of research. Together with the Conquer Cancer Foundation, we hope to bring candidates into the field that will help us to achieve our vision of a world that is free of death and suffering from renal cancers.” “KCA has been an incredible, loyal supporter of the Conquer Cancer Foundation of ASCO Young Investigator Award program. Their consistent support of early-career research in kidney cancer is creating a pipeline

What the Latest Breast Cancer News Means For Patients

irect your patients to www.cancer.net/breastsymposium to learn about the research highlighted at the 2012 Breast Cancer Symposium in the special online newsletter, Cancer Advances: News for Patients from the 2012 Breast Cancer Symposium. In addition, your patients can listen to a podcast of the symposium highlights online or download it free of charge at www.cancer.net/podcasts.

■

of research talent that will enrich the field for years to come, building momentum with every project they support,” says Nancy R. Daly, MS, MPH, Executive Director of the Conquer Cancer Foundation. “Together, we will all realize the Conquer Cancer Foundation’s ultimate vision:

creating a world that’s free from the fear of cancer.” Applications for the 2013 Young Investigator Award are due on September 27, 2012. To learn how to apply, please visit www.conquercancerfoundation.org/yia. To learn more about the Kid-

ney Cancer Association, please visit www.kidneycancer.org. To learn more about the Conquer Cancer Foundation, visit www.conquercancerfoundation.org.

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The ASCO Post | SEPTEMBER 15, 2012

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Direct from ASCO

A Great IDEA: Supporting the Next Generation of Oncology Leaders in Low- and Middle-income Countries

eadership has been cited as a critical success factor in improving access to cancer care in low- and middle-income countries.1 Effective clinical leaders in these countries can be transformative by supporting the development of cancer treatments to meet the needs of their patients, by advocating for national and international anticancer policies, and by developing and leading national and regional organizations that can advance cancer control in a localized, sustainable way. The Conquer Cancer Foundation of ASCO International Development and Education Award (IDEA) aims to support the development of oncology practice and improve access to cancer care in low- and middle-income countries by promoting the professional development of young oncologists from

these countries. Each IDEA recipient is carefully matched with a senior ASCO member mentor. Recipients attend the ASCO Annual Meeting and participate in a post-Meeting visit to their mentor’s institution in the United States or Canada. The true emphasis, however, is on the ongoing mentoring relationship after mentees return to their country.

Substantial Results The IDEA program produces substantial results. There are currently 205 IDEA alumni from over 40 countries,

many of whom have assumed leadership positions on ASCO committees and in their local societies; received fellowships and other research opportunities; pursued longer-term collaborations with their mentors; helped organize ASCO trainings and other activities in their co u nt r i es ; and, in some instances, created oncology societies where none previously existed. In addition, on average, each IDEA alumnus shared the information and new skills they learned with 50 colleagues in his or her country. The application cycle for the IDEA

program opens October 1. Use the QR code here to learn more or visit www.conquercanSee Page 81 cerfoundation.org/ IDEA to apply or make a gift.

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Reference 1. Knaul F, et al: Closing the cancer divide: A blueprint to expand access in low and middle income countries. Boston, Harvard Global Equity Initiative, 2011. This article was partially excerpted from “ASCO and the Conquer Cancer Foundation: A Global Oncology Community Sharing Knowledge to Improve Patient Care,” which will be published in Cancer Control 2013 on November 5, 2012, by publisher Global Health Dynamics.

Inaugural Quality Care Symposium Will Detail How to Pioneer Successful Quality Initiatives in Your Practice

ver the past 10 years, Wilshire Oncology Medical Group of La Verne, California, has reengineered itself so that all processes— from front-desk operations at all eight locations to the 10 oncologists’ interactions with patients and payers—capture quality data that can be used for robust benchmarking and, ultimately, improving oncology health outcomes and quality. How exactly did they do it? Linda D. Bosserman, MD, President of the Wilshire Oncology Medical Group, will explain the process in fine detail during the session she leads at ASCO’s first annual Quality Care Symposium, to take place November 30–December 1 in San Diego.

Success Stories: Front and Center Because the field of quality measurement is young and the meeting is brand new, it is especially important for attendees to hear all about quality programs that worked well in different settings, as well as learn how to marry quality measurements with today’s technology, said Craig Earle, MD, MSc, Co-Chair of the symposium and Director of the Health Services

Research Program for Cancer Care Ontario and the Ontario Institute for Cancer Research. The meeting has already generated substantial interest. More than 300 abstracts—significantly more than expected in this inaugural meeting—were submitted. “We’ll have descriptions of successful quality initiatives in community, academic, and international settings,” Dr. Earle explained. “And we’re going to have sessions on how information technology can support quality improvement.” Other important areas covered will include private and public payer perspectives on quality and how payment reform and accountable care organizations could drive the discipline of quality measurement, Dr. Earle said.

Keynote: Kenneth W. Kizer UC Davis Health System’s Kenneth W. Kizer, MD, MPH—one of the nation’s preeminent authorities on public health and health-care quality improvement—will give the symposium’s keynote address, “The Evolving Concept of Quality in Cancer Care.” Like most meetings that ASCO hosts, the Quality Care Symposium

will be multidisciplinary, welcoming all providers whose work touches health services research and outcomes in the field of oncology. But unlike other ASCO meetings, it will include healthcare industry players such as payers, who will participate as attendees and speakers. After all, quality measurement and reimbursement are becoming more enmeshed. “Oncologists will learn how to incorporate quality into their practice, and payers and providers will learn about the state of the art in quality measurement, including things that may not be possible now but are on the horizon,” said Dr. Earle.

Quality Is Key, No Matter Your Aim ASCO Past President and current Co-Chair of the symposium Douglas W. Blayney, MD, noted that no matter where you are in your career, or what your exact aim is, if you’re focused on the emerging discipline of quality measurement, the conference is not to be missed. Dr. Blayney is Ann and John Doerr Medical Director and Stanford Cancer Center Professor of Medicine in Palo Alto, California. “You should attend if you’re a

policymaker; if you’re attempting to influence government policy; if you’re attempting to influence policy around third-party payment mechanisms; and you should attend if you’re an advocate who has a strong role and a strong interest in shaping the quality agenda,” Dr. Blayney said.

Patients First ASCO desires to keep the patient front and center at the Quality Care Symposium, now and in the future, Dr. Earle said. “Reaching out to patient advocates and patient advocacy organizations is very important, because they are the ultimate determiners of quality. If we cure people’s cancer and they don’t get back to their normal life, then that’s not a real quality outcome. So we want to think, ‘How can we incorporate the view of the patient and the patient advocate into these quality measures and into the quality improvement interventions that may come out of this and subsequent meetings?’” For more information and to register for the symposium, go to quality2012.asco.org.

■

In metastatic melanoma

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

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

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

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

dEcodE metastatic melanoma.

ExtEnd

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

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

Percentage surviving

80 60

Not reached

7.9

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

20 0

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

‡

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

OS (months) ZELBORAF (n=337)

†

Dacarbazine (n=338)

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

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

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

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

Percentage surviving

80 60

13.6 9.7

ASCO=American Society of Clinical Oncology

20 0

Patients crossing over to ZELBORAF were censored.3

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

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

OS (months) Updated analysis of ZELBORAF

Updated analysis of dacarbazine

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

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

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

zelboraf.com

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FDA Update

FDA Grants Priority Review to Supplemental New Drug Application for Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer

anssen Research & Development, LLC, announced that the FDA has granted Priority Review to the supplemental New Drug Application (sNDA) for abiraterone acetate

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

(Zytiga) administered in combination with prednisone for the treatment of patients with metastatic castrationresistant prostate cancer who are asymptomatic or mildly symptomatic

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.

after failure of androgen deprivation therapy.

Priority Review Designation The FDA grants Priority Review

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

to medicines that may offer major advances in treatment, or provide a treatment option where no adequate therapy exists. Under the Prescription Drug User Fee Act, the FDA will aim to conclude its review within 6 months of the sNDA submission. The sNDA for abiraterone was submitted in June. “We believe that men with metastatic castration-resistant prostate cancer whose disease is asymptomatic or mildly symptomatic, for whom chemotherapy may not be immediately necessary, have limited treatment options and that this disease setting represents a critical unmet medical need,” said Michael L. Meyers, MD, PhD, Vice President, Compound Development Team Leader, Zytiga.

About Abiraterone Abiraterone is an oral agent that inhibits CYP17, an enzyme expressed in testicular, adrenal, and prostatic tumor tissue that is required for androgen biosynthesis. The abiraterone sNDA submission is based on the efficacy and safety results of an international phase III, randomized, double-blind, placebo-controlled clinical study that evaluated abiraterone plus prednisone compared to placebo plus prednisone in 1,088 asymptomatic or mildly symptomatic men with metastatic castration-resistant prostate cancer who had not received chemotherapy. Data from this study were presented at the 48th ASCO Annual Meeting in June. Abiraterone in combination with prednisone was approved by the FDA in April 2011 for the treatment of patients with metastatic castrationresistant prostate cancer who have received prior chemotherapy containing docetaxel. The most common adverse reactions (greater than or equal to 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.

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In the Clinic Gastrointestinal Oncology

New Indication for Cetuximab plus FOLFIRI to Treat EGFR-positive, Wild-type KRAS Metastatic Colorectal 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.

Indication

n July 2012, cetuximab (Erbitux) was approved for use in combination with FOLFIRI (irinotecan, fluorouracil [5-FU], leucovorin) for first-line treatment of patients with KRAS mutation–negative (wild-type), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer as determined by FDA-approved tests.1,2 The Therascreen KRAS RGQ PCR Kit (by QIAGEN) was approved for use in determining KRAS mutation status concurrently with the cetuximab approval. Cetuximab has several indications in squamous cell head and neck cancer. In EGFR-positive, wild-type KRAS metastatic colorectal cancer, cetuximab was already approved for use in combination with irinotecan in patients refractory to irinotecan-based chemotherapy and as single-agent treatment when irinotecan- or oxaliplatin-based chemotherapy has failed or in patients who were intolerant of irinotecan. Approval of cetuximab was based on retrospective analyses of outcomes of cetuximab treatment in patients with EGFR-positive, wild-type KRAS metastatic colorectal cancer in the CRYSTAL trial and two supporting trials, CA225025 and OPUS.

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).

