TAP Vol 4 Issue 10 by Harborside Press LLC

Laparoscopic vs Open Surgery for Rectal Cancer

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VOLUME 4, ISSUE 10

JUNE 25, 2013

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

ASCOPost.com

ASCO Annual Meeting

GM-CSF Boosts Survival Benefit of Ipilimumab in Metastatic Melanoma

It’s Déjà Vu All Over Again

By Caroline Helwick

By Joseph M. Connors, MD

or metastatic melanoma, the activity of ipilimumab can be boosted by the addition of granulocyte-macrophage colonystimulating factor (GMCSF, Leukine), according to a phase II study that found the combination improved overall survival, vs ipiF. Stephen Hodi, MD limumab alone. The results were presented at the 2013 ASCO Annual Meeting.1 “Ipilimumab has been shown to improve survival in metastatic melanoma and is FDA-approved. The question then becomes, ‘How can we improve on this treatment?’” said lead investigator F. Stephen Hodi, MD, Associate Professor of Medicine at Harvard Medical School and Director of the Melanoma Center at Dana-Farber Cancer Institute, Boston.

“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” he said at an ASCO press briefing.

Study Rationale GM-CSF is a chemical signal in the immune system that enhances granulocytes and macrophages. Ipilimumab is an antibody that “takes the brakes off ” the CTLA-4–associated immune blockade. In mice, CTLA-4 blockade and GM-CSF–secreting tumor vaccine combinations have demonstrated synergy, which provides the rationale for trying this approach in metastatic melanoma patients, Dr. Hodi explained. continued on page 5

Perspective

Financial Revamping of Medical Education By Richard J. Boxer, MD, FACS

he American medical education system was in a state of crisis in 1910 when Abraham Flexner published his treatise, Report on Medical Education in the United States and Canada (Carnegie Foundation Bulletin Number Four).1 A century later, we face another crisis in medical education— not in terms of its scientific foundation or quality standards as in Flexner’s exposé, but in its financial basis. According to a report from the Association of

American Medical Colleges (AAMC), the median 4-year cost of attending a U.S. medical school ranges from $187,000 (public school) to $264,000 (private school).2 Moreover, the median cost of medical school has grown at almost twice the rate of inflation, and the median debt medical students have at graduation is staggering.

Squeezed Tighter Each Year

It is estimated that 86% of medical students have substantial educational debt; the average debt is $205,674 for osThe median cost of medical school teopathic medicine stuhas grown at almost twice the rate dents and $162,000 for allopathic students.3-5 of inflation, and the median debt According to the AAMC, medical students have at graduation is depending on the repayment structure, a medistaggering. cal school graduate with —Richard J. Boxer, MD, FACS $162,000 of debt would

ogi Berra offered the comment “It’s déjà vu all over again” when he witnessed Mickey Mantle and Roger Maris repeatedly hitting back-to-back home runs in the early 1960s. His pithy remark neatly summarizes my reaction when I read the article, “DoseAdjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma,” by Drs. Dunleavy, Wilson, and colleagues in The New England Journal of Medicine.1 The report nicely caps more than a decade of clinical investigation carried out by Dr. Wilson’s group at the National Cancer Institute, focused on the use of infusional immunochemotherapy to treat various aggressive non-Hodgkin lymphomas (see a summary of the report on page 23 of this issue of The ASCO Post). Briefly, this group demonstrated continued on page 27

Dr. Connors is Clinical Director, BC Cancer Agency Centre for Lymphoid Cancer, Vancouver, British Columbia.

MORE IN THIS ISSUE ASCO Annual Meeting Gynecologic Cancers �� 2, 22 Thyroid Cancer �� 3 Melanoma �� 5, 10 Breast Cancer �� 11, 14 KRAS Status and Lung Cancer �� 30 Direct from ASCO �� 40–43 Oncogenic Mutations in Leukemia �� 54 Hand-Foot Syndrome �� 69 FDA Update �� 13, 29, 72, 86, 98 Pioneers in Oncology: Janet D. Rowley, MD �� 97

continued on page 12

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The ASCO Post | JUNE 25, 2013

PAGE 2

ASCO Annual Meeting Plenary Presentation

Practice-changing Study Shows Survival Benefit for Antiangiogenesis in Advanced Cervical Cancer By Alice Goodman

antiangiogenic drug increased ogy at University of California, Irvine. overall survival and also im‘Paradigm Shift’ proved progression-free sur“This study is the first one to show vival and response rates. No an overall survival benefit in cervinew side effects were reported, cal cancer. This represents a paradigm and all serious adverse events shift. Cervical cancer occurs mainly occurred in less than 10% of in young women, who suffer the bulk patients. Further, the addition of the disease burden,” said Jyoti D. of bevacizumab did not come Patel, MD, Associate Professor of Krishnansu S. Tewari, MD Jyoti D. Patel, MD at an increased cost in quality Medicine at Robert H. Lurie Compreof life,” stated Krishnansu S. he addition of bevacizumab (Avashensive Cancer Center of NorthwestTewari, MD, Assistant Professor in the tin) to chemotherapy prolongs ern University in Chicago, who modDepartment of Obstetrics & Gynecoloverall survival in women with metastatic cervical cancer compared with chemotherapy alone, according to the Bevacizumab plus Chemotherapy in Cervical Cancer results of a randomized phase III study presented at the Plenary Session of the ■ The addition of bevacizumab to chemotherapy extended survival by about ASCO Annual Meeting.1 Women on the 4 months in women with metastatic cervical cancer. bevacizumab-containing arms lived an ■ This is the first targeted agent to improve overall survival in a gynecologic average of 4 months longer than those cancer. on chemotherapy alone. ■ This study provides a platform for trials of other antiangiogenic agents in “This study was a triple-header. The this setting. combination of chemotherapy plus an

Simple Rapid Vinegar Test Cuts Cervical Cancer Death Rates by One-third in Rural India

erated a press conference devoted to Plenary Session presentations. More than 500,000 cases of cervical cancer and 250,000 related deaths are reported each year worldwide. Approximately 4,000 women die of cervical cancer each year in the United States, and the death rate is so low because of Pap screening. Human papillomavirus (HPV) infection causes cervical cancer, and the average age at diagnosis is 47 years. Treatment options are limited for advanced-stage disease and for relapses. Cisplatin/paclitaxel doublet is the standard of care. “Although standard chemotherapy can cure patients, those who relapse after initial treatment are resistant to cisplatin. The drug is less effective due to previous exposure to cisplatin, continued on page 18

Plenary Presentation

By Alice Goodman

n the era of personalized medicine for cancer care, it was both surprising and encouraging to hear about a simple lowtech intervention delivered by women in the community that cut the rate of death from cervical cancer in India by about one-third. The intervention, a simple vi-

Meeting Plenary Session.1 “Today’s results show that progress can happen at both ends of the technology spectrum—from cutting-edge drugs to the simple use of vinegar to detect cervical cancer. Using primary health-care workers and a simple technique saved

There is no national cancer screening program in India, and Pap screening is not feasible because of an inadequate infrastructure, high cost, and other factors. —Surendra Shastri, MD

sual inspection after acetic acid (vinegar) is applied to the cervix with a cotton swab, could prevent about 22,000 deaths from cervical cancer in India each year and close to 72,000 deaths each year in the developing world. A study of the technique was reported at the ASCO Annual

lives. Congratulations!” said press conference moderator Jyoti D. Patel, MD, Associate Professor of Medicine at Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. “This study has tremendous implications for women around the world, because

cervical cancer affects the most disadvantaged women in every society.”

Education Is the Key to Screening “Cervical cancer is the number 1 cause of cancer-related death in India and in most parts of the developing world. But in the developed world, the incidence has declined due to screening. There is no national cancer screening program in India, and Pap screening is not feasible because of an inadequate infrastructure, high cost, and other factors,” explained lead author Surendra Shastri, MD, Head of the Department of Preventive Oncology at Tata Memorial Centre in Mumbai, India. The study included more than 150,000 women from 20 slum clusters in Maharashtra, a state in western India. Aged 35 to 64 years and with no history of cancer, the women were randomly assigned to undergo screening by visual inspection with application of acetic acid to the cervix (75,360) or no screening (76,178). The screening technique was performed by women in the community

who had at least a 10th grade education and good communication skills. It takes 1 minute to obtain results from the screening test. After vinegar is applied to the cervix, if white areas appear in or near the transformation zone on the endocervix and/ or ectocervix, the result is considered positive; if not, it is negative. The paramedical community workers were trained to perform the technique over a 4-week session. Both groups received cancer education and biennial monitoring for cervical cancer; the screening group also received four rounds of biennial visual inspection with acetic acid screening delivered by the primary health workers. In the screening group, women with positive results were referred to the Tata Memorial Hospital for confirmation of diagnosis, whereas in the control group, women with signs of cervical cancer were directed to the Tata Memorial Hospital or other private continued on page 20

ASCOPost.com | JUNE 25, 2013

PAGE 3

ASCO Annual Meeting Head and Neck Cancer

Sorafenib Halts Disease Progression in Metastatic Differentiated Thyroid Cancer By Caroline Helwick

or the first time in decades, a drug has halted disease progression in treatment-resistant differentiated thyroid cancer, according to the results of a phase III study presented at the 2013 ASCO Annual Meeting.1

radioactive iodine, many patients require repeated radioactive iodine treatments, and 5% to 15% develop resistance to it. In this subset, median survival is around 2.5 to 3.5 years and disease-related complications are common, she said. The fact that the 89-center study rapidly enrolled hundreds of patients “speaks to the unmet needs of these patients,” she said.

Progression-free Survival Improvement Marcia Brose, MD, PhD

No new drugs have been approved for differentiated thyroid cancer in 40 years, but this could soon change. In patients with the disease who were refractory to radioactive iodine therapy, sorafenib (Nexavar) significantly prolonged progression-free survival by 5 months, reported Marcia Brose, MD, PhD, Assistant Professor of Otolaryngology and Head and Neck Surgery at the University of Pennsylvania Perelman School of Medicine, Philadelphia.

DECISION Trial “DECISION is the first phase III study of a targeted agent in radioactive iodine–refractory differentiated thyroid cancer, which is a rare condition with a poor prognosis and no effective standard treatment,” Dr. Brose said. “Sorafenib is a potential new treatment option for these patients.” Differentiated thyroid cancer is the most common subtype of thyroid cancer, with an estimated 60,000 new cases a year and 1,850 related deaths. While most patients can be cured by surgery and

DECISION was a randomized, double-blind, placebo-controlled phase II trial in which 417 patients with radioactive iodine–refractory, locally advanced or metastatic differentiated thyroid cancer were randomly assigned to sorafeninb, 400 mg twice daily, or placebo until disease progression. Sorafenib was available to nonresponding placebo recipients in the open-label component of the trial. Median progression-free survival was 10.8 months in the sorafenib arm vs 5.8 months in the placebo arm (hazard ratio = 0.587; P < .0001). Response by RECIST criteria was observed in 12.2% of the sorafenib arm vs 0.5% of the placebo arm (P < .0001). .0001). Stable disease was observed in an additional 41.8% of patients receiving sorafenib, vs 33.2% with placebo, reflecting disease control rates of 54.1% and 33.8%, respectively (P < .0001). The median duration of response to sorafenib was 10.2 months. Median overall survival has not been reached in either arm, but there is currently a 20% non–statistically significant reduction in mortality with sorafenib, despite a 71% rate of crossover to sorafenib. The adverse event profile was simi-

Sorafenib for Differentiated Thyroid Cancer ■ Patients with locally advanced or metastatic differentiated thyroid cancer that was refractory to radioactive iodine had a 5-month improvement in progression-free survival with sorafenib treatment, vs placebo.

■ This is the first effective treatment for this patient population in decades.

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

lar to the known toxicity profile for the multi–tyrosine kinase inhibitors. Serious adverse events were observed in 37.2% of the sorafenib arm and 26.3% of the placebo arm, including secondary malignancies (4.3% vs 1.9%), pleural effusion (2.9% vs 1.9%), and dyspnea (3.4% vs 2.9%). One drug-related grade 5 event occurred in each arm. Dose modifications due to adverse events were necessary in 77.8% and 30.1%, respectively, and permanent discontinua-

tions due to toxicity were seen in 18.8% and 3.8%, respectively. n Disclosure: Dr. Brose has served in a consultant or advisory role for Bayer and Onyx, and has received honoraria or research funding from Bayer.

Reference 1. Brose MS, Nutting C, Jarzab B, et al: Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. 2013 ASCO Annual Meeting. Abstract 4. Presented June 2, 2013.

EXPERT POINT OF VIEW

“T

hese patients finally have options,” commented the DECISION trial’s discussant at the ASCO Plenary Session, Ezra Cohen, MD, Associate Professor of Medicine and Associate Director for Education at the University of Chicago Comprehensive Cancer Center. He further noted that differentiated thyroid cancer is a cancer on the rise worldwide. But while Dr. Cohen was enthusiastic about the findings, he noted that not all iodine-refractory patients require treatment. Ezra Cohen, MD Interestingly, 25% of placebo recipients did not show disease progression while on study, he said. In addition, other studies show that patients who are negative for positronemission tomography (PET) avidity have a median overall survival of more than 3 years, and in clinical practice, most radioactive iodine–refractory patients are asymptomatic, he reminded oncologists.

Treatment Decision Factors “Clearly, there are patients who do not need immediate treatment,” Dr. Cohen emphasized. He would, therefore, base his decision to use sorafenib (Nexavar) on the patient’s symptom burden, and the location and growth rate of anatomic disease, he said. Sorafenib is one of six vascular endothelial growth factor receptor (VEGFR) inhibitors either indicated for or being evaluated in thyroid cancer. While these agents prolong remission, they do not induce complete responses or cure the disease. In fact, patients will inevitably become resistant to these agents. Therefore, new drugs or combinations continue to be needed, he pointed out. In a phase I/II trial,1 the novel combination of the VEGFR inhibitor cediranib plus lenalidomide (Revlimid) “appears to be quite active, with almost all patients showing some degree of tumor shrinkage,” he noted. Beyond this type of novel regimen, he predicted that future treatments will involve targeting the distinct molecular phenotypes of the disease, he added. The use of vemurafenib (Zelboraf) in patients with BRAF mutations has looked promising, he noted. n Dislcosure: Dr. Cohen receives honoraria from Exelixis, AstraZeneca, and Bayer.

Reference 1. National Institutes of Health: Cediranib maleate with or without lenalidomide in treating patients with thyroid cancer. Available at clinicaltrials.gov. Accessed June 13, 2013.

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.

The ASCO Post | JUNE 25, 2013

PAGE 4

ASCO Annual Meeting ASCO President Clifford Hudis, MD, on the 2013 ASCO Annual Meeting

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

Michael P. Link, MD Stanford University Medical Center

Associate Editors Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

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

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center

George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lynn D. Wilson, MD Yale University School of Medicine

E. David Crawford, MD University of Colorado

Stanley H. Winokur, MD Singer Island, Florida

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

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

Bishoy Morris Faltas, MD Weill Cornell Medical College John A. Fracchia, MD New York Urological Associates Alison Freifeld, MD University of Nebraska Medical Center 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

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

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

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

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

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

Harborside Press® Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Sarah McGullam, Assistant Editor Sarah@harborsidepress.com Michael Buckley, Art Director Terri Caivano, Kristina O’Toole, Layout Artists

Gail Van Koot, Editorial Coordinator Wendy McGullam, Director of Production Wendy@harborsidepress.com Frank Buchner, Chief Technology Officer Frank@harborsidepress.com Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com Anthony Cutrone, President Anthony@harborsidepress.com John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Contributing Writers: Charlotte Bath, Jo Cavallo, Alice Goodman, Caroline Helwick, Susan

London, Caroline McNeil, Eileen O’Gara-Kurtis, Ronald Piana, Matthew Stenger, Marian Wiseman

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

—Clifford Hudis, MD

Samuel Silver, MD, PhD University of Michigan Health System

John Cox, DO Texas Oncology

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

intervention using vinegar and locally trained people could reduce the burden of cervix cancer (Abstract 2), potentially saving up to a quarter of a million lives a year. The fact that the Plenary audience applauded for this abstract the same way we do for exciting new targeted therapies and novel technologies shows us the

Preventing cancer beats treating it every day of the week.

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

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

Paul F. Engstrom, MD Fox Chase Cancer Center

his year’s ASCO Annual Meeting was really exciting in two specific ways. First, we saw the development of high-tech novel therapies and combinations that effectively manipulate the immune system and extend survival in historically difficult-to-treat diseases, like metastatic melanoma (eg, Abstracts

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

Jay S. Cooper, MD Maimonides Medical Center

George D. Demetri, MD Dana-Farber Cancer Institute

CRA9007, CRA9006, and 9012). This has the potential to influence treatment across a wide range of cancers in the coming years, and has been a long-sought goal of immunologists and cancer investigators. I think this is the beginning of something important. The second issue relates to our critical responsibility to deliver high-quality care around the world. It was exciting to see, in a Plenary Session presentation by investigators from India, that an inexpensive

heart and soul of ASCO’s membership. Preventing cancer beats treating it every day of the week. These two stories highlight the full spectrum of what ASCO offers and what attendees heard this year, but there was so much more in the individual sessions. I urge everyone to access the virtual meeting to catch what you may have missed. n Editor’s note: Watch for continuing coverage of the 2013 ASCO Annual Meeting in future editions of The ASCO Post.

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

ASCOPost.com | JUNE 25, 2013

PAGE 5

ASCO Annual Meeting GM-CSF plus Ipilimumab continued from page 1

Eastern Cooperative Oncology Group (ECOG) 1608 randomly assigned 245 previously treated metastatic melanoma patients to receive

cant 36% reduction in mortality risk (P = .014). One-year survival rates were 52.9% with ipilumumab alone vs 68.9% with the combination. Progression-free survival was not significantly different: 34.0% with the

With both drugs commercially available, these findings have implications for the current treatment of melanoma patients. At the same time, we still need to clarify the best way to apply these findings in everyday practice. —F. Stephen Hodi, MD

ipilimumab at a dose of 10 mg/kg every 3 weeks for four cycles, then maintenance treatment at a dose of 10 mg/kg every 12 weeks, or the same ipilimumab schedule plus sargramostim at 250 µg subcutaneously (selfadministered) daily for days 1 to 14 of a 21-day cycle, for four cycles. Dr. Hodi pointed out that ipilimumab was dosed at 10 mg/kg—highmg/kg—higher than the FDA-approved dose of 3 mg/kg—because mg/kg—because the minimally effective dose had not been established at the time the trial was designed. He said future studies will evaluate the combination using the approved dose of ipilimumab.

combination and 29.6%, with ipilimumab alone. Response rates were also comparable between the arms: 15.5% vs 14.8%, respectively. The relatively low response rate represents a “discordance” with clinical outcomes that is often seen with immunotherapies, Dr. Hodi pointed out. “Ipilimumab and GM-CSF cause a proinflammatory microenvironment in the tumor, and radiographic studies may not adequately assess their clinical benefit,” he said. “Progression by standard criteria does not necessarily correlate with the gold standard of benefit, which is overall survival.”

Improved Overall Survival with GM-CSF

Interestingly, the combination was associated with fewer serious side effects, the greatest differences observed in pulmonary and gastrointestinal adverse events. Grade 3 to 5 adverse events occurred in 45% of the combination arm and 58% of the single-

After a median of 13.3 months follow-up, the addition of GM-CSF to ipilimumab significantly improved overall survival, from a median of 12.7 months with ipilimumab alone to 17.5 months, yielding a statistically signifi-

Combination Better Tolerated

GM-CSF plus Ipilimumab ■ The addition of granulocyte-macrophage colony-stimulating factor

(GM-CSF) to ipilimumab improved overall survival by almost 5 months, vs ipilimumab alone, in metastatic melanoma.

agent ipilimumab arm (P = .038). Grade 5 adverse events, in particular, were more common with ipilimumab alone, including multiorgan failure (n = 2), colonic perforation (n = 2), hepatic failure (n = 1), and respiratory failure (n = 2); in patients receiving both drugs, colonic perforation (n = 1) and cardiac arrest (n = 1) were observed. There were two possible treatmentrelated deaths in the combination arm and seven with the single agent. “With both drugs commercially available, these findings have implications for the current treatment of mel-

anoma patients,” Dr. Hodi suggested. “At the same time, we still need to clarify the best way to apply these findings in everyday practice,” he added. n Disclosure: Dr. Hodi reported he has served in a consulting or advisory role with and has received research funding from BristolMyers Squibb.

References 1. Hodi FS, Lee SJ, McDermott DF, et al: Multicenter, randomized phase II trial of GM-CSF plus ipilimumab versus ipi alone in metastatic melanoma: E1608. 2013 ASCO Annual Meeting. Abstract CRA9007. Presented June 1, 2013.

GM-CSF plus Ipilimumab: Ready to Use in the Clinic?

ynn Mara Schuchter, MD, the C. Willard Robinson Professor of Hematology-Oncology and Program Leader of the Melanoma Program at Abramson Cancer Center of the University of Pennsylvania, Philadelphia, commented on the wealth of promising agents now dotting the formerly barren landscape for metastatic melanoma—and said this combination, as distinct from some others—has the advantage of being immediately available in the clinic.

Lynn Mara Schuchter, MD

These are intriguing data based on interesting preclinical work, where a combination of immunotherapies not only gives better survival, but, surprisingly, fewer side effects. —Lynn Mara Schuchter, MD

“It’s premature to say that we will be adding GM-CSF [Leukine] to ipilimumab [Yervoy], but these are intriguing data based on interesting preclinical work, where a combination of immunotherapies not only gives better survival, but, surprisingly, fewer side effects,” she said. While more study is needed, she pointed out that this combination “is the one new treatment we can actually think about using when we get back to the clinic.” She also cautioned that more data are needed before this approach can be considered standard. n Disclosure: Dr. Schuchter reported no potential conflicts of interest.

■ The combination was better tolerated than ipilimumab alone.

Don’t Miss These Important Reports in This Issue of The ASCO Post Ann Partridge, MD, on Adjuvant Tamoxifen and Duration of Therapy see page 11

Gottfried Konecny, MD, on Antiangiogenesis in Cervical Cancer see page 18

Visit The ASCO Post online at ASCOPost.com

Jon Levenson, MD, on Physical and Psychological Symptoms of Cancer see page 58

VOTRIENT® (pazopanib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).1

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

11.1

12 10

MONTHS

9.2

MONTHS

7.4

8 Months

VOTRIENT Placebo

MONTHS

4.2

MONTHS

4.2

MONTHS

2.8

MONTHS

2 0 HR 0.46; 95% CI 0.34-0.62 (P<0.001)

HR 0.40; 95% CI 0.27-0.60 (P<0.001)

HR 0.54; 95% CI 0.35-0.84 (P<0.001)

All patients

Treatment-naïve patients

Cytokine-pretreated patients

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC of clear cell or predominantly clear cell histology were randomized (2:1) to receive either VOTRIENT 800 mg (n=290) once daily or placebo (n=145). The study included treatment-naïve patients receiving VOTRIENT (n=155) or placebo (n=78) as well as cytokine-pretreated patients receiving VOTRIENT (n=135) or placebo (n=67).1

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

• Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. • Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. • Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial 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 RCC trial, venous thromboembolic

events were reported in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. • Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. • Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be wellcontrolled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than 1 week), and frequently thereafter. Treat increased blood pressure promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. • Wound Healing: VOTRIENT may impair wound 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 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial and in no patients receiving placebo. Monitoring of thyroid function tests is recommended.