These analyses showed that the addition of cetuximab to chemotherapy or best supportive care resulted in improved overall survival, progression-free survival, and overall responses rates in the subset of patients with wild-type KRAS tumors, with potential harm or no benefit being observed in patients with KRAS mutant tumors. In the open-label, randomized, controlled CRYSTAL trial, 1,217 patients with EGFR-positive tumors and no prior therapy for metastatic disease received FOLFIRI with or without cetuximab; the primary endpoint was progression-free survival. Retrospective evaluation for

OF NOTE Cetuximab binds to EGFR on tumor cells, thereby blocking phosphorylation and activation of receptor-associated kinases, inhibiting cell growth, inducing apoptosis, and decreasing matrix metalloproteinase and VEGF. KRAS mutation status in 89% of the patients (1,079/1,217) showed that 676 (63%) had wild-type tumors and 403 (37%) had mutant tumors. Among patients with wild-type KRAS, the addition of cetuximab to FOLFIRI significantly improved median overall survival from 19.5 to 23.5 months (HR = 0.80, 95% CI = 0.67–0.94), as well as significantly improving median progression-free survival (9.5 vs 8.1 months, HR = 0.70, 95% CI = 0.57–0.86) and increasing overall response rate (57% vs 39%). Among patients with mutant KRAS, the addition of cetuximab resulted in no improvement in overall survival, progression-free survival, or overall response rate. CA225025 was an open-label, randomized trial comparing cetuximab plus best supportive care vs best supportive care alone in 572 patients with previously treated EGFRpositive metastatic colorectal cancer; the primary outcome measure was overall survival. Tumor tissue was evaluable for KRAS mutation status in 79% of patients. Among patients

Cetuximab/FOLFIRI and Therascreen in Metastatic Colorectal Cancer ■■ The monoclonal antibody cetuximab was approved for use with

FOLFIRI to treat patients with KRAS mutation–negative, EGFR-positive metastatic colorectal cancer. Concurrently, the Therascreen KRAS RGQ PCR Kit was approved for use in determining KRAS mutation status.

■■ When used in combination with FOLFIRI, cetuximab should be given at an

initial dose of 400 mg/m2 as a 120-minute infusion and at a weekly dose of 250 mg/m2.

with wild-type KRAS, cetuximab significantly increased median overall survival from 5.0 to 8.6 months (HR = 0.63, 95% CI = 0.47–0.84) and significantly increased progression-free survival from 1.9 to 3.8 months (HR = 0.42, 95% CI = 0.32– 0.56). No improvement in overall survival, progression-free survival, or overall response rate was observed with cetuximab treatment among patients with mutant KRAS. OPUS was an open-label, randomized, phase II study comparing cetuximab plus FOLFOX4 (5-FU, leucovorin, oxaliplatin) with FOLFOX4 alone as first-line treatment in 337 patients with EGFR-positive metastatic colorectal cancer; overall response rate was the primary outcome measure. Tumor tissue was evaluable for analysis of KRAS mutation status in 93% of patients. Among patients with wild-type KRAS, the addition of cetuximab improved overall response rate (57% vs 34%), median progression-free survival (8.3 vs 7.2 months, HR = 0.57, 95% CI = 0.38–0.86), and median overall survival (22.8 vs 18.5 months, HR = 0.86, 95% CI = 0.60– 1.22). No improvement in overall survival, progression-free survival, or overall response rate was observed with the addition of cetuximab in patients with mutant KRAS.

How It Works EGFR is constitutively expressed in normal epithelial tissues, and expression is also detected in many human cancers, including those of the head and neck, colon, and rectum. Cetuximab is a monoclonal antibody that binds specifically to EGFR on both normal and tumor cells, competitively inhibiting binding of EGF

and other ligands, such as transforming growth factor-α. Cetuximab binding blocks phosphorySee Page 81 lation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and VEGF (vascular endothelial growth factor). Signal transduction through EGFR results in activation of wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continu-

OF NOTE Cetuximab carries a boxed warning for infusion reactions and cardiopulmonary arrest/sudden death, as well as warnings for pulmonary toxicity, dermatologic toxicity, and hypomagnesemia. ously active and appears to act independent of EGFR regulation. The QIAGEN Therascreen test is a real-time polymerase chain reaction assay that detects seven different mutations of the KRAS gene. Tumors are considered to be wild-type KRAS if they are negative for these mutations.

How It Is Given Cetuximab is given in combination with FOLFIRI at a recommended initial dose of 400 mg/m2 as a 120-minute infusion and at a weekly dose of 250 mg/m2 (maximum infusion rate of 10 mg/min for both). Cetuximab infusion should occur 1 hour prior to FOLFIRI administration. Patients should be premedicated with an IV H1 antagocontinued on page 56

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In the Clinic

Cetuximab for Metastatic Colorectal Cancer continued from page 55

nist (eg, diphenhydramine, 50 mg) 30 to 60 minutes prior to the first dose of cetuximab. For subsequent doses, premedication should be based on clinical judgment and the presence and severity of prior infusion reactions. Infusion rate should be reduced by 50% for grade 1, 2, and nonserious grade 3 infusion reactions, and cetuximab should be immediately and permanently discontinued for serious infusion reactions. For each of the first three occurrences of severe acneiform rash, infusion should be delayed for 1 to 2 weeks. If there is no improvement by this time, cetuximab should be discontinued; if improvement occurs, cetuximab should be continued at 250 mg/ m2 after the first occurrence, reduced to 200 mg/m2 and 150 mg/m2 after the second and third occurrences, respectively, and discontinued after the fourth occurrence.

Safety Profile The frequency and nature of the adverse events, including adverse events typically associated with cetuximab (acneiform rash, infusion reactions, cardiac events, and hypomagnesemia) observed in CRYSTAL, CA225025, and OPUS in the wild-type KRAS population were consistent with the known adverse drug reaction profiles of cetuximab, chemotherapy agents, or the underlying disease. Among patients with wild-type KRAS, grade 3 or 4 adverse events that occurred more frequently among patients receiving cetuximab compared with FOLFIRI alone in the CRYSTAL trial included acne-like rash (18% vs < 1%), diarrhea (16% vs 10%), palmar-plantar erythrodysesthesia (4% vs < 1%), paronychia (4%

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

vs 0%), and stomatitis (3% vs 0%). Cetuximab carries a boxed warning for infusion reactions and for cardiopulmonary arrest/sudden death, the latter having been observed in patients with head and neck cancer receiving cetuximab combined with radiation therapy or platinum-based therapy including 5-FU. In addition, cetuximab

carries warnings/precautions for pulmonary toxicity, dermatologic toxicity, and hypomagnesemia.

■

References 1. U.S. Food and Drug Administration: Cetuximab in combination with FOLFIRI/Therascreen. Available at www.fda. gov/Drugs/InformationOnDrugs/Ap-

provedDrugs/ucm310933.htm. Accessed July 24, 2012. 2. ERBITUX (cetuximab) injection prescribing information. ImClone LLC, a wholly owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company, July 2012. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2012/125084s225lbl.pdf. Accessed July 24, 2012.

CD30-directed therapy Important Safety Information BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS™ (brentuximab vedotin).

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.

CT SCANS confirmed responses in relapsed patients Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9 120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/ Lin:DCM/id:ID W:200 L25

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FDA Update

FDA Approves New Drug for Late-stage Prostate Cancer

he FDA has approved enzalutamide (Xtandi) to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Approved for patients with prostate cancer previously

treated with docetaxel, enzalutamide was reviewed under the FDA’s priority review program. The drug received FDA approval 3 months ahead of the product’s prescription drug user fee goal date of November 22, 2012. The safety and effectiveness of

enzalutamide was evaluated in a placebocontrolled study of 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel. The median overall survival for patients receiving enzalutamide was 18.4 months, vs 13.6 months for pa-

After multiple failures,

single-agent response Indicated for the treatment of:

Important Safety Information (continued)

• 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

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

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

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

2011 August 19 Acq Tm: 14:05:52

• 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 newonset 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.

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A R

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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/2011/0104e

855.4SEAGEN (855.473.2436) SeaGenSecure.com

tients who received placebo. The most common side effects observed with enzalutamide included weakness or fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, and headache.

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In the Clinic Gastrointestinal Oncology

Ziv-aflibercept with FOLFIRI in Metastatic Colorectal Cancer By Matthew Stenger

Indication

n August 2012, the antiangiogenic agent ziv-aflibercept (Zaltrap) was approved for use in combination with FOLFIRI (fluorouracil, leucovorin, iri-

ized, double-blind phase III study (VELOUR trial) in which 1,226 patients with metastatic colorectal cancer that had progressed during or within 6�� months after oxaliplatin-based com-

notecan) for the treatment of metastatic colorectal cancer resistant to or progressing after an oxaliplatin-containing regimen.1,2 Approval was based on a random-

bination chemotherapy received FOLFIRI plus ziv-aflibercept (n = 612) or placebo (n = 614) every 2 weeks.2 Patients were enrolled irrespective of prior bevacizumab (Avastin) treatment. Ziv-aflibercept was given at 4 mg/kg via IV infusion over 1 hour prior to FOLFIRI.

OF NOTE 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.

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. 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%).

Patients had a median age of 61 years, 59% were male, 87% were white, and 98% had ECOG performance status of 0 or 1. All had received prior oxaliplatin; 90% of patients in the ziv-aflibercept group and 89% in the placebo group had received oxaliplatin-based treatment in the advanced/ metastatic disease setting. Overall, 28% had received bevacizumab in combination with oxaliplatin-based treatment. The primary endpoint was overall survival, and treatment assignment was stratified by ECOG performance status and prior exposure to bevacizumab.

OF NOTE Ziv-aflibercept carries a boxed warning for hemorrhage, gastrointestinal perforation, and compromised wound healing.

Renal impairment

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.

Ziv-aflibercept binds to VEGF-A, VEGF-B, and placental growth factor, thus inhibiting receptor activation and leading to reduced tumor angiogenesis and metastasis.

General dosing information

Dose modification

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

The median number of treatment cycles was nine in the ziv-aflibercept group and eight in the placebo group. Median overall survival was 13.5 months in the ziv-aflibercept group vs 12.1 months in the placebo group, representing a significant 18% reduction in mortality with ziv-aflibercept (HR = 0.82, 95% CI = 0.71–0.94, P = .0032 on stratified log-rank test). Median progression-free survival was 6.9 months in the ziv-aflibercept group vs 4.7 months in the placebo group (HR = 0.76, 95% CI = 0.66– 0.87, P = .00007). Overall response rates were 19.8% in the ziv-aflibercept group and 11.1% in the placebo group (P = .0001).

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 59

In the Clinic

How It Works Ziv-aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. Ziv-aflibercept acts as a soluble receptor that binds to VEGF-A, VEGF-B, and placental growth factor, thus blocking binding of these growth factors to their respective receptors and inhibiting receptor activation. This inhibition can reduce neovascularization and vascular permeability, resulting in reduced tumor angiogenesis and metastasis. In animal studies, ziv-aflibercept inhibited the proliferation of endothelial cells and thus the growth of new blood vessels. The drug also inhibited the progression of colon tumor xenografts.

How It Is Given Ziv-aflibercept is given at 4 mg/ kg by IV infusion over 1 hour every 2�� weeks in combination with FOLFIRI. It must be administered before any component of FOLFIRI on the day of treatment, and it must be administered through a 0.2-micron polyethersulfone filter. Ziv-aflibercept should be discontinued for severe hemorrhage, gastrointestinal (GI) perforation,

compromised wound healing, fistula formation, hypertensive crisis or hypertensive encephalopathy, arterial thromboembolic events, nephrotic syndrome or thrombotic microangiopathy, and reversible posterior leukoencephalopathy syndrome. Treatment should be temporarily suspended before elective surgery (≥ 4 weeks prior), for recurrent or severe hypertension until controlled, and for proteinuria of 2 g/24 hours until resolved. Treatment should be reinstituted at a dose of 2 mg/kg after hypertension is controlled and in cases of recurrent proteinuria. Treatment should not be restarted until ≥ 4 weeks after major surgery and until complete healing of the surgical wound.

Safety Profile In the VELOUR trial, the most common adverse events occurring in ≥�� 20% of ziv-aflibercept–treated patients and with ≥ 2% greater frequency than in the placebo group were leukopenia (78% vs 72%), diarrhea (69% vs 57%), neutropenia (67% vs 57%), proteinuria (62% vs 41%), increased AST (62% vs 54%) and ALT (50% vs 39%), stomatitis (50% vs 33%), fatigue (48% vs 39%), thrombocytopenia (48% vs 35%), hypertension (41% vs 11%), decreased weight (32% vs 14%), decreased appetite

Ziv-aflibercept in Metastatic Colorectal Cancer ■■ Ziv-aflibercept (Zaltrap) was approved for combined use with FOLFIRI to treat metastatic colorectal cancer resistant to or progressing after oxaliplatin-based chemotherapy.

■■ The new drug is administered at 4 mg/kg by IV infusion over 1 hour every 2 weeks in combination with FOLFIRI, prior to any component of the FOLFIRI regimen on the day of treatment.

(32% vs 24%), epistaxis (28% vs 7%), abdominal pain (27% vs 24%), dysphonia (25% vs 3%), increased serum creatinine (23% vs 19%), and headache (22% vs 9%). The most common grade 3 or 4 adverse events occurring in ≥ 5% of ziv-aflibercept patients and ≥ 2% more frequently than in the placebo group were neutropenia (37% vs 30%), diarrhea (19% vs 8%), hypertension (19% vs 1.5%), leukopenia (16% vs 12%), stomatitis (13% vs 5%), fatigue (13% vs 8%), proteinuria (8% vs 1%), and asthenia (5% vs 3%). Grade 3 or 4 hemorrhagic events occurred in 2.9% of patients in the zivaflibercept group compared with 1.7% of placebo patients. Arterial thromboembolic events were observed in 2.6% and 1.7% of patients, respectively, and venous thromboembolic events were observed in 9% and 7%, respectively. Ziv-aflibercept carries a boxed warning for hemorrhage (including

GI hemorrhage), GI perforation, and compromised wound healing. The drug also carries warnings/precautions for fistula formation, hypertension, arterial thromboembolic events, proteinuria, neutropenia and neutropenic complications, diarrhea and dehydration, and reversible posterior leukoencephalopathy syndrome.

■

References 1. U.S. Food and Drug Administration: Hematology/oncology (cancer) approvals & safety notifications. Ziv-aflibercept. Available at http://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ ucm314438.htm. Accessed August 20, 2012. 2. ZALTRAP ® (ziv-aflibercept) injection for intravenous infusion prescribing information. Regeneron Pharmaceuticals, Inc/Sanofi-Aventis, US, LLC, August 2012. Available at http://www. accessdata.fda.gov/drugsatfda_docs/ label/2012/125418s000lbl.pdf. Accessed August 20, 2012.

Supplement to The ASCO Post

Now le b Availa

Comprehensive Coverage of Key Abstracts from

Best of ASCO® Annual Meeting ‘12 Don’t miss this special supplement to The ASCO Post, mailed with this issue (September 15, 2012).

Best of ASCO® Boston

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Featuring coverage of abstracts in • Breast Cancer • Gastrointestinal Cancer • Genitourinary Cancer • Gynecologic Cancer • Hematologic Malignancies • Lung Cancer • and much more To view these comprehensive reports on important abstracts, visit ASCOPost.com.

The ASCO Post | SEPTEMBER 15, 2012

PAGE 60

Book Review

Getting the Right End-of-life Care: Coming to Terms with the Realities of Advanced Disease and Mortality By Ronald Piana

“D

ying is at once a fact of life and a profound mystery.” That was the opening sentence of a 1997 Institute of Medicine report, Approaching Death: Improving Care at the End of Life, a much-needed jump-start in the national dialogue over identifying the barriers that impede the delivery of high-quality, compassionate care for patients with advanced illness. In the ensuing years, the clinical term “quality of life” has become a standard measure of cancer care; however, “quality of death” remains a more challenged concept. That, too, is changing, led by progressive sectors of the oncology community, especially those in palliative care.

Instructive Blueprint A recently published book, Having Your Own Say: Getting the Right Care When It Matters Most, elucidates the hard and necessary work ahead to achieve the contributors’ collective goal: “A true transformation [of health care] so that all Americans with advanced illness, especially the sickest and most vulnerable, will receive comprehensive, high-quality care that is consistent with their goals and values and that honors their dignity.” Edited by Bernard J. Hammes, PhD, Gunderson Health System, Having Your Own Say—a collection of expert-authored articles, instructive essays, and first-person accounts—is an instructive blueprint on delivering sensible, compassionate end-oflife care that should be embraced by health-care professionals and policymakers in Washington. On top of his editor’s duties, Dr. Hammes also contributed chapter 2, “Creating Person-Centered Care When it Matters Most: Lessons Learned at Gunderson Health System.”

Overarching Message “Let’s begin with a story … this story is a moral drama that has featured or will likely feature each of us.” So Dr. Hammes opens his chapter, which drills to the heart of the book’s overarching message about the invaluable benefits of timely selfdetermination regarding one’s health care as life nears its end. Blending

compassion and objectivity, he articulates the societal worth of fairly new laws that permit adults to sign documents specifying their preferences for future health-care decisions. These documents typically fall into two categories: living wills and powers of attorney for health care. As Dr. Hammes points out, both documents, which fall into the advance directives category, are important tools for documentation, but by themselves do not answer the moral and human question faced by caregivers: “How should I take care of this person in these circumstances?” He answers that universally imposing question by introducing the reader to La Crosse, Wisconsin, a community that has developed its

Title: Having Your Own Say: Getting the Right Care When It Matters Most Editor: Bernard Hammes, PhD Publisher: CHT Press, Washington, DC Publication date: 2012 Price: $19.95 More information: www.havingyourownsay.org

into successful innovative programs that have led to better, more costeffective care. For instance, chapter 6, “The Value of Palliative Care to Patients and Family Outcomes,” by Drs. R. Sean Morrison and Diane E.

The contributors’ goal: A true transformation [of health care] so that all Americans with advanced illness, especially the sickest and most vulnerable, will receive comprehensive, high-quality care that is consistent with their goals and values and that honors their dignity. “own comprehensive model to help individuals and families create personal health plans for these morally complex health issues.” The La Crosse experience is based largely on reshaping societal awareness on mortality issues; honest, timely dialogue about end-of-life issues is the foundation of the La Crosse approach. Dr. Hammes refers to the person-centered care model in La Crosse as one that can “not only tailor medical treatments to the person but also avoid unnecessary suffering for that person.” Subsequent chapters make a convincing case that improving the way we care for patients with advanced illness is an essential improvement in our overall health-care system that we cannot allow divisive politics and misperceptions to derail.

Coordinated Windows This well-organized, 16-chapter book never suffers from redundancy. Each chapter serves as a self-contained booklet, giving the reader a set of coordinated windows

Meier, elucidates the essential elements of palliative care and explains how integrating this approach into guideline-driven care could transform our health-care system. Drs. Morrison and Meier—both nationally regarded palliative care experts—also contribute chapter 15, “Better Care, Higher Quality, and Lower Costs for the Seriously Ill.” This selection is a nuts-and-bolts miniprimer on value, which in the vernacular of health care is defined as the ratio of quality to cost. Citing data from multiple studies, the authors underscore a fundamental principle that is often obscured in today’s contentious health-care debate by politically driven myths such as “death panels”: “Value can be enhanced by improving quality, by reducing costs, or—preferably, as in the case of palliative care—both.” Moreover, backed by a substantial bank of data, Drs. Morrison and Meier come to a telling conclusion: “The only current intervention that has shown empirically to directly enhance the health-care value equation is palliative care.”

The ultimate success of Having Your Own Say rests chiefly on the clarity it adds to the complex issue of dealing with advanced illness that foreshadows death. Tom Koutsoumpas, Executive Director of the Mintz Levin Center for Health Law and Policy, and Bill Novellli, Professor, McDonough School of Business at Georgetown University, opened the book’s forward with an elegantly frank statement, which sets the table for the ensuing chapters: “Nearly everyone has a personal story about a loved one with an advanced illness. Many of these stories are about the frustrations of dealing with a healthcare system that truly doesn’t serve our needs.” This is not a hyperbolic attack on our health-care system; it is simply stating the reality of a massive structure that has not come to full terms with the uncomfortable realities of advanced disease and mortality. Recognizing the system’s weaknesses, as the authors point out throughout the book, is an essential component in creating new models that deliver better care in this most difficult of clinical scenarios.