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

Once-daily oral dosing1 • The recommended starting dose of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg • Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose • In advanced RCC, initial dose reduction should be 400 mg and additional dose decrease or increase should be in 200-mg steps based on individual tolerability • In the Phase 3 advanced RCC trial, 42% of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose reduced • The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day • Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment • Monitor serum liver tests before initiation of treatment and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4 • For additional information on dosing modifications based on drug interactions, please see Section 2.2 in accompanying Brief Summary

VOTRIENT: Summary of serious and common adverse reactions1 • Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended • Serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial thrombotic and venous thromboembolic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, impaired wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, increased toxicity in developing organs, and fetal harm • Most common adverse reactions (≥20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting Please see additional Important Safety Information and Brief Summary of Prescribing Information, including Boxed Warning, for VOTRIENT on adjacent pages.

NCCN Guidelines Category 1 recommendation as a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options.3

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• Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. 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 interruption or 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. A safe and effective combination dose has not been established with these regimens. • Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Animal studies have demonstrated pazopanib can severely affect organ growth and maturation during early post-natal development, and resulted in toxicity to the lungs, liver, heart, and kidney and in death. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age. • 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. • Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. • Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. • Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice. Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

The most common adverse reactions (≥20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (≥5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%). References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.1.2013. ©National Comprehensive Cancer Network, Inc. 2013. All rights reserved. Accessed February 1, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

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 RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

VOTRIENT.com/HCP GSKSource.com

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. 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 RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Periodic monitoring should then continue after Month 4. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)]. 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 RCC trials of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy trials. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had postbaseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. 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: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/ intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial 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 RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 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 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism. In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 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 Increased Toxicity in Developing Organs: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is not indicated for use in pediatric patients. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early post-natal development. Administration of pazopanib to juvenile rats less than 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals. VOTRIENT may potentially cause serious adverse effects on organ development in pediatric patients, particularly in patients younger than 2 years of age [see Use in Specific Populations (8.4)]. 5.16 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous 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)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290) All All Gradesa Gradesa Grade 3 Grade 4 % % % % Adverse Reactions Diarrhea 52 3 <1 9 Hypertension 40 4 0 10 Hair color changes 38 <1 0 3 Nausea 26 <1 0 9 Anorexia 22 2 0 10 Vomiting 21 2 <1 8 Fatigue 19 2 0 8 Asthenia 14 3 0 8 Abdominal pain 11 2 0 1 Headache 10 0 0 5 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

(N=145) Grade 3 % <1 <1 0 0 <1 2 1 0 0 0

Grade 4 % 0 0 0 0 0 0 1 0 0 0

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo. Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N=290) All Gradesa %

Grade 3 %

Placebo (N=145) Grade 4 %

All Gradesa %

Parameters Hematologic Leukopenia 37 0 0 6 Neutropenia 34 1 <1 6 Thrombocytopenia 32 <1 <1 5 Lymphocytopenia 31 4 <1 24 Chemistry ALT increased 53 10 2 22 AST increased 53 7 <1 19 Glucose increased 41 <1 0 33 Total bilirubin increased 36 3 <1 10 Phosphorus decreased 34 4 0 11 Sodium decreased 31 4 1 24 Magnesium decreased 26 <1 1 14 Glucose decreased 17 0 <1 3 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Grade 3 %

Grade 4 %

0 0 0 1

0 0 <1 0

1 <1 1 1 0 4 0 0

0 0 0 <1 0 0 0 0

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Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 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 drugdrug interaction studies 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.16)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from day 9 through day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver and heart at approximately 0.1 times the clinical exposure, based on AUC in adult patients receiving VOTRIENT. At approximately 0.4 times the clinical exposure (based on the AUC in adult patients), pazopanib administration resulted in mortality. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses ≥30 mg/kg (approximately 0.1 to 0.2 times the AUC in human adults at the clinically recommended dose). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5 to 0.7 times the exposure in adult patients at the clinically recommended dose, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.15)]. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged ≥65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC(0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical trials for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility

in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at Weeks 3, 5, 7, and 9. Thereafter, monitor at Month 3 and at Month 4, and as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. • Prolonged QT intervals and torsades de pointes have been observed. Patients should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. • Cardiac dysfunction (such as CHF and LVEF decrease) has been observed in patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. • Serious hemorrhagic events have been reported. Patients should be advised to report unusual bleeding. • Arterial thrombotic events have been reported. Patients should be advised to report signs or symptoms of an arterial thrombosis. • Reports of pneumothorax and venous thromboembolic events including pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. • Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). • Hypertension and hypertensive crisis have been reported. Patients should be advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. • GI perforation or fistula has occurred. Advise patients to report signs and symptoms of a GI perforation or fistula. • VEGFR inhibitors such as VOTRIENT may impair wound healing. Advise patients to stop VOTRIENT at least 7 days prior to a scheduled surgery. • Hypothyroidism and proteinuria have been reported. Advise patients that thyroid function testing and urinalysis will be performed during treatment. • Serious infections including some with fatal outcomes have been reported. Advise patients to promptly report any signs or symptoms of infection. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

The ASCO Post | JUNE 25, 2013

PAGE 10

ASCO Annual Meeting Melanoma

MEK Inhibitor Improves Outcomes in Metastatic Uveal Melanoma By Caroline Helwick

or the first time, a drug has proven effective in the treatment of uveal (ocular) melanoma that has metastasized, according to a randomized multicenter phase II study presented at the 2013 ASCO Annual Meeting.1

Richard D. Carvajal, MD

“This study is the first to demonstrate an improved clinical outcome with any systemic therapy in patients with metastatic uveal melanoma. MEK inhibition with selumetinib resulted in a median progression-free survival that was double that achieved with chemotherapy,” said Richard D. Carvajal, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, who presented the findings. Dr. Carvajal noted that effective treatments are lacking for metastatic uveal melanoma. Therefore, the current standard of care is clinical trial participation. Selumetinib is a non-ATP competitive inhibitor of MEK1/2. It was evaluated in 98 patients with metastatic uveal melanoma, 84% of whom harbored the GNAQ or GNA11 (GNAQ/11) genetic alterations that are common in ocular melanoma and that are known to activate the MAP kinase pathway, promoting tumor growth. The MEK protein is a key component of this pathway. “GNAQ/11 mutations are early oncogenic events found in uveal melanoma and result in susceptibility to treatment with MEK inhibition,” Dr. Carvajal explained. Studies have

shown that selumetinib decreases the viability of uveal melanoma in a mutation-dependent fashion, he said.

Study of 98 Patients The multicenter study enrolled 98 patients, most with metastatic disease involving the liver, who had received no more than one prior treatment for metastatic disease, including prior ipilimumab (Yervoy) in approximately 20%. Patients were randomly assigned to selumetinib at 75 mg twice daily or temozolomide at 150 mg/m2 daily for 5 days in 28-day cycles (four patients received dacarbazine at 1,000 mg/m2 every 21 days). The response patterns were very different between the treatment arms. With the MEK inhibitor selumetinib, 50% of patients had tumor regression and 15% had a response by RECIST criteria. “This is quite remarkable, because radiographic tumor shrinkage is uncommon in this disease,” he said. With temozolomide, in contrast, tumor shrinkage was 11% with no major RECIST responses observed. Clinical outcomes corresponded with the significantly different response patterns observed. With selumetinib, 35 of 46 (76%) patients achieved stable disease. Another 7 (15%) achieved a RECIST response. The median duration of response was 23 weeks (range, 7.9–40.3).

Survival Rates Progression-free survival was improved with selumetinib, in both the overall and mutation-only populations. For the overall population, median progression-free survival was 15.9 weeks with selumetinib and 7.0 weeks with temozolomide—a 54% reduction in risk that was highly significant (P = .0005). In the 84% of patients who had mutations in exon 5 GNAQ/11, it was 15.4 vs 7.0 weeks—a 45% reduction in risk (P = .011), he reported. The progression-free survival rates for the overall population were 43.1% vs 8.5% at 4 months and 22.9% vs

Selumetinib in Uveal Melanoma ■ The MEK inhibitor selumetinib is the first drug to improve clinical outcomes in metastatic uveal melanoma.

■ Compared to temozolomide, selumetinib improved progression-free survival.

5.7%, respectively, at 6 months. The 16 patients with wild-type GNAQ/11 had similar outcomes, he noted. Despite an 80% crossover rate, a trend toward an improvement in overall survival was also observed, with median survival times of 10.8 and 9.4 months, respectively, or a 21% nonsignificant reduction in risk (P = .4).

Adverse Events Selumetinib was associated with more anemia (30% vs 14%), CPK elevations (49% vs 0%), diarrhea (40% vs 8%), elevations in liver enzyme tests (49% vs 12%), edema (40% vs 2%), and muscle

weakness (8% vs 0%). However, most side effects were grade 1 or 2, he said. Dr. Carvajal called the treatment “promising” and said the MEK inhibitor provides a platform for the development of combinatorial therapeutic approaches. n

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

Reference 1. Carvajal RD, Sosman JA, Quevedo F, et al: Phase II study of selumetinib versus temozolomide in gnaq/Gna11 mutation uveal melanoma. 2013 ASCO Annual Meeting. Abstract CRA9003. Presented June 1, 2013.

EXPERT POINT OF VIEW

ynn Mara Schuchter, MD, the C. Willard Robinson Professor of Hematology-Oncology and Program Leader of the Melanoma Program at Abramson Cancer Center of the University of Pennsylvania, Philadelphia, commented at a press briefing that the study “will ultimately be practicechanging.” She noted, “This has been a very difficult disease to treat, and the MEK inhibitors make biological sense.” The paper’s formal discussant, Michael A. Davies, MD, PhD, Assistant Professor in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, Michael A. Davies, MD, PhD Houston, commented on the “interesting” finding that patients who lack the activating GNAQ or GNA11 mutations nevertheless derived clinical benefit. “So it would not be rational to exclude these patients from future clinical trials of these pathway inhibitors,” he said. Speaking to a packed ballroom, Dr. Davies reflected back on the advances seen in this disease in the past several years. “I remember my first ASCO in 2005, and the melanoma oral abstract session, where you clearly had no trouble getting a seat. The most memorable part of the session was a debate between presenters as to whose data was ‘the most spectacularly negative’. Now, when the 2013 ASCO schedule came out, I was somewhat disappointed that the streak of plenary presentations on melanoma had been broken. However; this disappointment was tempered by the recent approval of two more agents for patients with metastatic melanoma.”

‘Landmark’ Study The study by Carvajal et al “truly is the first randomized trial to demonstrate improvement in clinical outcomes in patients with metastatic uveal melanoma, and this is a landmark,” he noted. “The question now is how to build upon this initial activity.” He suggested that future studies attempt to characterize the patients with wild-type GNAQ/11 who also responded to selumetinib, pharmacodynamically evaluate the drug’s effect on the MEK pathway, and characterize the compensatory signaling events and tumor biology upon disease progression in order to identify and prioritize rational combinatorial approaches. n

Disclosure: Dr. Davies is on the advisory board of GlaxoSmithKline, Roche/Genentech, and Novartis. He also receives research funding from AstraZeneca, GlaxoSmithKline, Roche/ Genentech, Merck, Oncothyreon, and Myriad.

ASCOPost.com | JUNE 25, 2013

PAGE 11

ASCO Annual Meeting Plenary Presentation

Study Confirms 10 Years of Adjuvant Tamoxifen Is Superior to 5 Years By Alice Goodman

he landmark aTTom study showed that 10 years of adjuvant tamoxifen is superior to 5 years of tamoxifen in reducing the risk of breast cancer recurrence or death but that the full survival benefits of extended treatment do not emerge until after the 10 years of treatment. These findings, which were presented at the ASCO Annual Meeting,1 mirror those of the companion study ATLAS, which was presented at the San Antonio Breast Cancer Symposium in December 2012.2

Proof Beyond Doubt “ATLAS and aTTom between them provide proof beyond a reasonable doubt that continuing [adjuvant] tamoxifen beyond 5 years reduces recurrence over the long term, with the benefit [reduced recurrence] seen mainly

“T

Duration of Adjuvant Tamoxifen in Breast Cancer ■ Ten years of adjuvant tamoxifen further lowered the risk of breast cancer recurrence and death compared with 5 years in two large randomized controlled trials in women with early breast cancer.

■ It takes about 10 years for the benefits of extended tamoxifen to emerge.

Richard G. Gray, MSc

after year 7. Extended tamoxifen also reduces the risk of breast cancer mortality, and this reduction is seen after year 10,” stated lead author Richard G. Gray, MSc, Professor of Medical Statistics, University of Oxford, United Kingdom. Previous studies demonstrated that 5 years of tamoxifen reduced the breast cancer death rate by about 33% throughout 15 years of follow-up. The aTTom trial showed that 5 years more of tamoxifen therapy reduced tumor re-

can be given after 5 years of aromatase inhibitor therapy, but data do not support continuing an aromatase inhibitor beyond 5 years, she said. Options for women who develop amenorrhea on tamoxifen include switching to an aromatase inhibitor after 5 years of tamoxifen. “Continued tamoxifen is reasonable if there is resumption of ovarian function,” Dr. Partridge noted.

or to stop tamoxifen. The women were evaluated annually to assess tumor recurrence, rates of hospitalization and death, and compliance. About 75% of women in the 10-year tamoxifen group were adherent to treatment. “An interim analysis of this trial in 2008 showed no significant benefit of extended tamoxifen in terms of tumor recurrence and breast cancer death. But follow-up was not long enough. Five years later, there is remarkable improvement with 10 years of tamoxifen,” Prof. Gray told listeners at the Plenary Session. At 10 years of follow-up from randomization, extended tamoxifen significantly reduced the risk of tumor recurrence: 28% vs 32% for women stopping after 5 years of tamoxifen (P = .003). The mortality benefit of extended tamoxifen was also evident: 21% in the extended tamoxifen group vs 24% in the placebo group, for borderline significance (P = .06). “Taken together, ATLAS and aTTom show that there is definitely a survival benefit from longer tamoxifen treatment, with the curves diverging after 10 years,” he emphasized.

No Prior Standard

Tamoxifen Drawbacks

“There is no prior standard for premenopausal women who remain premenopausal on tamoxifen. Extending tamoxifen is a great new option where there has been no prior standard. These women have the greatest potential for risk reduction from extended therapy and the lowest risk of toxicity. But there is a potentially greater effect on longterm quality of life and future fertility in this group of patients,” she stated. It is reasonable to stop therapy [for premenopausal women] if they want to preserve fertility, the absolute risks are high, or quality of life is a priority. “These are difficult decisions for some women. They need support in making this decision. It may not be a one-time, 15-minute clinic visit,” Dr. Partridge concluded. n Disclosure: Dr. Partridge reported no po-

The downside of 10 years of tamoxifen is a doubling of the number of endometrial cancers, from 45 (1.3%) with 5 years to 102 (2.9%) with 10 years (P < .0001). Also, more women on longer tamoxifen treatment died of endometrial cancer: 20 deaths after 5 years of tamoxifen and 37 deaths after 10 years (P = .02). Despite this, fewer deaths from all causes were observed with 10 years of treatment, he said. n

currence and breast cancer death rates by an additional 25% from year 10 onward compared with 5 years. Thus, the researchers estimate, compared to taking no tamoxifen, 10 years of tamoxifen reduces breast cancer death rate by a third in the first 10 years after diagnosis and by half subsequently.

Major Results The study enrolled 6,953 women with early breast cancer who had taken adjuvant tamoxifen for 5 years. Participants were randomly assigned to receive 5 years of additional tamoxifen

EXPERT POINT OF VIEW

his study showed that 10 years of adjuvant tamoxifen reduced the risk of late recurrence in hormone receptor-positive breast cancer, which is a major problem. The

Ann Partridge, MD

study also showed that ‘patience is a virtue’,” stated formal discussant Ann Partridge, MD, Director of the Adult Survivorship Program at the DanaFarber Cancer Institute in Boston. The benefit of chemotherapy is seen primarily in years 1 to 5 after treatment, she said. However, the benefits of additional tamoxifen appear later. With 10 years of tamoxifen, the absolute reduction in tumor recurrence is 4%, and 10 years later, the absolute reduction in death is 2%. Many postmenopausal women with early hormone receptor–positive breast cancer are now treated initially with an aromatase inhibitor, but the optimal

duration of endocrine therapy with an aromatase inhibitor is not known. “Several studies are looking at this question, and we eagerly await results,” she noted.

Decision-making Factors At present, the question is how to factor available data into decisionmaking regarding adjuvant hormonal therapy. This decision should be based on the individual patient and her personalized risk, Dr. Partridge continued. Factors such as stage, tumor biology, and gene expression profiles should be considered. Also, comorbidity and age will influence treatment decisions. “The risks of extended tamoxifen are an important consideration for each individual. Serious adverse events include endometrial cancer, which occurred in about 3% of women on extended tamoxifen vs 1.6% on 5 years of tamoxifen. The symptoms can affect quality of life. Patient preferences and values should be taken into account. Minor side effects can become deeply troubling over time, and adherence is a challenge in the real world. Adherence to adjuvant tamoxifen wanes over time, and one can only wonder what will happen when we prescribe more extended endocrine therapy,” she said. Current options for most postmenopausal women include an aromatase inhibitor for the first 5 years. Tamoxifen

tential conflicts of interest.

Disclosure: Prof. Gray reported no potential conflicts of interest.

References 1. Gray RG, et al: aTTom: ASCO Annual Meeting. Abstract 5. Presented June 2, 2013. 2. Davies C, et al, for the ATLAS Collaborative Group: ATLAS—10 v 5 years of adjuvant tamoxifen in ER+ disease. 2012 San Antonio Breast Cancer Symposium. Abstract S1-2. Presented December 5, 2012.

The ASCO Post | JUNE 25, 2013

PAGE 12

Perspective

Medical Education continued from page 1

have monthly payments ranging from $1,500 to $2,100 after residency training.2 In addition, the Obama administration and some members of Congress want to cut the funding of resident training in more than 1,000 of the nation’s teaching hospitals. (Each year the federal government contributes about $9.5 billion in Medicare funds, and approximately $2 billion in Medicaid dollars, and the states add about $3.78 billion through Medicaid funds.6) So the costs and debt have been going up, while the training and compensation have been going down. The new graduates are being squeezed tighter each year. The economic reality of medical school debt certainly affects decisions about choosing between primary care and one of the traditionally more lucrative subspecialties. A primary care position pays about $150,000 per year, whereas a surgical subspecialist may earn $400,000 or more. Thus, the cost of education and the incurred debt are public health issues. The American Academy of Family Physicians predicts that the United States will require an additional 40,000 family physicians by 2020. It is little wonder that the aging population will be faced with a shortage of primary care doctors. In addition, if the medical home concept and accountable care organizations are to work in the future, the gap between the growing need and the expected primary care physician shortage must be closed.

dency salary) for their education, yet continue the annual stipend for primary care residents,7 and there are numerous medical schools in the United States and England that offer a 3-year medical school without any apparent reduction in the quality of the education.8 Only through creative, fresh ap-

Dr. Boxer is Clinical Professor at the University of Wisconsin School of Medicine and Public Health, Madison, and the Medical College of Wisconsin.

ing off debt, results in a reduction in exactly the physicians who we need to care for Americans now and into the future. n Disclosure: Dr. Boxer reported no potential conflicts of interest.

B:15

References 1. Flexner A: Report on Medical

A Critical Connection Between B-Cell Signaling and the Tumor Microenvironment* Until recently, research of B-cell malignancies has been focused primarily on the B cell itself.1 However, new insights have revealed that there are important interactions between the B cell and the extracellular microenvironment that are dependent on intracellular signaling pathways mediated by various kinases including Bruton’s tyrosine kinase (BTK).2,3 These interactions suggest an important role in B-cell homing, adhesion, and migration.4,5 Further elucidation of these processes could change how we view and approach B-cell malignancies.

BTK signaling pathways and the microenvironment*† FDC BCR TLR T cell MyD88

BTK

Lyn

CXCR4/5 PI3K

MSC

PIP3

Syk

BTK

G G

Resolving the Debt There are a number of methods of loan forgiveness: States help repay or forgive loans if doctors serve in rural areas, the NIH helps repay loans when doctors enter into research programs, and the National Health Service Corps also has loan repayment plans. There is even a proposal to charge subspecialty residents (by not giving them a resi-

proaches will the public health issue of medical school debt be resolved. Doctors are privileged in many ways, accounting for 18 of the 20 highest paid professions in the United States. But disincentives to enter primary care including relatively less income compared to their specialty colleagues and greater difficulty pay-

Nucleus

PLCγ2

B cell

BTK

DAG NF-κB

IP3

PKC Ca

Based on in vitro data. Illustrations not to scale.

†

Pharmacyclics, Inc., and Janssen Biotech, Inc., are currently investigating BTK in search of insights that could improve the lives of patients with B-cell malignancies. Visit us at www.BCellSignals.com.

T:15

5.5”

5.25”

ASCOPost.com | JUNE 25, 2013

PAGE 13

Perspective

Education in the United States and Canada: A Report to the Carnegie Foundation for the Advancement of Teaching, Bulletin No. 4. New York, The Carnegie Foundation, 1910. 2. Association of American Medical Colleges: Trends in cost and debt at U.S. medical schools using a new measure of medical school cost of attendance. Analysis in Brief, July 2012. Available at www.

BCR

aamc.org/download/296002/data/aibvol12_no2.pdf. Accessed April 5, 2013. 3. Krupa C: Medical students still burdened by high debt loads. Available at www.amednews. com/article/20120827/profession/308279940/6/. Accessed April 8, 2013. 4. Association of American Medical Colleges: Medical student education:

Debt, costs, and loan repayment fact card, October 2012. Available at www.aamc. org/ download/152968/data/debtfactcard.pdf. Accessed April 5, 2013. 5. Association of American Medical Colleges: Tuition and student fees reports. Available at services.aamc.org/ tsfreports/report_median.cfm?year_of_ study=2013. Accessed April 8, 2013. 6. Dower C: Graduate medical edu-

FDA Approves New Silicone Gel-filled Breast Implant

CD79A CD79B

Prosurvival Signals Lyn

Syk

BTK PLCγ2

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cation. Health Policy Briefs. August 16, 2012. Available at www.healthaffairs. org/healthpolicybriefs/brief.php?brief_ id=73. Accessed April 8, 2013. 7. Bach P, Kocher R: Why medical school should be free. NY Times, May 28, 2011. 8. Emanuel EJ, Fuchs VR: Shortening medical training by 30%. JAMA 307:1143-1144, 2012.

Normal and malignant B cells rely on multiple prosurvival pathways to avoid apoptosis.6-9 In B-cell malignancies, microenvironmental cues may inappropriately initiate signaling cascades through several kinases, including BTK, driving uncontrolled growth and survival of malignant B cells.5,10-13

NF-κB

B-Cell Homing Cells in the microenvironment secrete chemoattractant factors to promote the homing of B cells to lymphoid tissue.14 These factors act via signaling pathways involving BTK and other kinases.4,15

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VCAM-1

Adhesion and Migration

VLA-4

The upregulation and increased migration of B cells may lead to retention of malignant cells in proliferative environments and the promotion of chemoresistance.16-18 BTK is an essential mediator of multiple adhesion and migration processes.4

References: 1. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103. 2. Kil LP, de Bruijn MJW, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3:71-83. 3. Pighi C, Gu T-L, Dalai I, et al. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol (Dordr). 2011;34:141-153. 4. de Gorter DJJ, Beuling EA, Kersseboom R, et al. Bruton’s tyrosine kinase and phospholipase C 2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26:93-104. 5. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367-3375. 6. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175-1184. 7. Rauch M, Tussiwand R, Bosco N, Rolink AG. Crucial role for BAFF-BAFF-R signaling in the survival and maintenance of mature B cells. PLoS One. 2009;4:e5456. 8. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol. 2007;85:471-475. 9. Grumont RJ, Rourke IJ, O’Reilly LA, et al. B lymphocytes differentially use the Rel and nuclear factor B1 (NF- B1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med. 1998;187:663-674. 10. Nishio M, Endo T, Tsukada N, et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1 . Blood. 2005;106:1012-1020. 11. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120:4684-4691. 12. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF- B activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563-574. 13. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88-92. 14. Okada T, Ngo VN, Ekland EH, et al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med. 2002;196:65-75. 15. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658-3667. 16. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113:4604-4613. 17. Binsky I, Lantner F, Grabovsky V, et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. J Immunol. 2010;184:4761-4769. 18. Kurtova AV, Balakrishnan K, Chen R, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114:4441-4450.