Actionable Solutions What elevates Having Your Own Say above other books on this subject is that the contributors weave a human story, a medical journey, sometimes heart-wrenching, that ends with actionable solutions to the problems our system faces. If the editor of this fine and valuable book is up to another challenge, it might be worthwhile to distill the essence of Having Your Own Say into a handout booklet for policymakers on the Hill.

■

To confront a

Common Threat in the 2 leading causes of cancer death1...

Indications 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. 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. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Think Avastin Percentage Surviving

First-line metastatic non-squamous NSCLC: 19% increase in median OS in combination with PC (Study E4599)2

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)

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; HR=hazard ratio; CI=confidence interval.

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)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%)3

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

Because overall survival matters Proven to extend overall survival (OS) in the 2 cancers with the highest mortalities1 First-line MCRC in combination with IV 5-FU–based chemotherapy: 30% increase in median OS in combination with IFL (Study 2107)2,4,5

Percentage Surviving

100

First-line median OS: 20.3 vs 15.6 months (HR=0.66 [95% CI, 0.54–0.81], P<0.001)

80 60 40 20

Avastin + IFL (n=402) Placebo + IFL (n=411)

0 6

18 12 OS (Months)

MCRC=metastatic colorectal cancer; IV=intravenous; 5-FU=5-fluorouracil; IFL=5-FU/leucovorin (LV)/irinotecan.

OS in second-line MCRC Study E3200: Median OS of 13.0 months with Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4) vs 10.8 months with FOLFOX4 alone (HR=0.75 [95% CI, 0.63–0.89], P=0.001)2,6

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 In NSCLC, 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%)

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. References: 1. American Cancer Society. Cancer Facts and Figures 2010. http://www. cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 21, 2011. 2. Avastin Prescribing Information. Genentech, Inc. September 2011. 3. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 4. Data on file. Genentech, Inc. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.

www.avastin.com

T:10.25" S:9.5"

AVASTIN ® (bevacizumab)

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004

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 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).]

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).]

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))

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.

5.2 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%

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 4198 patients with CRC, non‑squamous NSCLC, 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).] The population was aged 18‑88 years (median 60 years), 43.6% male and 83.8% white. The population included 1783 first‑ and second‑line mCRC patients who received a median of 10 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. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. 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,

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).] 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 (CHF) 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 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. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were signficantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. 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

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%

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. 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

55% 55% 19%

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).

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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).]

5.6 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).]

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ASCOPost.com | SEPTEMBER 15, 2012 AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

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)

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.

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%

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 ); 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). 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.

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).] 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).] 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. 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).] 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.

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 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

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

Lab Notes

Ongoing Molecular Research continued from page 46

OUTCOME PREDICTORS VEGF Pathway Biomarker for Outcome with Bevacizumab No biomarkers are available to guide patient selection for treatment with the anti-VEGF monoclonal antibody bevacizumab (Avastin). Lambrechts and colleagues from VIB and KULeuven and University Hospital Gasthuisberg, Belgium, and F. Hoffmann-La Roche in Basel, Switzerland, have identified a locus in the VEGF receptor 1 gene (VEGFR1) that appears to be associated with poorer outcome of bevacizumab treatment. The investigators first assessed the association of 138 single nucleotide polymorphisms (SNPs) with outcome in 154 white patients, including 77 bevacizumab recipients, from the phase III AViTA trial of gemcitabine/erlotinib (Tarceva) plus bevacizumab or placebo in metastatic pancreatic adenocarcinoma. Only rs9582036, a single nucleotide polymorphism in VEGFR1, was significantly associated with overall survival in bevacizumab recipients after correction for multiple comparisons, with a perallele hazard ratio of 2.1 (P = .00014); this SNP was also significantly associated with progression-free survival (perallele HR = 1.89, P = .00081). Compared with the AA genotype, AC (HR = 2.0, P = .0091) and CC (HR = 4.72, P = .0002) variants were associated with significantly worse overall survival among bevacizumab recipients. No such effects were observed among placebo patients, and the genotype by treatment interaction was significant (P = .041). Fine-mapping studies of the locus showed that the single nucleotide polymorphism rs7993418 was the functional variant associated with these predictive effects. This SNP affects tyrosine 1213 in the VEGFR1 tyrosine kinase domain, causing a shift in codon usage and resulting in increased VEGFR1 expression and downstream signaling. Analysis of outcomes among a subgroup of white patients in the AVOREN trial, which assessed interferon alfa-2a (Roferon A) plus either bevacizumab or placebo in metastatic renal cell carcinoma, showed a significant association of this VEGFR1 locus with progression-free survival (HR = 1.81, P = .033) but not overall survival (HR = 0.91, P = .78) among bevacizumab recipients. According to the investigators, prospective evaluation

is underway to validate the predictive value of this potential biomarker. Funding for the study was provided by F. Hoffman-La Roche.

Lambrechts D, et al: Lancet Oncol 13:724-733, 2012.

TARGETED THERAPY TRIM27 as Target in Cancer Development The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that reduces induction of cell senescence by retinoblastoma-associated protein (RB1). High levels of TRIM27 expression occur in several human cancers and have been associated with poor prognosis in breast and endometrial cancers. Zoumpoulidou and colleagues from University College London, Technology Transfer CIBER of Respiratory Diseases in Barcelona, and Oregon Health and Science University, Portland, Oregon, recently examined the role of TRIM27 expression and loss of expression in cancer development. Studies using cancer profiling arrays containing paired human tumor and normal cRNA showed that TRIM27 transcript levels were significantly elevated in common human cancers, including colon and lung cancer, compared with normal tissue (P < .001). Transcript levels were also significantly elevated in chemically induced mouse skin cancer compared with matched normal tissue (P < .001). TRIM27-deficient (TRIM27-/-) mice were resistant to chemically induced skin cancer compared with wildtype (TRIM27+/+) littermates (57% vs 8% tumor-free). Assessment of the propensity for senescence in mouse embryonic fibroblasts showed that TRIM27-/- mouse embryonic fibroblasts had significantly enhanced senescence propensity compared with TRIM27+/+ mouse embryonic fibroblasts in response to both replicative (P < .001) and oncogenic (P < .05) stress. These responses were reduced with inactivation of murine RB1. TRIM27-/- mice were not protected from cancer caused by RB1 deletion. As the investigators concluded, “TRIM27 expression is a modifier of disease incidence and progression relevant to the development of common human cancers and is a potential target for intervention in cancer.”

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Zoumpoulidou G, et al: J Natl Cancer Inst 104:941-952, 2012.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

S:12.5"

T:13"

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 Hepatobiliary disorders: Gallbladder perforation 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

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The ASCO Post | SEPTEMBER 15, 2012

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News

Researchers Awarded NCI Grants to Address ‘Provocative Questions’

wo scientists are among the first recipients of grants geared to answer “Provocative Questions” in cancer research, a new project funded by the National Cancer Institute (NCI), part of the National Institutes of Health

(NIH). Cynthia Sears, MD, and Peter Searson, PhD, both of Johns Hopkins, will receive more than $500,000 combined in the first of 5 years of funding. The federally funded “Provocative Questions” project will distribute more

than $22 million this year among 57 grant recipients nationwide. Each grant aims to provide answers to one of 24 questions, solicited from the research community, that address neglected or unsolved areas of cancer research.

Dr. Sears and Dr. Searson’s projects were chosen by a specially-designed peerreview process from among more than 700 applications submitted by scientists.

Infection and Cancer Dr. Sears will receive $236,480 in the first year of funding to examine how and why certain cancers may be caused by infections. An infectious disease expert, Dr. Sears has previously linked some colon cancers to common diarrheal bacteria, and her research will further explore how these and other microbes may cause colon cancer. Dr. Sears, a professor of medicine and oncology at Johns Hopkins, says these discoveries may help physicians detect earlier those at risk for colon cancer and prevent it more effectively.

Cynthia Sears, MD

Metastasis

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research.

With $316,513 in first-year funding, Dr. Searson will develop a new method to study metastasis. He proposes a device with an artificial blood vessel and other cellular components to study the spread of cancer. The “lab-on-a-chip” approach could replicate processes that occur in metastasis and provide a testing ground for experiments with a method easily reproduced by scientists. Dr. Searson is the Joseph R. and Lynn C. Reynolds Professor of Materials Science and Engineering and directs the Johns Hopkins Institute for NanoBioTechnology.

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.

Peter Searson, PhD

For more about NCI’s Provocative Questions, visit http://provocativequestions.nci.nih.gov/

Learn more at the new GSKoncology.com

04/12

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2012 Oncology Meetings September 1st Multidisciplinary Symposium: Molecular Oncology: From Laboratory Bench to Medicine September 17-22 • Kyiv, Ukraine For more information: http://rmd.org.ua/en Cancer Vaccines: Advances in Design, Therapy and Efficacy September 19-20 • London, United Kingdom For more information: www.smi-online.co.uk/events 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 Molecular Diagnostics World Congress September 25-26 • San Diego, California For more information: selectbiosciences.com/conferences 1st Malaysian Proteomics Conference September 26-27 • Penang, Malaysia For more information: www.informm.usm.my/mpc2012 Sydney Cancer Conference September 27-28 • Sydney, Australia For more information: sydney.edu.au/cancer-research/ SCC2012 European Conference of Oncology Pharmacy September 27-29 • Budapest, Hungary For more information: www.ecco-org.eu/home/conferences

Chicago Breast Reconstruction Symposium September 28 • Chicago, Illinois For more information: www.ucmcsymposium.com

ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: www.accc-cancer.org

37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org

American College of Surgeons Annual Clinical Congress September 30-October 4 • Chicago, Illinois For more information: www.facs.org

14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer

October

44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org

2nd Annual Next Generation Sequencing Asia Congress October 1-2 • Singapore For more information: www.discoveryontarget.com/HDACInhibitors 6th Next-Generation Histone Deacetylase Inhibitors October 1-2 • Boston, Massachusetts For more information: www.discoveryontarget.com/HDACInhibitors Targeting the Ubiquitin Pathway: Discovery and Development of Novel Inhibitors October 1-2 • Boston, Massachusetts For more information: www.discoveryontarget.com/ Ubiquitin-Pathway 27th Annual Critical Issues in Tumor Microenvironment, Angiogenesis, and Metastasis October 1-4 • Cambridge, Massachusetts For more information: http://steele.mgh.harvard.edu Functional Genomics Screening Strategies October 2-3 • Boston, Massachusetts For more information: www. discoveryontarget.com/RNAiScreens-Functional-Genomics Global Summit on International Breast Health: Guidelines for International Breast Health and Cancer Control: Supportive Care and Quality of Life October 3-5 • Vienna, Austria For more information: portal.bhgi.org

Emerging Strategies and Advances in Treatment of Solid Tumors and Hematological Malignancies for Practicing Physicians and Health-care Professions October 6 • Jersey City, New Jersey For more information: www.cancernetus.com/oct-6emerging-strategies-overview.php Ethics and Compliance in Oncology Research Conference October 6-8 • Houston, Texas For more information: www.mdanderson.org/conferences 32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org Ninth International Conference of the Society for Integrative Oncology October 8-10, 2012 • Albuquerque, New Mexico For more information: www.integrativeonc.org

Oncology Clinical Development Congress October 10-11 • Manchester, Cheshire, United Kingdom For more information: www.oncologyclinicaldevelopmentcongress.com 3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer Markers in Cancer: A Joint Meeting by ASCO, EORTC, and NCI October 11-13 • Hollywood, Florida For more information: www.molecularmeeting.org 15th Annual APAO Conference October 11-14 • Scottsdale, Arizona For more information: www.apao.cc 14th Biennial Meeting of the International Gynecologic Cancer Society October 13-16 • Vancouver, Canada For more information: www2.kenes.com/igcs2012/Pages/ home.aspx 2nd Annual Oncology Market Access Forum October 16-17 • Barcelona, Spain For more information: pharma.flemingeurope.com/ oncology-market-access/ Current Approaches to Diagnosis and Treatment of Non-Hodgkin’s Lymphoma October 18-19 • Kiev, Ukraine For more information: nbscience.com/current-approachesto-diagnosis-and-treatment-of-nonhodgkins-lymphoma 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: www.gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com continued on page 71

The median age of patients treated in the VISTAยง trial was 71 years (range: 48-91).

APPROVED FOR SUBCUTANEOUS ADMINISTRATION*

Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP† vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months‡; 60.1-month median follow-up§)

VELCADE (bortezomib) Indication and Important Safety Information INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

▼ Women should avoid becoming pregnant while being treated with VELCADE (bortezomib). Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page. *The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL). † Melphalan+prednisone. ‡ HR=0.695 (95% CI, 0.57-0.85); p<0.05. § VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated MM. The primary endpoint was time to progression (TTP). Secondary endpoints were complete response (CR), overall response rate (ORR), progression-free survival (PFS), and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. In an updated analysis at a median follow-up of 36.7 months, the overall survival advantage was sustained despite subsequent treatments.

Living Proof

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. 3790_milpro_fa1_gry_ascopst.indd 2

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, 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 VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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2012 Oncology Meetings continued from page 67

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 Society for Immunotherapy of Cancer: Primer on Tumor Immunology and Cancer Immunotherapy October 25 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/primer 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 9th Oncologic Imaging: A Multidisciplinary Approach Conference October 25-28 • New York, New York For more information: www.mdanderson.org/conferences Society for Immunotherapy of Cancer 27th Annual Meeting October 26-28 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/annualmeeting Optimization Methods for Radiation Diagnosis in Oncology October 27-28 • Odessa, Ukraine For more information: nbscience. com/optimization-methods-forradiation-diagnosis-in-oncology 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

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

PEGS Europe – The Essential Protein & Antibody Engineering Summit November 6-9 • Vienna, Austria For more information: www.pegsummiteurope.com Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org

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 2012 Science of Global Prostate Cancer Disparities Conference November 1-4 • Nassau, The Bahamas For more information: cancer.ufl.edu/research/symposiaand-conferences 7th Urologic Oncology Conference: Advances in Clinical Practice November 2-3 • Houston, Texas For more information: www.mdanderson.org/conferences 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com 8th NCRI Cancer Conference November 4-7 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ 24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu

Cancer Summit: Novel Approaches to Drug Discovery November 8-9 • Boston, Massachusetts For more information: www.gtcbio.com The Second International Conference on Cancer and the Heart November 9-10 • Houston, Texas For more information: www.mdanderson.org/conferences 7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com World Circulating Tumor Cells Summit November 12-15 • Boston, Massachusetts For more information: www.ctc-summit.com AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Joint Meeting of IPOS 14th World Congress and COSA’s 39th Annual Scientific Meeting November 13-15 • Brisbane, Australia For more information: www.ipos-cosa.org

2nd Symposium Targeted Cancer Therapy November 19-20 • Heidelberg, Germany For more information: www.dfkz.de/en/symposiumTCT/ 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 2nd Annual Best of Oncology Conference November 30 • Toronto, Ontario For more information: www.oncologyeducation.com/ conferences/best-of-oncology-2012. html ASCO’s Quality Care Symposium November 30-December 1 • San Diego, California For more information: quality2012.asco.org Global Conference on Perioperative Medicine: Care of the Elderly and the Cancer Patient November 28-December 2 • Houston, Texas For more information: www.mdanderson.org/conferences

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

2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

The ASCO Post | SEPTEMBER 15, 2012

PAGE 72

In the News

CT Scans in Childhood Can Triple Risk of Leukemia and Brain Cancer Later in Life, Study Finds By Charlotte Bath In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

omputed tomography scans with cumulative doses of about 50 mGy received during childhood can nearly triple the risk of leukemia, and cumulative doses of about 60 mGy can triple the risk of brain cancer, according to a retrospective cohort study of patients who were younger than 22 when they received CT scans and had no previous cancer diagnoses. In their interpretation of the data, the authors of the study published in The Lancet1 noted that even though “the cumulative absolute risks are small,” they should be outweighed by the clinical benefits. “[R]adiation doses from CT scans ought to be kept as low as possible and alternative procedures, which do not involve ionising radiation, should be considered if appropriate,” they added. “This cohort study provides the first direct evidence of a link between exposure to radiation from CT and cancer risk in children,” said senior author Amy Berrington de González, PhD, Senior Investigator, Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI). “Ours is the first population-based study to capture data on every CT scan to an individual during childhood or young adulthood and then

measure the subsequent cancer risk.”2 In the time since the study was first published online in June, there has been much “positive feedback about the importance of the study findings from physicians, parents, and researchers,” Dr. Berrington de González commented to The ASCO Post. “However, it is too early at this point to know what the impact might be on practice. We will monitor levels of use and dose levels to assess the potential long-term impact.”

UK Data, U.S. Analysis Patients were scanned at National Health Service (NHS) Centres in Great Britain between 1985 and 2002. Data for cancer incidence, mortality, and loss to follow-up were obtained from the NHS Central Registry, which “holds computerized records of everyone registered with an NHS general practitioner in Great Britain (most residents),” the study authors noted. “To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT.” Leading the study were researchers from NCI and the Institute of Health and Society, Newcastle University, England. “The NCI scientists provided expertise in radiation epidemiology, radiation dosimetry, and statistical analysis,” Dr. Berrington de González explained. “The Intramural Research Program of the NCI also cofunded the study along with the United Kingdom Department of Health.” The study merited news coverage by BBC News as well as major media in the

Unique Considerations for Radiation Exposure in Children

here are three “unique considerations” for radiation exposure in children, according to Radiation Risks and Pediatric Computed Tomography (CT): A Guide for Health Care Providers, an educational leaflet for health-care providers that was developed by the NCI: ■■ Children are considerably more sensitive to radiation than adults, as demonstrated in epidemiologic studies of exposed populations. ■■ Children have a longer life expectancy than adults, resulting in a larger window of opportunity for expressing radiation damage. ■■ Children may receive a higher radiation dose than necessary if CT settings are not adjusted for their smaller body size. “As a result,” the NCI press release continues, “the risk for developing a radiation-related cancer can be several times higher for a young child compared with an adult exposed to an identical CT scan.”

■

Expect Questions from Parents

esults of a study finding that exposure to radiation from multiple CT scans in childhood can triple the risk of leukemia and brain tumors may cause some parents to question the overall benefit of CT scans and to directly question physicians. “The three key questions that parents can ask are: (1) Why is the test needed? (2) Will the results change the treatment decisions? and (3) Is there an alternative test?” noted the study’s senior author Amy Berrington de González, PhD, Senior Investigator, Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI). “If the test is clinically justified, then parents can be reassured that the benefits will easily outweigh the small long-term risks,” she said. Studies in which parents were given information regarding the risks and benefits of CT have shown that this did not result in reduced compliance, according to Radiation Risks and Pediatric Computed Tomography (CT): A Guide for Health Care Providers, published by the NCI. This approach did result in parents asking more informed questions of the care providers. The American College of Radiology (ACR) urged that the results of the study “should not keep parents from getting needed medical imaging care for their children, but should be discussed with their physician and factored into their shared decision-making before an imaging scan is performed.” The ACR statement also recommended that parents keep a record of their child’s x-ray history. “Parents should certainly discuss risk with their provider, but not refuse care that may save and extend their child’s life,” commented Marta Schulman, MD, Chair of the ACR Pediatric Imaging Commission.

■

United States, including National Public Radio, The New York Times, the Los Angeles Times, and The Wall Street Journal.

Highly Sensitive Tissues Among 178,604 patients included in the leukemia analysis, 74 were diagnosed with leukemia. Among 176,587 patients included in the brain tumor analysis, 135 were diagnosed with brain tumors. The investigators chose these two cancer sites because “the red bone marrow and brain are highly sensitive tissues, especially in children.” Dr. Berrington de González noted that “the thyroid and breast are also highly radiosensitive if exposed at a young age. However, these cancers are very uncommon in childhood, so we do not yet have enough cases in our population. Once we do, these will be the next priorities for investigation.” In the analysis of leukemia risk, 64% of the CT scans involved the head, and the rate was similar for the brain tumor analysis. The next most common sites of CT scans were the abdomen and/or pelvis and chest. These rates are “also very typical of the distribution today,” according to Dr. Berrington de González. “The risk of leukaemia was positively

associated with estimated doses delivered by CT scans to the red bone marrow (P = .0097), as was the risk of brain tumors associated with estimated doses delivered by CT scans to the brain tissue (P = .0001),” the authors stated. While leukemia and brain tumors are common childhood cancers, they are still relatively rare childhood diseases. According to the NCI, annual incidence rates in the United States for children from birth through age 21 are 4.3 per 100,000 for leukemia and 2.9 for brain cancers. “Because these cancers are relatively rare, the cumulative risks are small: in the 10 years after the first scan for patients younger than 10 years, one excess case of leukaemia and one excess case of brain tumour per 10,000 head CT scans is estimated to occur,” the investigators reported.