B:10.75”

he FDA recently approved the MemoryShape Breast Implant for breast augmentation in women at least 22 years old and for breast reconstruction in women of any age. The MemoryShape Breast Implants are manufactured by Mentor Worldwide LLC. The FDA’s approval is based on 6 years of data from 955 women demonstrating that there is a reasonable assurance of safety and effectiveness for this implant. Mentor’s MemoryShape Breast Implant showed similar rates of complications and outcomes as previously approved breast implants. These complications included capsular contracture, reoperation, implant removal, breast asymmetry, and wrinkling. Fissures or cracks were observed in the gel of some MemoryShape Breast Implants. “It’s important to remember that breast implants are not lifetime devices. Women should fully understand the risks associated with breast implants before considering augmentation or reconstruction surgery, and they should recognize that long-term monitoring is essential,” said Jeffrey Shuren, MD, Director of the FDA’s Center for Devices and Radiological Health.

Post-approval Safety Studies The FDA requires that Mentor conduct a series of postapproval studies to assess long-term safety and effectiveness outcomes and the risks of rare disease. There were a number of conditions of approval for the MemoryShape Breast Implants, including that Mentor must continue to follow 955 women who received the MemoryShape Breast Implants as part of the premarket core study that provided safety and effectiveness data for the device approval. n

The ASCO Post | JUNE 25, 2013

PAGE 14

ASCO Annual Meeting Breast Cancer

Axillary Radiotherapy: New Standard of Care in Node-positive Breast Cancer? By Alice Goodman

adiotherapy to the axilla may replace axillary lymph node dissection for local tumor control in selected patients with sentinel node–positive breast cancer, sparing many patients lymphedema, according to the final results of the European Organisation for Research and Treatment of Cancer (EORTC) AMAROS trial presented at the ASCO Annual Meeting.1 “If radiation therapy is deemed necessary due to large tumor size and/ or positive sentinel lymph nodes, you can radiate the axilla at the same time and achieve similar local control as full lymph node dissection in the axilla. Radiotherapy to the axilla should be the standard of care. We are doing this in the Netherlands as an alternative treatment option. We know that axillary lymph node dissection is associated with high rates of side effects,” said lead author Emiel J. Rutgers, MD, PhD, a surgical oncologist at the Netherlands Cancer Institute in Amsterdam.

If radiation therapy is deemed necessary, you can radiate the axilla at the same time and achieve similar local control as full lymph node dissection in the axilla. —Emiel J. Rutgers, MD, PhD

Study Rationale It is important to treat patients with a positive sentinel lymph node early to achieve regional tumor control and improve prognosis, Dr. Rutgers said. In many countries, including the United States, the current standard of care for many patients with positive sentinel lymph nodes is further resection of additional axillary lymph nodes to prevent recurrence of cancer in the axilla (and treatment of the remaining nodes if deemed necessary). This study was designed to compare axillary dissection with radiotherapy to the axilla 12 years ago, with the goal of

EXPERT POINT OF VIEW

“T

his study shows us that less can be more in the sentinel lymph node era. We can avoid complete axillary resection. As a medical oncologist, I have learned that less can be more in many settings. As a result of this study, I will be able to reassure my patients that radiation therapy to the axilla is safe and can achieve local control,” said Andrew Seidman, MD, Attending Physician for the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York, who moderated a press conferAndrew Seidman, MD ence where this study was discussed. When asked whether radiation would become the new standard of care, Dr. Seidman said, “We heard the study results today. We will go back to our practices and digest the data over the next few months. I suspect that the study will change the standard of care for selected patients and that this will happen at my institution.” n Disclosure: Dr. Seidman reported no potential conflicts of interest.

Visit

lessening toxicity including lymphedema, impairment of shoulder movement, and reduced quality of life, he explained. The study employed radiation techniques in use at the time the study was designed, but researchers are now studying ways to deploy modern techniques, so as to reduce side effects further. AMAROS included 4,806 patients, with tumors up to 5 cm and no palpable lymph nodes; 1,425 (29.7%) had a positive axillary node on sentinel node dissection. In an intent-to-treat analysis, 744 patients were randomly assigned to lymph node dissection and 681, to axillary radiotherapy. About 85% of both groups received treatment as assigned.

Key Data At a median follow-up of 6.1 years, the risk of axillary relapse was low in both groups: 0.54% (4 patients) in the surgery group and 1.03% (7 patients) in the radiotherapy group. Diseasefree survival rates were similar. No

difference was seen in overall survival. Breast cancer-related deaths were reported in 53 patients (7.1%) in the surgery group vs 54 patients (7.9%) in the radiotherapy group. The rates of lymphedema were assessed at years 1, 3, and 5 following treatment. Patients assigned to radiotherapy had significantly lower lymphedema rates at all time points. At 1 year, 40% of the surgery group and 21.7% of the radiotherapy group had lymphedema; at 3 years, 29.8% and 16.7%, respectively; at 5 years, 28% and 13.6%, respectively. These differences were highly statistically significant (P < .0001 for all comparisons favoring radiotherapy). No difference in shoulder function was observed between the groups, although a trend was seen for impaired shoulder function in the radiotherapy group only during the first year after therapy. Evaluation of quality of life using the EORTC-QLQ-C30 and the QLQ-BR23 breast cancer module revealed no difference between groups. n

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

Reference 1. Rutgers EJ, Donker M, Straver ME, et al: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023). ASCO Annual Meeting. Abstract LBA1001. Presented June 3, 2013.

Axillary Radiotherapy vs Surgery in Node-positive Breast Cancer ■ In a large randomized trial, axillary radiotherapy achieved similar

locoregional tumor control in patients with node-positive breast cancer 6 years after treatment.

■ Patients treated with radiotherapy had significantly less lymphedema than did those treated with surgery. Quality of life was similar in both groups.

■ Axillary radiotherapy may replace complete axillary resection and become the standard care in node-positive breast cancer.

website at ASCOPost.com

For the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AND...

• 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53-0.75])1 • XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 —

In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1 • Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

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

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ﬂush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries

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

related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients and included non-pathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event. Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

L Learn earn m more ore a att X XtandiHCP.com tandiHCP.com References: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed December 20, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. © 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013A-076-7020-1 2/13 XTANDI, Astellas, and the ﬂying star logo are trademarks of Astellas Pharma Inc.

The ASCO Post | JUNE 25, 2013

PAGE 16

Awards

Brian Druker, MD, and Charles Sawyers, MD, Receive 2013 Taubman Prize for Excellence in Translational Medical Science

rian Druker, MD, of Oregon Health & Science University in Portland, and Charles Sawyers, MD, of Memorial Sloan-Kettering

Cancer Center in New York, will share the 2013 Taubman Prize for Excellence in Translational Medical Science. Â The $100,000 prize is given

by the A. Alfred Taubman Medical Research Institute, based at the University of Michigan Medical School in Ann Arbor, Michigan.

Dr. Brian Drukerâ&#x20AC;&#x2122;s work led to the development of imatinib (Gleevec) in chronic myelogenous leukemia (CML) and served as the proof of

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

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

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

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

ASCOPost.com | JUNE 25, 2013

PAGE 17

Awards

principle for targeted cancer therapies. Dr. Charles Sawyers studies on resistance to imatinib led to the development of second-generation drugs.

Role Models for Translational Medicine â&#x20AC;&#x153;Brian Druker and Charles Saw-

yers are quintessential role models for modern transitional medicine,â&#x20AC;? said David Ginsburg, MD, a Taubman Scholar and Professor of Internal Medicine at the University of Michigan Medical School and leader of the na-

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

Brian Druker, MD

Charles Sawyers, MD

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

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

ONCOLOGY

tionwide panel of translational research experts that selected the 2013 Taubman Prize recipients. â&#x20AC;&#x153;Their success in developing specific, targeted therapies for chronic myeloid leukemia, including secondgeneration drugs for resistant disease, has inspired the pharmaceutical industry and an entire generation of future physician-scientists,â&#x20AC;? Dr. Ginsburg said. The Taubman Prize is presented annually by the Taubman Institute and is open to clinician-scientists around the world. Â The prize is intended to recognize work in the field of translational medical science by the clinician-scientists who have done the most to transform laboratory discoveries into clinical applications for patients.

CML Now a Treatable Disease Dr. Druker and his team performed laboratory research that led to the development of imatinib. He then led the clinical trials with participation from Dr. Sawyers and Dr. Moshe Talpaz, who now serves on the faculty of the University of Michigan Medical School and is Associate Director for Translational Research at the University of Michiganâ&#x20AC;&#x2122;s Comprehensive Cancer Center. Dr. Sawyers, recognizing that some patients become resistant to imatinib, performed critical laboratory studies that led to a molecular understanding of the mechanism of this resistance. The understanding laid the groundwork for the development of drugs to combat resistance to imatinib. Together with Dr. Drukerâ&#x20AC;&#x2122;s work, this has converted CML from a fatal cancer into one that is highly treatable. â&#x20AC;&#x153;I am thrilled to be honored with Dr. Druker for our work leading to new therapies for chronic myeloid leukemia,â&#x20AC;? said Dr. Sawyers. Â â&#x20AC;&#x153;Of course the greatest satisfaction comes from knowing that thousands of patients, including many of my own, have benefited from our work. Drs. Druker and Sawyers will present the keynote addresses at the Instituteâ&#x20AC;&#x2122;s 2013 Annual Symposium on October 11 in Ann Arbor, where they will be awarded the Taubman Prize trophy. Â The prize was first awarded in 2012, to Harry Dietz, MD, of the Johns Hopkins University. Â For more information, visit www.taubmaninstitute.org. n

The ASCO Post | JUNE 25, 2013

PAGE 18

ASCO Annual Meeting Antiangiogenesis in Cervical Cancer continued from page 2

so new treatment options are needed. Angiogenesis is an attractive target to pursue,” Dr. Tewari told listeners.

Study Details Gynecologic Oncology Group (GOG) 240 was a randomized study that enrolled 452 women with recurrent or persistent stage IVB cervical cancer despite previous initial treatment with chemotherapy. Participants were randomized to one of four arms: chemotherapy alone with cisplatin/paclitaxel (control arm); topotecan/paclitaxel (a cisplatinfree arm); and each regimen plus bevacizumab. No previous chemotherapy for tumor recurrence was allowed. One of the goals of the trial was to see whether topotecan substituted for cisplatin would improve outcomes. However, no significant difference in survival was found between the two chemotherapy arms in an earlier interim analysis, Dr. Tewari said. For the present analysis of bevacizumab vs no bevacizumab, results were pooled for the two chemotherapyalone arms and the two bevacizumabcontaining arms. Overall survival was significantly improved with bevacizumab by 3.7 months. Median overall survival was 13.3 months in the chemotherapyalone arms vs 17.0 months in the bevacizumab arms (29% reduction in risk of death; P = .0035). “We feel that this nearly 4-month improvement in survival is clinically meaningful in a group of patients who typically don’t respond very well to treatment,” Dr. Tewari said. Bevacizumab improved progression-free survival as well. Median progression-free survival was 5.9 months with chemotherapy vs 8.2 months with chemotherapy plus bevacizumab, a difference that was highly significant (P = .0002). Response rates were 36% with chemotherapy alone vs 48% with bevacizumab.

EXPERT POINT OF VIEW

ormal discussant Gottfried Konecny, MD, Associate Professor of Medicine, David Geffen School of Medicine at UCLA, also viewed the study as a game changer. He cited

“Prior to this study, no regimen improved overall survival in advanced cervical cancer. Median overall survival barely reaches 12 months with the current standard of care. The results of this study are clinically meaningful and important, as bevacizumab extended survival up to 17 months,” Dr. Konecny said.