Number of Scans To reach the cumulative dose to the red bone marrow of 50 mGy estimated to nearly triple the risk of leukemia would “broadly speaking” require about 5 to 10 head scans with current scanner settings for children under 15, according to the authors. To reach the cumulative dose to the brain of 60 mGy

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 73

In the News

necessary to triple the risk of brain cancer would generally require about two to three CT scans with current settings. “Our understanding is that these estimates would also be typical of practice today in the United Kingdom and United States,” Dr. Berrington de González stated. The comparison groups for both analyses consisted of patients with cumulative doses of less than 5 mGy. An NCI press release about the study noted that while radiation dose levels for CTs have declined over the years, “the amount of radiation delivered during a single CT scan can still vary greatly and is often up to 10 times higher than that delivered in a conventional x-ray procedure.”2

early online release of the Lancet article (June 7, 2012). The brochure suggests that “communication between pediatric health care providers and radiologists can determine the need for CT and the technique to be used.” “There are standard indications for CT in children, and radiologists should

review reasons prior to every pediatric scan and be available for consultation when indications are uncertain. When appropriate, other modalities such as ultrasound or magnetic resonance imaging (MRI), which do not use ionizing radiation, should be considered,” according to the leaflet. Dr. Berrington de González noted,

“The radiation dose from conventional xrays are typically about 10 times smaller than CT. Use of these alternatives would be highly dependent on the clinical situation, but physicians can consult the ACR Appropriateness Criteria (http://www. acr.org/Quality-Safety/Appropriateness-Criteria) to assess what the best test

AMG 386: Phase III Clinical Trials in Ovarian Cancer

continued on page 74

Trials Now Enrolling

Using vs Not Using CT “This paper confirms that radiation, even in relatively low does, does lead to risk,” Alan W. Craft, MD, a coauthor of the paper and Emeritus Chair at Newcastle University said in an article in The Wall Street Journal.3 “There is no safe risk.” In a BBC news release, 4 he also noted, “There is a much greater risk of not doing a CT when it’s suggested. This study will push us to be even more circumspect about using it.” An American College of Radiology (ACR) news release stressed that quality and safety programs help ensure that medical imaging is safe and effective. “The authors correctly note that CT scanners from the period studied (1989–2003) used radiation doses much higher than those of today. Current protocols also allow for use of much lower dose than the study period,” according to the ACR. “As the authors highlight, providers are far more aware of the potential risks involved than in years past and are proceeding as if low doses of radiation cause harm.”5 In addition, the ACR statement noted: “Medical imaging exams are directly linked to greater life expectancy, declines in cancer mortality rates, and are generally safer and less expensive that the invasive procedures that they replace.”

Minimizing Radiation Doses “Physicians, other pediatric health care providers, CT technologists, CT manufacturers, and various medical and governmental organizations share the responsibility to minimize CT radiation doses to children,” according to Radiation Risks and Pediatric Computed Tomography (CT): A Guide for Health Care Providers,6 which is an educational leaflet for health care providers developed by the NCI and updated the same day as the

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

Primary

PFS

2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

ENDPOINTS

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

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)

The ASCO Post | SEPTEMBER 15, 2012

PAGE 74

Patient’s Corner

Being Well Informed Helped Me Cope with Breast Cancer

Doing research about my disease and being proactive in my care made me feel empowered instead of scared. By Kate Callahan, as told to Jo Cavallo

had been putting off getting a screening mammogram for a few years. When I finally made an appointment in March 2011 and was told that I needed a follow-up sonogram because the test had picked up a suspicious-looking mass in my right breast, I knew I was in trouble. A biopsy of the tumor showed that I had invasive ductal carcinoma. Because the tumor was small—2½ cm—my surgeon recommended a lumpectomy. Fortunately, the pathology report showed that the cancer had only spread to two axillary lymph nodes and that I had clear tumor margins, so the disease was classified as stage IIA. I was prescribed 28 sessions of adjuvant radiation therapy, no chemotherapy, and a daily dose of letrozole for 5 years. Even though my oncologist said that my prognosis looks good, I’m not taking anything for granted. Having always maintained a pretty healthy lifestyle, I’ve stepped it up since my breast cancer diagnosis, eliminating processed foods and sugar from my diet and increasing my exercise routine to stave off recurrence.

Challenges to Overcome My biggest concern from the start was the effect my diagnosis would have on my two daughters, aged 24 and 19. I wanted to keep them as calm as possible, and I put as positive a face on my ordeal as I could to keep them from being afraid. What helped me the most was the research I did on my type of breast

CT Scans in Childhood continued from page 73

is considered to be for a wide variety of diagnostic scenarios.” The NCI brochure also suggests adjusting exposure parameters for pediatric CT based on the individual child’s size and weight, limiting the region scanned to the smallest possible area, and considering lower mA and/or kVp settings for skeletal and lung imaging, and for some CT angiographic and follow-up examinations. The highest-quality images (requiring the most radiation) “are not always required to make diagnoses,” the NCI leaflet notes. “In many cases, lower-resolution scans are diagnostic. Providers should be

cancer. Being informed and proactive in my care was empowering to me, and I never felt panicky. I just stayed focused on becoming cancer-free. Along the way, I had to deal with a series of mishaps, including a methicillinresistant Staphylococcus aureus (MRSA) infection following my lumpectomy that was so serious I had to wear a

I never experienced real frustration as I went through my treatment and recovery, especially with some members of my medical team. Although I was assigned a nurse navigator to help me understand my treatment protocol and to answer my questions, she was so busy helping other patients, I never felt I was getting her full attention. My concerns

When you have cancer, it’s imperative to have a medical team you can count on to help you decipher the medical jargon being thrown at you and to get you through the maze of treatment options so you can make informed decisions about your care. —Kate Callahan

wound vacuum to drain the infection. Next, basement flood ruined furniture and mementoes from my daughters’ childhood and cost me $7,000 to clean up. Nevertheless, I wouldn’t allow myself to get discouraged. I looked at everything that was happening as a challenge to overcome, and that attitude really gave me—and my daughters— the courage to move forward.

Frustrations with the Medical Team Being successful at facing down challenges, however, didn’t mean that familiar with the dose descriptors available on CT scanners and minimize the use of CT examinations that use multiple scans obtained during different phases of contrast enhancement (multiphase examinations). These multiphase examinations result in a considerable increase in dose and are rarely necessary, especially in body (chest and abdomen) imaging.” The article in The Lancet pointed out that CT rates “have been rising rapidly in the developed world.” Asked if at least some of that increase could be due to availability of testing rather than strictly diagnostic need, Dr. Berrington de González responded, “Yes, despite the rises in many developed countries, rates of use still vary widely and seem to

were either dismissed or smoothed over. The same thing happened with the second nurse navigator I was assigned, but this time the consequences were more than just mere inconvenience. Four days after my lumpectomy, I called my nurse navigator to tell her that I had severe bloody leakage from my incision. She said to put a clean dressing pad on the wound and to call the office emergency number the next day, which was a Saturday, if the incision was still leaking. When I spoke to the on-call surgeon the next day and explained the problem, she told me to just change the dressing pad. be somewhat related to availability. For example, rates of CT scan use are seven times higher in the U.S. than in the UK. Strategies that could prevent rates from rising further are to avoid repeat testing in different facilities by transferring medical records, and using the ACR appropriateness criteria to ensure that an examination is clinically justified.”

■

Disclosure: Dr. Berrington de González reported no potential conflicts of interest.

References 1. Pearce MS, Salotti JA, Little MP, et al: Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: A retrospective cohort study. Lancet 380:499-505, 2012.

By the time I saw my surgeon for my regular follow-up appointment 3 days later, I had a raging MRSA infection. Having breast cancer put me in unchartered territory. I was depending on my medical team to help me understand what was happening to me and to help me get well. It’s not that I think that the nurse navigators were incompetent. I think they were just overburdened with too many patients and didn’t fully embrace the patient-centered medical home model being practiced in my hospital, which is meant to keep the focus on the patients.

Importance of Self-advocacy What I’ve learned from this experience is that patients have to be their own best health-care advocates. While my oncologist and radiologist have been very proactive and I’m very satisfied with them, I still believe a patient has to face a cancer diagnosis armed with the most accurate information available and persistently ask questions if anything is unclear or when problems arise. When you have cancer, it’s imperative to have a medical team you can count on to help you decipher the medical jargon being thrown at you and to get you through the maze of treatment options so you can make informed decisions about your care. Unfortunately, that was not always my experience.

■

Kate Callahan is an adult aftercare specialist in a mental health agency in Annapolis, Maryland.

2. National Cancer Institute: NIH study finds childhood cancer CT scans linked to leukemia and brain cancer later in life. Press release, June 7, 2012. Available at www.cancer.gov. Accessed July 31, 2012. 3. Wang SS: Children’s CT scans pose cancer risk. Wall Street Journal. June 7, 2012. 4. Dreaper J: CT scans on children ‘could triple brain cancer risk.’ BBC News. June 6, 2012. 5. American College of Radiology: Pediatric CT scans save lives when used appropriately. Press release, June 6, 2012. Available at www.acr.org. Accessed August 22, 2012. 6. National Cancer Institute: Radiation risks and pediatric computed tomography (CT): A guide for health care providers. Available at www.cancer.gov. Accessed July 31, 2012.