Important Distinction

Gottfried Konecny, MD

the strengths of the study, including its design, randomization with stratification, P values adjusted for multiple testing, and the fact that no crossover was allowed. Prognostic factors were well balanced in both arms. The control arm did not underperform, he said. Other strengths of the study include a strong translational component, detailed quality-of-life assessment, and exploratory subsets, which can provide rationales for future trials.

Adverse Events and Cost Issues There were four fatal adverse events in each arm. Bevacizumab treatment led to higher rates of fistula (3% vs 0%), hypertension (25% vs 2%), thrombosis/embolism (9% vs 2%), and grades 3 or higher GI bleeding (4% vs 1%), but all of the side effects were expected. “No new or unexpected adverse events were reported,” Dr. Tewari commented. Patient-reported quality-of-life measures of well-being and function on the Functional Assessment of Cancer Therapy Cervical Cancer Scale (FACT-Cx) showed no meaningful differences between the two groups. A

New from The ASCO Post

An important point is that the study demonstrated a progressionfree survival improvement that translated to improved overall survival. In studies of other cancers, bevacizumab improved progression-free survival but not overall survival, which is an important distinction. “This study demonstrates favorable outcomes with bevacizumab in terms of survival compared with other cancers in the first-line setting,” he emphasized. Study limitations cited by Dr. Konecny include the lack of a costbenefit analysis and no information on treatment withdrawal regarding chemotherapy or bevacizumab. Also, as only 17% of the patients had metadifference of 4 points or more on the quality-of-life scale is considered clinically meaningful, he said, but patients in the bevacizumab-containing arms differed from those on the chemotherapy-alone arm by an average of only about 1 point. Dr. Tewari said that cost is a major problem with bevacizumab. The authors plan to do a cost-effectiveness analysis of this trial. “We can demonstrate that antiangiogenic agents improve survival. This opens the door for studies of other antiangiogenic agents, which may be less expensive,” he said at an official press conference. Expert consensus is that the study will affect treatment decisions. “A re-

static disease, results may not be applicable to that group of patients, he said.

Future Studies Dr. Konecny agreed with Dr. Tewari that this trial paves the way for other studies on angiogenic inhibitors such as tyrosine kinase inhibitors. However, this effort is hampered by the lack of prospectively validated predictors, although several are under study, he continued. Furthermore, studies of antiangiogenic agents are needed in earlier-stage disease and in patients with positive lymph nodes to determine whether they improve survival. “It is critical to extend the global reach of antiangiogenic therapies for women with cervical cancer. We need to develop strategies that will benefit the global population, because the disease burden is much greater in developing countries than in the United States,” he concluded. n

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

duction in death is the gold standard. We need to review the full published study, but ultimately this should be practice-changing,” said Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center in New York. n

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

Reference 1. Tewari KS, Sill M, Long HJ, et al: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. ASCO Annual Meeting. Abstract 3. Presented June 2, 2013.

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The ASCO Post | JUNE 25, 2013

PAGE 20

ASCO Annual Meeting Cervical Cancer Screening in India continued from page 2

facilities for confirmation of diagnosis. Confirmed cases of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer were treated at no cost at Tata Memorial Hospital or other private facilities. “Before education, these slum communities were naive in terms of screening for any kind of health condition. We had to pass through several levels of community values to gain acceptance for our program. This included talking to religious, community, and political leaders. Once the program was accepted, communities provided places for health education and a clinic to ensure a sense of ownership among the communities,” he told listeners. The rate of screening participation was 89%. “This is huge for India,” Dr. Shastri said. In the control group, 91% participated in the education. A total of 86% of the screening group completed treatment, compared with 72% of the control group.

Screening Reduced Death Rates The incidence of invasive cervical cancer was similar in the two groups: 26.7 per 100,000 in the screening group and 27.5 per 100,000 among controls. Dr. Shastri pointed out that these results showed that screening did not lead to overdiagnosis. Cervical cancer–specific death rates were reduced by 31% with screening (P

= .003): 11.1 per 100,000 in the screening group and 16.2 per 100,000 in controls. There was also a 7% reduction in allcause mortality in the screening group, although this difference was not statistically significant. Five percent of women in the screening group were randomly screened by an expert, and in those cases, the results confirmed those obtained by the trained primary health workers. “This screening program is widely implementable in the developing world and gives immediate results, which is important in rural areas, where women might have to travel hours to see a doctor,” Dr. Shastri said. In the area where the study was conducted, primary health workers were the only ones available to deliver the screening test. The authors of this study plan to train primary health workers to provide visual inspection with acetic acid screening every 24 months to all women aged 35 to 64 in the state where the trial was conducted. The Indian government is also working to implement the screening technique throughout the country and plans to partner with other countries in the developing world to offer training resources. n Disclosure: Dr. Shastri reported no potential conflicts of interest.

Reference 1. Shastri SS, Mittra I, Mishra G, et al: Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India. ASCO Annual Meeting. Abstract 2. Presented June 2, 2013.

Cervical Cancer Screening in India ■ Cervical cancer is the number 1 cause of cancer death among women in India. ■ Although screening can decrease the rate of cervical cancer deaths dramatically, no screening program exists in India.

■ A simple visual inspection test using vinegar swabs on the cervix allowed

detection of cervical cancer and lowered the rate of related deaths by 31%.

■ Screening with the vinegar test was delivered by women from the community who were trained in 4-week sessions.

EXPERT POINT OF VIEW

ormal discussant Electra D. Paskett, PhD, Professor of Medicine at The Ohio State University, was enthusiastic about these trial results and the potential of visual inspection with acetic acid screening, as well as low-cost human papillomavirus (HPV) screening to save lives in the developing world. “To develop organized screening in low-resource areas of the world, we need to maximize participation and use tests that have maximal feasibility, af-

Can we conquer cervical cancer? I think we can, but we need to address this in the setting of poverty, where the greatest burden of this disease occurs.… I think we could save 250,000 lives each year. —Electra D. Paskett, PhD

fordability, and sensitivity. [Visual inspection with acetic acid] is simple, inexpensive, provided by trained nonmedical personnel, accurate, and can detect more lesions likely to progress,” Dr. Paskett said. Unique characteristics of the study were its population (previously unscreened women from the slums), large sample size, high participation rate, and its community-friendly nature based on community rapport. “The real implications of this study are that it was done in the setting of poverty, where knowledge is poor and the relative importance of prevention is low compared with everyday survival. Disparities in health regardless of the country are caused by poverty. The health of a country is equal to the wealth of a country,” she stated. Dr. Paskett suggested that the next study could be a comparative effectiveness study of visual inspection with acetic acid vs low-cost HPV screening. “A study done in rural China established the accuracy of low-cost HPV screening, administered by inexperienced but trained workers.1 Such a study could be done in a low-resource country if embraced by the community,” she commented. “Can we conquer cervical cancer? I think we can, but we need to address this in the setting of poverty, where the greatest burden of this disease occurs. I’m going bigger than Dr. Shastri. I think we could save 250,000 lives each year,” Dr. Paskett told listeners. n Disclosure: Dr. Paskett receives grant funding from Merck.

Reference 1. Li N, Ma CP, Sun LX, et al. Evaluation on the visual inspection with Lugol’s iodine in cervical cancer screening program. Zhonghua Liu Xing Bing Xue Za Zhi 27:15-18, 2006.

Coming in the Next Issue of The ASCO Post See next month’s issue of The ASCO Post for continuing coverage of the 2013 ASCO Annual Meeting..

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | JUNE 25, 2013

PAGE 21

News Global Oncology

ASCO Joins a Global Alliance to Enable Responsible Sharing of Genomic and Clinical Data

SCO has joined more than 70 leading health care, research, and disease advocacy organizations from around the world in taking the first steps to form an international alliance dedicated to enabling secure sharing of genomic and clinical data. The cost

comes, with great promise for medicine. The organizations participating in the Global Alliance recognize that the

public interest will be best served by working together to develop and promulgate technical and regulatory stan-

dards that make it possible to share and interpret this wealth of information in an effective and responsible manner. n

Clifford A. Hudis, MD

of genome sequencing has fallen onemillion fold, and more and more people are choosing to make their genetic and clinical data available for research, clinical, and personal use. However, interpreting these data requires an evidence base for biomedicine that is larger than any one party alone can develop, and that adheres to the highest standards of ethics and privacy. “Collaboration has been integral to our success in the field of oncology,” said Clifford A. Hudis, MD, President of ASCO. “ASCO’s participation in this global alliance underscores our belief that standards for responsible and ethical data sharing are crucial for the fastest possible development of better treatments for our patients.” Technological advances have led to large-scale collection of data on genome sequencing and clinical out-

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As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives. We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

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02/13 ONCE/ONC/0001/13

The ASCO Post | JUNE 25, 2013

PAGE 22

ASCO Annual Meeting Plenary Presentation

Pazopanib Maintenance Therapy Extends Progression-free Survival in Patients with Ovarian Cancer By Alice Goodman

aintenance therapy with the targeted therapy pazopanib (Votrient) extended progression-free

and after completion of primary treatment—to demonstrate superior outcome for a targeted therapy. Other trials have shown that bevacizumab (Avastin) given as initial therapy and continued through maintenance improves progressionfree survival.2

No Overall Survival Trend

Andreas du Bois, MD

survival in women with ovarian cancer who were disease-free following initial treatment with surgery and chemotherapy, according to results of a phase III trial presented at the 49th Annual Meeting of ASCO.1 Women on the maintenance therapy arm lived about 5.6 months longer than those on placebo. This is the first positive phase III trial in the pure maintenance setting—ie, maintenance therapy was initiated 7 months after diagnosis

“[Maintenance therapy with] pazopanib prolongs the time the patient has control over the disease vs the time the disease controls the patient’s life. Overall survival data are immature, and so far there is no survival trend in either direction. Pazopanib might be a valuable option for treatment of stage II–IV ovarian cancer,” stated lead author Andreas du Bois, MD, Professor of Gynecologic Oncology at Kliniken Essen Mitte in Essen, Germany. Dr. du Bois said toxicities of pazopanib are class-specific to angiogenesis inhibitors: hypertension, elevated liver enzymes, neutropenia, and diarrhea. Ovarian cancer has the highest

Pazopanib Maintenance in Ovarian Cancer ■ In the first successful phase III trial of maintenance therapy for ovarian cancer, pazopanib extended progression-free survival by 5.6 months.

■ Questions remain about the optimal timing of angiogenesis inhibition in ovarian cancer. Should it be given earlier, as maintenance therapy, or at relapse?

mortality among all gynecologic cancers. Seventy percent of women have advanced disease at the time of diagnosis. Although patients respond to initial therapy with surgery and chemotherapy, about 75% of patients will relapse, providing a rationale for maintenance therapy to maintain response, Dr. du Bois explained. Pazopanib is an oral, multitargeted kinase inhibitor that binds to VEGFR, PDGFR, and several other proteins involved in angiogenesis, tumor proliferation, and cell survival. The drug is approved by the U.S. Food and Drug Administration for the treatment of patients with renal cancer and soft-tissue sarcoma.

EXPERT POINT OF VIEW

ommenting on these results, Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center, New York, said, “There is currently no standard of care for maintenance therapy. Evidence continues to mount that targeting angiogenesis is important in ovarian cancer. The bottom line from several studies is that targeting angiogenesis is effective in ovarian cancer. These results show that pazopanib extends progressionfree survival as maintenance therapy, similar to the results of previous trials of bevacizumab.”

longer when treated with an angiogenesis inhibitor. We need further study and clarification about how to use these drugs. What is the right time? What is the right drug? Should we put

treat ovarian cancer is an evolving story. Neither bevacizumab nor pazopanib is approved for treatment of ovarian cancer in the United States, although bevacizumab is reg-

It’s clear to us that [ovarian cancer] patients live longer when treated with an angiogenesis inhibitor. We need further study and clarification about how to use these drugs. —Carol Aghajanian, MD

Evolving Story Given the importance of having an angiogenesis inhibitor on board, questions remain regarding how to best exploit these drugs, she continued. “It’s clear to us that patients live

off therapy when the patient is in remission, giving her a longer time when she is not on chemotherapy? The benefits might be better if we waited to treat,” she suggested. “The question of how best to

istered in Europe for use concurrently with chemotherapy and subsequently as maintenance therapy,” Dr. Aghajanian said. n Disclosure: Dr. Aghajanian reported no potential conflicts of interest.

Study Background The phase III multicenter trial included 940 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer randomly assigned in a 1:1 ratio to receive pazopanib orally for 2 years vs placebo. Patients had stage II to IV ovarian cancer and were treated successfully with standard therapy (surgery and five or more cycles of chemotherapy). After a 7-month disease-free interval, they were randomly assigned to the study arms. “Keep that extra 7 months in mind when we look at the [not yet mature] survival data, which was evaluated from time of randomization,” he noted. For the primary endpoint of progression-free survival, median time to progression from randomization was 17.9 months for the pazopanib group vs 12.3 months for placebo, representing a 5.6-month advantage for those on the targeted therapy, for a 24% reduction in risk of recurrence or death. At a median follow-up of 24.3 months, no significant difference in overall survival was observed. n

Disclosure: Dr. du Bois reported no potential conflicts of interest.

References 1. Du Bois A, Floquet A, Kim JW, et al: Randomized, double-blind placebo, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Results of an international Intergroup trial (AGO-OVAR16). ASCO Annual Meeting. Abstract LBA5503. Presented June 2, 2013. 2. Perren TJ, Swart AM, Pfisterer J, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:24842496, 2011.

ASCOPost.com | JUNE 25, 2013

PAGE 23

Journal Spotlight Hematology

Radiation-sparing Dose-adjusted EPOCH-Rituximab for Primary Mediastinal B-cell Lymphoma By Matthew Stenger

umor control is frequently not achieved with standard immunochemotherapy in patients with primary mediastinal B-cell lymphoma, requiring consolidation with mediastinal radiotherapy. However, radio-

untreated disease. Patients had a metigators at Stanford University Medidian age of 30 years (range, 19–52 cal Center who had begun to use DAyears), 59% were women, and the EPOCH-R for primary mediastinal median tumor diameter was 11 cm. B-cell lymphoma in 2007. Review of Bulky tumor with a greatest diameter charts from 2007 to 2012 identified of 10 cm or more was present in 65% 16 previously untreated patients who of patients, 78% had elevated had been consecutively treated with lactate dehydrogenase levels, DA-EPOCH-R, with none requiring and 29% had stage IV disconsolidation radiotherapy. ease. Patients received cheBaseline characteristics of these motherapy plus filgrastim patients were similar to those in the for 6 to 8 cycles, with disease prospective NCI cohort except for a sites being evaluated by comsignificantly greater age (median, 33 puted tomography (CT) afvs 30 years, P = .04) .04) and a significantsignificantter cycles 4 and 6. ly smaller proportion with extranodal After treatment, residual disease sites (19% vs 53%, P = .02). tumor mass was measured In this retrospective cohort, 100% of Wyndham Wilson, MD, PhD Kieron Dunleavy, MD 18 by FDG-PET-CT ( F-fluopatients (95% CI = 79%–100%) were rodeoxyglucose–positron-emission therapy is associated with serious late alive and event-free after median tomography-CT). Patients with a adverse effects and is still associated follow-up of 37 months (range, 5–53 maximum standardized uptake value with disease progression in approximonths). greater than that of the mediastinal mately 20% of patients. More aggresThe authors also assessed longerblood pool in the residual mediastisive chemotherapy has been associterm outcome of 18 patients in their nal mass had repeat scans at approxiated with improved outcomes. initial phase II trial of DA-EPOCH mately 6-week intervals until normalIn this context, Wyndham (no rituximab). Baseline characterisization or stabilization. Wilson, MD, PhD, and colleagues tics of these patients were similar to At a median follow-up of 63 months from the Center for Cancer Rethose of patients in the prospective (range, 3–156 months), event-free sursearch at the National Cancer InstiDA-EPOCH-R trial. Over a median tute (NCI) found that dose-intense Treating Primary Mediastinal B-cell Lymphoma chemotherapy with dose-adjusted ■ DA-EPOCH-R treatment obviated the need for radiotherapy in all but 2 of etoposide, doxo51 patients with primary mediastinal B-cell lymphoma in a prospective rubicin, and cyclocohort, and no patients had recurring disease over a median follow-up of phosphamide with vincristine and more than 5 years (maximum > 13 years). prednisone (DA-EPOCH) produced ■ In a Stanford retrospective cohort of patients receiving DA-EPOCH-R a favorable overall survival rate (79%) without radiotherapy, 100% of patients were alive and event-free after a without consolidation radiotherapy median of 37 months. in a phase II II study in primary mediastinal B-cell lymphoma patients.1 They hypothesized that the addition of vival was 93% (95% confidence interfollow-up of 16 years, event-free surrituximab (Rituxan)—DA-EPOCHval [CI] = = 81%–98%) and overall survival was 67% and overall survival was R—could further improve response. vival was 97% (95% CI = 81%–99%). 78%. Event-free survival (P = .007) As recently reported in The New Three patients had evidence of residual and overall survival (P = .01) in the England Journal of Medicine by disease, two with persistent focal discohort receiving DA-EPOCH-R Kieron Dunleavy, MD, also from the ease and one with disease progression. were significantly better than in the Center for Cancer Research at NCI, Two of the patients underwent medicohort receiving DA-EPOCH alone, and colleagues, a prospective phase II astinal radiotherapy, and one was obsuggesting that the addition of rituxtrial of DA-EPOCH-R and filgrastim served after excisional biopsy. All beimab may account for the improved (Neupogen) without radiotherapy came disease-free; one later died from outcome. performed by the NCI investigators acute myeloid leukemia (AML) while Absence of Cardiotoxcity showed high event-free and overall in remission from primary mediastinal In the NCI prospective cohort, survival in patients with primary meB-cell lymphoma at 49 months after 90% of patients received 6 cycles of diastinal B-cell lymphoma without treatment. DA-EPOCH-R and 10% received 8 late morbidity or cardiotoxic effects.2 Stanford Retrospective Cohort cycles. More than half of the patients Prospective NCI Study To provide an independent ashad a marked dose escalation (to The prospective NCI study insessment of DA-EPOCH-R, the NCI at least dose level 4, a 73% increase cluded 51 patients with previously investigators collaborated with invesover dose level 1), and 6% of patients

had no dose escalation. More than half of patients received a doxorubicin dose of 69 mg/m2 for at least 1 cycle and cumulative doses of 345 to 507 mg/m2. Left-ventricular ejection fractions were measured in 42 patients to assess cardiotoxic effects. All had normal ejection fractions for up to 10 years after treatment, and there were no significant associations between ejection fraction and length of time since treatment (P = .30) .30) or cumulative doxorubicin dose (P = .20) and no significant interaction of ejection fraction with dose and time interval (P = .40). The target absolute neutrophil count of less than 500 cells/µL occurred during 50% of the total of 294 cycles of DA-EPOCH-R. Thrombocytopenia occurred in 6% of cycles, and hospitalization for fever and neutropenia occurred in 13% of cycles. Nonhematologic toxicities were consistent with those reported in other studies of DA-EPOCH-R treatment. As noted, one patient died from AML while in remission from primary mediastinal B-cell lymphoma. Given the unexpected severe neutropenia observed in this patient during treatment, the investigators sought evidence of a germline telomerase mutation associated with chemotherapy intolerance and myeloid leukemia, and found telomerase shortening and the presence of a heterozygous mutation for the telomerase reverse transcriptase gene (TERT, codon Ala1062Thr). The investigators concluded, “The use of DA-EPOCH-R obviated the need for radiotherapy in all but 2 of 51 patients (4%) with primary mediastinal B-cell lymphoma in a prospective cohort, and no patients had recurring disease over a median follow-up of more than 5 years (maximum, > 13). Furthermore, in an independent retrospective cohort, treatment with DA-EPOCH-R … resulted in an event-free survival rate of 100%. Despite the limitations of the phase II study and the retrospective study, these findings suggest that DA-EPOCH-R is a continued on page 27

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS. Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimens). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. 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 is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. 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. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib 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 INLYTA, 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 efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. 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). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

May 2012

ASCOPost.com | JUNE 25, 2013

PAGE 27

Perspective

Joseph M. Connors, MD continued from page 1

that when they used dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [Rituxan]) to treat primary mediastinal large B-cell lymphoma in 51 patients, almost all of the patients appeared to have been cured. Specifically, the 4-year eventfree survival was 93%, and the overall survival was 97%. This apparent “home run” in lymphoma treatment is noteworthy and will be of keen interest to clinicians and lymphoma investigators. However, the déjà vu aspect arises when one notes the authors’ opinion that “DAEPOCH-R is a therapeutic advance for this type of lymphoma,”1 with the clear implication that this regimen is superior to the more widely employed standard CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab). When we encounter claims of superiority in a modestly sized phase II trial, we need to examine the evidence closely and with a healthy skepticism.

Remembering the Past Another quote is worth recalling as we consider this article about dose-adjusted EPOCH-R: George Santayana reminded us in his philosophical work The Life of Reason that “Those who cannot remember the past are condemned to repeat it.” In the 1980s, several groups, including my own, reported remarkably better outcomes for patients with diffuse large cell lymphoma when they were treated with ProMACE-CytaBOM (cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and prednisone)2; m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone)3; or MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin).4 I think it is safe to say that each of our groups was convinced that we had achieved a “home run” against this disease. Of course, history has shown

DA-EPOCH-Rituximab for B-cell Lymphoma continued from page 23

therapeutic advance for this type of lymphoma. Our results suggest that rituximab significantly improves the outcome of chemotherapy in pa-

otherwise. The eventual high-priority randomized trial led by the Southwest Oncology Group (SWOG) demonstrated that none of these regimens is in fact more effective.5,6

Role of Patient Selection Where had we gone astray? What accounted for the apparent but unverified superiority of the new-generation

Hope vs Evidence Remembering the past is very helpful when we consider the remarkable results with DA-EPOCH-R. Such phase II results do not prove superiority, but rather, suggest testable hypotheses. Fortunately, a large randomized phase III study is addressing the relative efficacy of DA-EPOCH-R and CHOP-R for diffuse large B-cell

We do not know today whether DA-EPOCH-R is genuinely superior to CHOP-R for primary mediastinal large B-cell lymphoma. The report by Drs. Dunleavy, Wilson, and colleagues does, however, move us a major step closer to finding out. —Joseph M. Connors, MD

regimens? In retrospect, it seems simple: patient selection. Try as one might, it is impossible to eliminate patient selection in phase II trials. It is important not to be misled by the term “patient selection,” which almost sounds like investigators picked and chose patients with a favorable prognosis and selectively enrolled them on their phase II trials. Nothing so egregious occurred. The “selection” arose not by intention, but as a result of passive but powerful sets of factors encouraging or discouraging trial enrollment. With the emergence of prognostic scoring systems such as the International Prognostic Index (IPI),7 we learned that factors such as age, tumor burden, organ compromise, and performance status have a powerful influence on treatment outcome. But, subsequent studies employing biologic investigations have also taught us that we cannot identify all the important prognostic factors, no matter how hard we try. Consider the impact of immunophenotype (T vs B cell) or cell of origin (germinal B cell vs activated B cell)8,9 on outcome for diffuse large B-cell lymphoma, factors entirely unappreciated when the 1980s regimens were tested.

lymphoma in general (ClinicalTrials. gov NCT00118209), and a separate trial in children with primary mediastinal large cell lymphoma (ClinicalTrials.gov NCT01516567) is underway. Those and other similar efforts will provide the evidence needed to determine if DA-EPOCH-R is a home run. There are grounds to be hopeful. The NCI group demonstrated that they could markedly reduce the use of radiation with DA-EPOCH-R and careful application of fluorodeoxyglucose positron-emission tomography (PET) for postchemotherapy assessment and follow-up. In a retrospectively gathered series, 16 patients treated with DA-EPOCH-R at Stanford had similarly impressive outcomes. Finally, there is a strong biologic rationale for infusional chemotherapy for primary mediastinal large B-cell lymphoma. However, as strong as these circumstantial pieces of evidence may seem, we need to be careful not to allow hope to triumph over evidence. We also need to remember that DA-EPOCH-R did not triumph over mantle cell lymphoma (presented at a meeting of the Lymphoma Research Foundation Mantle Cell Consortium), with the majority of

tients with primary mediastinal Bcell lymphoma.” Confirmatory evidence of this approach is currently being sought in an international trial of DA-EPOCH-R in children with primary mediastinal B-cell lymphoma (ClinicalTrials.gov

number NCT01516567). n

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

References 1. Wilson WH, Grossbard ML, Pittaluga S, et al: Dose-adjusted EPOCH chemo-

patients relapsing within 3 to 5 years of treatment. An exploratory SWOG trial testing infusional CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) showed no superiority over standard CHOP.10 A small Egyptian randomized trial of infusional EPOCH vs standard CHOP showed no difference in outcome.11 Thus, the circumstantial evidence comes down on both sides of the question.