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 Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

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

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

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: 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. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

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

JAK targeted to make a difference

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 trans16.8% 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 registered 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 © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: June 2012 RUX-1040a

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In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Enzalutamide Significantly Prolonged Survival in Men with Castrate-resistant Metastatic Prostate Cancer “Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy” in an international phase III, doubleblind, placebo-controlled trial, investigators reported in The New England Journal of Medicine. Median overall survival, the primary endpoint, was 18.4 months among the 800 men randomly assigned to receive oral enzalutamide at 160 mg per day vs 3.6 months among 399 patients receiving placebo (P < .001). The men were stratified according to Eastern Cooperative Oncology Group performance status score (0 or 1 vs 2) and pain intensity (no pain to mild pain vs moderate to severe pain). The study was stopped after a planned interim analysis showed a 37% reduction in the risk of death with enzalutamide vs placebo. “On the basis of these results, an independent data and safety monitoring committee recommended that the study be halted and unblinded, with eligible patients in the placebo group offered treatment with enzalutamide,” the authors wrote. “The superiority of enzalutamide over placebo was shown with respect to all secondary endpoints,” the investigators stated. These included the pro-

portion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs 2%, P < .001); time to PSA progression (8.3 vs 3.0 months, HR = 0.25, P < .001); radiographic progression-free survival (8.3 vs 2.9 months, HR = 0.40, P < .001); soft-tissue response rate (29% vs 4%, P < .001); time to first skeletalrelated event (16.7 vs 13.3 months, HR = 0.69, P < .001); and qualityof-life response rate (43% vs 18%, P < .001). Formerly known as MDV3100, enzalutamide “targets multiple steps in the androgen receptor–signaling pathway, the major driver of prostate-cancer growth,” according to the AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) investigators.

Adverse Events Compared with the placebo group, men in the enzalutamide group had a lower incidence of grade 3 or higher adverse events (45.3% vs 53.1%) and a longer median time to the first such adverse event (12.6 vs 4.2 months). Fatigue, diarrhea, and hot flashes were reported more frequently in the enzalutamide group. Seizures were not reported in the placebo group, but were reported in 5 (0.6%) of the men receiving enzalutamide, and the drug was discontinued. “Caution should be used in administering enzalutamide to patients with a history of seizure or who have other predisposing factors, including under-

lying brain injury, stroke, brain metastases, or alcoholism, or to patients receiving concomitant medication that may lower the seizure threshold,” the investigators noted. The authors anticipated that enzalutamide would “join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy. Clinical trials of enzalutamide in earlier-stage prostate cancer are ongoing.” Scher HI, et al: N Engl J Med. August 15, 2012 (early release online).

COLORECTAL CANCER Cetuximab Dose Escalation May Increase Responses among Patients with Mild or No Initial Skin Reactions Escalating the dose of cetuximab (Erbitux) among patients with metastatic colorectal cancer who developed no or mild skin reactions on standard-dose cetuximab plus irinotecan “seemed to lead to an increase in response rate” as well as in the diseasecontrol rate, according to a phase I/ II study reporting clinical and pharmacokinetic data. Patients receiving escalated doses did not, however, have clear benefits in progression-free or overall survival compared to patients maintained on the standard cetuximab regimen. The Evaluation of Various Erbitux Regimens by Means of Skin and Tumor Biopsies (EVEREST) study included 89 patients with no or grade 1 skin reactions in the first 21 days of treatment with standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan. Patients were randomly assigned to either continue the standard dose (group A, 45 patients) or to be doseescalated to 500 mg/m2 per week (group B, 44 patients). The weekly doses “were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups,” the investigators stated. Dose escalation was associated with an in-

crease in grade 2 or greater skin reactions, occurring in 59% of patients in group B vs 38% in group A. The overall response rate was higher in group B (30% vs 16%), as was disease control rate (70% vs 58%), “although neither difference reached statistical significance,” the authors reported. Moreover, “there was no significant difference between these treatment groups for [progression-free or overall survival]. There was a tendency for a greater reduction in tumor size after response to treatment in group B than in group A.”

Genetic Marker As in other randomized studies of cetuximab combined with chemotherapy in patients with metastatic colorectal cancer, “clinical outcomes were significantly superior for evaluable patients with KRAS wild-type compared with mutant tumors. Indeed, all but one of the patients with partial responses in the current study had KRAS wild-type tumors (35 of 89 patients with wild-type tumors vs 1 of 57 patients with mutant tumors),” the investigators noted. “The [overall response rate] in patients with KRAS wild-type tumors with no or mild skin reactions after 21 days receiving a dose increase of cetuximab (group B) was 43% compared with 30% in patients treated with the standard dose (group A). We do not consider this difference to be practicechanging in view of the sample size of the study,” the authors wrote. In an ongoing larger prospective study (EVEREST 2) of first-line treatment for metastatic colorectal cancer, patients without rash receive progressively higher doses of cetuximab.

Van Cutsem E, et al: J Clin Oncol 30:2861-2868, 2012.

Patients with Unresectable Metastases Can Be Spared Noncurative Resection of Intact Primary Tumor Patients with surgically unresectable metastatic colon cancer and an asymptomatic intact primary tumor can be spared initial noncurative resection of their intact primary tumor, National Surgical Adjuvant Breast and Bowel Project (NSABP) C-10 trial investigators reported in the Journal of Clinical Oncology. All 86 continued on page 80

The ASCO Post | SEPTEMBER 15, 2012

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In the Literature

Emerging Clinical Data continued from page 79

enrolled patients received infusional fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6) combined with bevacizumab (Avastin). “Combining [modified FOLFOX6] with bevacizumab did not result in an unacceptable rate of obstruction,

perforation, bleeding, or death related to [the intact primary tumor]. Survival was not compromised,” the investigators stated. “The primary objective of this trial was to determine the rate of major morbidity resulting from the presence of the [intact primary tumor] in patients treated initially with FOLFOX plus

bevacizumab,” the authors explained. Any event related to the intact primary tumor that led to surgery or death was considered a major morbidity. Specifically, the primary endpoint was defined as “colonic bleeding, perforation, bowel obstruction, or fistula formation requiring surgery or resulting in patient death.” Results showed that 86% of pa-

InsIght

Initial Treatment Controversial

NEW iN EvERy iSSuE Of

JnCCn

The authors noted that the initial treatment approach is controversial for patients with unresectable metastatic disease and an asymptomatic intact primary tumor. While initial resection of the primary tumor has been advocated to prevent future complications of colonic obstruction, bleeding, or perforation, “the 30-day operative mortality of colon resection for patients with distant metastases is as high as 10%.” Retrospective series have suggested that with current chemotherapy regimens, problems related to the intact primary tumor may occur in 10% to 20% of patients. FOLFOX combined with bevacizumab has demonstrated improved overall survival in patients with metastatic colorectal cancer, but use of “bevacizumab has previously raised concerns of increased risk of tumor perforation for patients with [an intact primary tumor],” the authors wrote. In the current study, the cumulative incidence of major morbidity was 16.3% at 24 months. “Importantly, we identified perforation of the [intact primary tumor] as a relatively rare event that should dispel a widespread and persistent reluctance to use bevacizumab” in this setting, the researchers reported. ”We believe this approach of primary systemic treatment with expectant observation … should define a new standard of care,” the investigators concluded.

NEW

Read the September Issue of JNCCN:

NEW

• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Adolescent and Young Adult Oncology NCCN Guidelines® insights: prostate Cancer, Version 3.2012 In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

tients did not develop symptoms from the intact primary tumor that required surgery or problems resulting in death. “Of the 10 surgeries performed for symptoms related to the [intact primary tumor], only four (4.7%) were urgent among all 86 patients, and only three patients (3.5%) required permanent ostomies,” the researchers reported. “There were two patient deaths in which the [intact primary tumor] was likely a contributing cause.”

DOwNlOAD the JNCCN App Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.

• Hypofractionated Whole Breast Radiation and Partial Breast Radiation for Early-Stage Breast Cancers • Metastatic Mucinous Ovarian Cancer and Treatment Decisions Based on Histology and Molecular Markers Rather Than the Primary Location • Management of Extramedullary Leukemia as a Presentation of Acute Myeloid Leukemia

McCahill L, et al: J Clin Oncol August 6, 2012 (early release online).

IMAGING STUDIES High-cost Imaging Used Frequently in Elderly with Stage IV Cancer Register for your free subscription at JNCCN.org

AD_JNCCN_App_General (TAP-Island).indd 1

Patients with stage IV breast, colorectal, lung, and prostate cancers undergo frequent high-cost imaging procedures throughout the continuum of their care, and rates of imaging 8/31/12 2:33 PM

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In the Literature

have steadily increased, according to an analysis of claims from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. These imaging procedures included computed tomography (CT), magnetic resonance imaging (MRI), positron-emission tomography (PET), and nuclear medicine (NM) scans. “Among the stage IV patients diagnosed between January 2002 and December 2006, 95.9% underwent a high-cost diagnostic imaging procedure, with a mean number of 9.79 (SD = 9.77) scans per patient and 1.38 (SD = 1.24) scans per-patient per-month of survival,” the researchers reported. “After the diagnostic phase, 75.3% were scanned again; 34.3% of patients were scanned in the last month of life.” CTs were the most commonly used imaging procedures, with 93.7% of patients receiving at least one CT and most receiving several CTs. “Currently, few guidelines attempt to define the appropriate role of imaging in patients with advanced disease, and those that do largely reflect expert opinion. Routine use of imaging is recommended only in patients with colorectal cancer metastatic to the liver or lung; in such patients, the National Compre-

hensive Cancer Network (NCCN) advises a CT or MRI every 2 months after initiating chemotherapy to reevaluate for resectability, followed by every 2 to 3 months during palliative chemotherapy if conversion is not accomplished. In stage IV breast, lung, and prostate cancer, the guidelines either do not specify parameters for testing or advocate use

only as indicated by symptomatology,” the investigators noted. “Despite these recommendations, we found that the vast majority of patients with breast, lung, and prostate cancer undergo imaging after diagnosis at rates similar to (or higher than) that of the colorectal subset,” the authors continued. “Such discretionary deci-

sion-making, ie, the ‘gray’ area where recommendations are equivocal or nonexistent, is known to drive higher healthcare spending.”

■

Hu Y-Y, et al: J Natl Cancer Inst 104:1164-1172, 2012.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life? Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

Using QR Codes

Look inside for these important topics! • Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

When you see a code that you would like to scan, start your code-reading application.

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

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About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

The ASCO Post | SEPTEMBER 15, 2012

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Letters to the Editor

More Thoughts on PSA continued from page 2

tute, Methods in Cancer Research, and Journal of Urology, and some of these publications have been celebrated by the American Urological Association, Journal of Urology, and American Association for Cancer Research as “landmark,” practice-changing pa-

pers. This record contrasts with the paucity of material supporting Dr. Ablin’s claims.

Acknowledging Limits and Benefits The PSA test has its limits, to be sure. Dr. Ablin notes correctly that PSA testing is not, of itself, an indi-

cator of prostate cancer aggressiveness. However, PSA, when used in combination with prior PSA values, Gleason score, and tumor stage, is a very good tool for assessing prostate cancer aggressiveness. An important fact left out of the recent article is that prostate cancer mortality in America has fallen by

2013 ASCO Special Awards Nomination Period Open ASCO’s Special Awards are the Society’s highest and most prestigious awards. Including time-honored awards such as: • American Cancer Society Award and Lecture • B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology • David A. Karnofsky Memorial Award and Lecture • Distinguished Achievement Award • Gianni Bonadonna Breast Cancer Award and Lecture • Humanitarian Award • Partners in Progress Award

more than 40% since the introduction of the PSA test. PSA has revolutionized our ability to detect prostate cancer in its early stages and monitor the effectiveness of treatment. Before we had the PSA test, very few men diagnosed with prostate cancer could be cured and too many were diagnosed with prostate cancer when it had spread to their bones and caused pain. We share Dr. Ablin’s apprehensions about improper use of PSA testing and overtreatment of prostate cancer. There is legitimate concern that indiscriminate use of the PSA test may overdiagnose prostate cancer and put men at risk for complications from unnecessary treatments. The value of PSA for early detection of prostate cancer has been diminished by its application to older men who are at low risk of death from prostate cancer; unfortunately, as many as one-fourth of American men over 85 have had a PSA measured in the past year. But it’s not the use of the PSA test that’s at the root of the national debate—it’s how physicians and patients respond to the information it yields. In up to 40% of men in whom prostate cancer is detected by an elevated PSA, the cancer probably does not require treatment. But to cease all use of PSA testing in asymptomatic men, as Dr. Ablin and the U.S. Preventive Services Task Force would have us do, would almost certainly return us to the days when most men who were diagnosed with prostate cancer were likely to die a long, painful death from it.

• Pediatric Oncology Award and Lecture

Appropriate Use

• Public Service Award

There is a reasonable way to use PSA appropriately that is based on reliable medical evidence: Use PSA testing to detect prostate cancer in men who are at increased risk for developing aggressive prostate cancer and who will live long enough to suffer death from prostate cancer. Men should: ■■ Know their risk for developing prostate cancer, which is considerably higher if they are African American or have a father or brother who developed the disease prior to age 65 ■■ Have their PSA levels tested according to the recommendations of any of the three main prostate cancer guidelines organizations—the National Comprehen-

• Science of Oncology Award and Lecture • Special Recognition Award To find out more about these awards, including the criteria and how to make a nomination, please visit asco.org/specialawards.

Nomination period closes October 5, 2012. Individuals may be nominated for more than one award as long as they meet the criteria for each. Nominating an individual requires answering a few questions concerning the nominee’s qualifications for that particular ASCO award. If you have any questions or need assistance, please contact specialawards@asco.org.

ASCOPost.com | SEPTEMBER 15, 2012

PAGE 83

Letters to the Editor

sive Cancer Network (NCCN), the American Urological Association, or the American Cancer Society ■■ Make any decisions about whether and how to treat their prostate cancer after weighing their options— including deferring treatment in favor of active surveillance, observation, operation, and radiation— carefully and in consultation with their physician. This is a straightforward, effective approach to using PSA—appropriately—for early detection of prostate cancer.

Challenging and Urgent Need We agree that the need for a more precise early-detection tool is both challenging and urgent. Researchers at RPCI and other institutions are focused on developing a test that will distinguish aggressive cancers from those that are slow-growing and not life-threatening, so that appropriate treatment decisions can be made more easily. While Dr. Ablin is entitled to share his views on the merits and limitations of PSA testing, your readers deserve to be accurately informed about his accomplishments. Dr. Ablin had no role in the discovery of the molecule now known as PSA or in development of the PSA test used worldwide, and has not been involved in the clinical diagnosis or treatment of prostate cancer. Publications that continue to misidentify Dr. Ablin as the discoverer of, and an authority on, PSA may seek to “add clarity to this ongoing debate,” but they do just the opposite. James Mohler, MD Chair, Department of Urology, Roswell Park Cancer Institute Chair, National Comprehensive Cancer Network Prostate Cancer Guidelines Panel

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Donald L. Trump, MD President & CEO, Roswell Park Cancer Institute References 1. Letter to the Editor and Reply Re: Carl S. Killian et al. Prognostic importance of prostate-specific antigen for monitoring patients with stage B2 to D1 prostate cancer. Cancer Res 45:5984-5985, 1985. 2. Wang MC, Valenzuela LA, Murphy GP, Chu TM: Which prostate antigen is which? Clin Chem 31:1405-1406, 1985.

Dr. Ablin’s Reply

iven my explanation and widely publicized opinion on the improper use of the prostate-specific antigen (PSA) test for screening asymptomatic men for prostate cancer—most recently expressed in a

A scientific misunderstanding continues…as to who did what and when on the subject of PSA. —Richard J. Ablin, PhD, DSc (Hon)

feature article in The ASCO Post (August 15, 2012)—I was pleased to read that Drs. James Mohler and Donald L. Trump share my concern in what they describe as “apprehensions about improper use of PSA testing and overtreatment of prostate cancer.” However, beyond this, a scientific misunderstanding continues, perpetuated by Dr. Mohler, and now Dr. Trump, as to who did what and when on the subject of PSA.

Chronology Reconsidered Drs. Mohler and Trump’s claim that “Dr. Ablin had no role in the discovery of the molecule now known as PSA” is not only patently false but also ironic, considering a direct quote from Milestones in Urology: Advances in Patient Care, a commemorative calendar and monograph published in 2001 by the American Urological Association (AUA): “The PSA test is a product of many minds collaborating over many decades. In 1970, immunologist R. J. Ablin, of the State University of New York, Buffalo, initially observed PSA. Roswell Parks’ T. Ming Chu, with other investigators set out to extend Ablin’s observations.” Moreover, the consensus from any of a number of papers in the literature is clear and unified, eg, in quoting Polascik et al1: “PSA was first identified in human prostate tissue extracts in 1970 [Ablin et al: J Reprod Fert 22:573-574, 1970], purified and characterized in 1979 [Wang et al: Invest Urol, 17:159163, 1979] … ” The PSA test was subsequently initiated by Papsidero et al.2 I have never claimed a role in the test’s development. Drs. Mohler and Trump’s statement—“Dr. Ablin discovered a ‘pros-

tate-specific antigen’ that appears in normal prostate tissue, but [Chu] identified and purified another protein … from normal, benign, and malignant human prostate tissue,”—is once again thoroughly contradicted by the literature: Ablin et al3,4 referenced ongoing studies in the benign and malignant human prostate, which were subsequently reported by Ablin.5 Further, Drs. Mohler and Trump assert that, “Dr. Ablin’s antigen was found only in the normal prostatic tissue,” while Dr. Chu’s PSA is found not only in prostate tissue but also in prostatic fluid and semen, and they try torturing their assertion into fact by referencing published exchanges between Chu and me. There is either an incongruity in semantics regarding what our studies actually showed or a misunderstanding of the results by Drs. Mohler and Trump. In this regard, a subsequent paper by Wang et al6 concluded that PSA in seminal plasma originated from prostatic fluid, which is what I demonstrated in Ablin et al.3,4

Volumes of Articles Surprisingly, Drs. Mohler and Trump rolled out the tanks in comparing Chu’s impressive “practice-changing” publishing history against “the paucity of material supporting Dr. Ablin’s claims.” I can cite volumes of articles in journals such as Cancer, Urology, Cancer Treatment Reviews, Prostate, etc, that attribute the discovery of PSA to me. Again, the physics of their posture is wrong, because no amount of volume can displace a fact that is indelible in the literature: I discovered PSA. Given Drs. Mohler and Trump’s anxiety over erroneous information, perhaps they should look inward at the initial report by Chu7 in what was described as prostate tissue–specific antigen. Therein, Wang et al stated that the prostate tissue–specific antigen they identified “was not of glycoprotein nature” and had “a molecular weight of 220,000 Daltons” (22 kilodaltons [kDa]). This finding starkly contrasts with their 1979 paper in Investigative Urology,8 in which they affirmed that prostate tissue–specific antigen is a glycoprotein with a molecular weight of 33 kDa. Additionally, Wang et al7 claimed to have identified a prostate tumor– specific antigen! If that were true, you can be certain that all of us of still looking for a prostate tumor– specific antigen would have heard of

it. To my knowledge, it has not yet been identified.

Remaining Optimistic Redressing Drs. Mohler and Trump’s arguments for using PSA testing as a diagnostic tool is beyond the scope of this reply. That said, I remain firm: Routine PSA screening in asymptomatic men is a national health-care disaster. The U.S. Preventive Services Task Force, along with a growing number of scientists and clinicians concur. Drs. Mohler and Trump will likely continue their efforts to discredit my role in the PSA saga—casting doubt on the messenger is an age-old ploy to cast doubt on the message. Through it all, however, I remain optimistic that unbiased science will eventually prevail, and the misuse of the PSA molecule I discovered in 1970 will come to an end. Richard J. Ablin, PhD, DSc (Hon) Department of Pathology University of Arizona College of Medicine The Arizona Cancer Center and BIO5 Institute Tucson, Arizona

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References 1. Polascik TJ, Oesterling JE, Partin AW: Prostate specific antigen: A decade of discovery—what we have learned and where we are going. J Urol 162:293-306, 1999. 2. Papsidero LD, Wang MC, Valenzuela LA, et al: A prostate antigen in sera of prostatic cancer patients. Cancer Res 40:24282432, 1980. 3. Ablin RJ, Soanes WA, Bronson P, et al: Precipitating antigens of the normal human prostate. J Reprod Fert 22:573-574, 1970. 4. Ablin RJ, Bronson P, Soanes WA, et al: Tissue- and species-specific antigens of normal human prostatic tissue. J Immunol 104:1329-1339, 1970 5. Ablin RJ: Immunologic studies of normal, benign, and malignant human prostatic tissue. Cancer 29:1570-1574, 1972. 6. Wang MC, Loor RM, Li SL, et al: Physico-chemical characterization of prostate antigen purified from human prostate gland and seminal plasma. IRCS J Med Sci 11:327-329, 1983. 7. Wang MC, Valenzuela LA, Murphy GP, et al: Tissue specific and tumor specific antigens in human prostate. Fed Proc 36:1254, 1977. 8. Wang MC, Valenzuela LA, Murphy GP, et al: Purification of a human prostate specific antigen. Invest Urol 17:159-163, 1979.

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.