Further Investigation Yogi Berra and George Santayana would have found much on which to agree. Both realized that the past informs the present. Lymphoma clinicians especially need to remember the past, both to encourage necessary skepticism and to provide the basis for further investigations. We do not know today whether DA-EPOCH-R is genuinely superior to CHOP-R for primary mediastinal large B-cell lymphoma. The report by Drs. Dunleavy, Wilson, and colleagues does, however, move us a major step closer to finding out. n

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

References 1. Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368:1408-1416, 2013. 2. Longo DL, DeVita VT Jr, Duffey PL, et al: Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: Results of a prospective randomized trial. J Clin Oncol 9:25-38, 1991. 3. Shipp MA, Yeap BY, Harrington DP, et al: The m-BACOD combination chemotherapy regimen in large-cell lymphoma: Analysis of the completed trial and comparison with the M-BACOD regimen. J Clin Oncol 8:84-93, 1990. 4. Klimo P, Connors JM: MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 102:596-602, 1985. 5. Fisher RI, Gaynor ER, Dahlberg S, et al: A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. continued on page 28

therapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy. Blood 99:2685-2693, 2002. 2. Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368:14081416, 2013.

The ASCO Post | JUNE 25, 2013

PAGE 28

Announcements

ASTRO to Award Society’s Highest Honor to Three Physicians and Researchers

he American Society for Radiation Oncology (ASTRO) will award Amato J. Giaccia, PhD, Radhe Mohan, PhD, FASTRO, and Prabhakar Tripuraneni, MD, FASTRO, with the Society’s highest honor—the ASTRO Gold Medal. The 2013 awardees will receive the ASTRO Gold Medal during the society’s 55th Annual Meeting in September. “Congratulations to my esteemed colleagues, Drs. Giaccia, Mohan, and Tripuraneni for receiving the ASTRO Gold Medal,” said ASTRO Chairman Michael L. Steinberg, MD, FASTRO. “Individually, they have influenced the direction of radiation oncology research, explored new technologies that guide the way we practice, and directly affected the growth of ASTRO and the specialty overall. The collective impact of their achievements has significantly improved the care for and resources available to cancer patients worldwide.” Dr. Giaccia is a radiation biologist at Stanford School of Medicine and

a 21-year ASTRO member who has made considerable contributions to radiation oncology research. His research has been focused on the role of tumor microenvironment in tumor progression and metastasis, specifically the response of tumors and normal tissue to a reduced oxygen environment, or hypoxia. “Winning the ASTRO Gold Medal is a tremendous honor for me personally, as well as for all of the past and current members of my laboratory,” Dr. Giaccia said. Dr. Mohan, a medical physicist at MD Anderson Cancer Center and 22-year ASTRO member, has had a major influence in several areas of radiation oncology, including radiation dosimetry, 3-D conformal radiation therapy, intensity modulated radiation therapy, and ongoing research in proton therapy. “Advancing the field through research, creativity and innovation is the most important contribution a physicist can make to help improve the efficiency, clinical effective-

ness and safety of patient care,” Dr. Mohan said. A 30-year ASTRO member and former ASTRO chairman, Dr. Tripuraneni, a radiation oncologist at Scripps Clinic in La Jolla California, has impacted the clinical aspect of radiation oncology through his insights in vascular brachytherapy. He was also instrumental within ASTRO through his leadership roles on ASTRO’s Board of Directors and on various committees in the areas of practice accreditation, website development and e-learning initiatives. “I am honored to receive ASTRO’s

Gold Medal and to be recognized by my peers. In many ways, I share this honor with numerous colleagues who willingly volunteer their time, energy and skill for the betterment of radiation oncology through their work on behalf of ASTRO,” said Dr. Tripuraneni.

Joseph M. Connors, MD

(CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993. 7. Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993. 8. Rosenwald A, Wright G, Chan WC,

et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937-1947, 2002. 9. Lenz G, Wright G, Dave SS, et al: Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359:23132323, 2008. 10. Gaynor ER, Unger JM, Miller TP, et al: Infusional CHOP chemotherapy

(CVAD) with or without chemosensitizers offers no advantage over standard CHOP therapy in the treatment of lymphoma: A Southwest Oncology Group Study. J Clin Oncol 19:750-755, 2001. 11. Khaled HM, Zekri ZK, Mokhtar N, et al: A randomized EPOCH vs. CHOP front-line therapy for aggressive nonHodgkin’s lymphoma patients: Long-term results. Ann Oncol 10:1489-1492, 1999.

continued from page 27

MACOP-B in patients with intermediateor high-grade non-Hodgkin’s lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol 5:91-95, 1994. 6. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen

Amato J. Giaccia, PhD

Radhe Mohan, PhD, FASTRO

Prabhakar Tripuraneni, MD, FASTRO

About the Gold Medal ASTRO’s Gold Medal, first awarded in 1977, is bestowed annually on up to three ASTRO members who have made outstanding contributions to the field of radiation oncology, including work in research, clinical care, teaching and service. n

Don’t Miss These Important Reports in This Issue of The ASCO Post Joseph M. Connors, MD, on Primary Mediastinal B-Cell Lymphoma see page 1

Ezra Cohen, MD, on Sorafenib in Thyroid Cancer see page 3

Lynn Mara Schuchter, MD, on GM-CSF plus Ipilimumab in Melanoma see page 5

Andrew Seidman, MD, on Axillary Radiotherapy in Nodepositive Breast Cancer see page 14

Electra D. Paskett, PhD, on Cervical Cancer Screening in India see page 20

Carol Aghajanian, MD, on Pazopanib Maintenance Therapy in Ovarian Cancer see page 22

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | JUNE 25, 2013

PAGE 29

FDA Update

FDA Approves Two Drugs, Companion Diagnostic Test for Advanced Skin Cancer

he U.S. Food and Drug Administration (FDA) recently approved two new drugs, dabrafenib (Tafinlar) and trametinib (Mekinist), for patients with advanced or unresectable melanoma. Dabrafenib, a BRAF inhibitor, is approved to treat patients with melanoma whose tumors express the BRAF V600E gene mutation (see page 63 in

ease have allowed for the development of Tafinlar and Mekinist, the third and fourth drugs the FDA has approved for treating metastatic melanoma in the

past 2 years,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and

Research. Vemurafenib (Zelboraf) and ipilimumab (Yervoy) were approved in 2011 for the treatment of metastatic or unresectable melanoma. n

Integrative Healing. Transform health care and promote

this issue). Trametinib, a MEK inhibitor, is approved to treat patients whose tumors express the BRAF V600E or V600K gene mutations (see page 78). Approximately half of melanomas arising in the skin have a BRAF gene mutation. Dabrafenib and trametinib were approved as single agents, not as a combination treatment.

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The FDA approved dabrafenib and trametinib with a genetic test called the THxID BRAF test, a companion diagnostic that will help determine if a patient’s melanoma cells have the V600E or V600K mutation in the BRAF gene. “Advancements in our understanding of the biological pathways of a dis-

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SGX942 Gets Fast Track Status for Treatment of Oral Mucositis

he FDA has granted fast track designation to the SGX942 development program for the treatment of oral mucositis as a result of radiation and/ or chemotherapy treatment in patients with head and neck cancer. SGX942 is a fully synthetic, 5-amino acid peptide with high aqueous solubility and stability and simultaneous anti-inflammatory and antiinfective activity. The agent has demonstrated safety in a phase I clinical study and efficacy in animal disease models. n 1888 Berkshire Lane, Plymouth, MN 55441 | toll free: (877) 742-7177 | www.unitechmedicalinc.com

The ASCO Post | JUNE 25, 2013

PAGE 30

JCO Spotlight Thoracic Oncology

KRAS Status Not Associated with Survival in Pooled Adjuvant Therapy Trials in Early-stage Lung Cancer By Matthew Stenger

RAS mutations have been reported in approximately 30% of lung adenocarcinomas. They occur most frequently in codons 12 and 13 in non– small cell lung cancer (NSCLC), and are most common in cancer in smokers and in nonsquamous NSCLC. Some data suggest that KRAS mutation is associated with poorer outcome in NSCLC. In an analysis of pooled data from NSCLC adjuvant therapy trials reported in Journal of Clinical Oncology, Frances A. Shepherd, MD, FRCPC, Professor of Medicine at the University of Toronto and Princess Margaret Cancer Centre, Toronto, Ontario, and colleagues found that, overall, KRAS mutation status was not significantly associated with overall prognosis or predictive of differential effects of adjuvant chemotherapy versus observation.1 Nevertheless, their findings did suggest a detrimental effect of chemotherapy in patients with codon 13 mutations and increased risk of secondary tumors in patients with KRAS mutations not receiving adjuvant therapy.

Study Details The analysis included patients from four randomized trials of adjuvant therapy vs observation in NSCLC patients: three Lung Adjuvant Cisplatin Evaluation (LACE) trials—consisting of IALT (stage IB-II disease), ANITA (stage IB-IIIA), and JBR.10 (stage IBII)—evaluating cisplatin-based therapy and the Cancer and Leukemia Group B (CALGB) 9633 trial (stage IB) evaluating carboplatin-based therapy. In total, the analysis included 1,543 patients, of whom 780 received adjuvant chemotherapy and 763 received observation.

KRAS mutations were found in 300 patients (19%). On univariate analysis, mutations were significantly more common in female patients, in younger patients, and in those with adenocarcinomas (34% vs 6% for squamous carcinomas and 23% for other nonadenocarcinomas). On multivariate analysis, only younger age and histology continued to be sig-

the observation group (HR = 1.04, P = .79), .79), or patients with adenocarcinoma (HR = 1.00, P = .97). Outcomes were similar for disease-free survival on these analyses. Trends toward worse overall survival in patients with KRAS mutations were observed in the subgroup with squamous carcinomas (HR = 1.41, 95% confidence interval [CI] = 0.89–

KRAS is not a significant prognostic marker in patients with resected NSCLC,... and at this time, it cannot be recommended as a tool to select patients for adjuvant chemotherapy. —Frances A. Shepherd, MD, FRCPC, and colleagues

nificantly associated with mutation. Mutations were found at codon 12 in 275 patients (92%), codon 13 in 24, and codon 14 in 1. The most frequent alteration was a G>T transversion, found in 223 patients. Mutations were found in 11 of 68 lifetime nonsmokers (codon 12 mutations in 10). The G>T transversion, considered to be the characteristic mutation from tobacco smoke exposure, accounted for 78% of codon 12 mutations in smokers (75/134) and 50% in nonsmokers (5/10).

Effect of Mutation Status After a median of 5.5 years of follow-up and accounting for effects of baseline characteristics in multivariate analyses, the presence of KRAS mutation vs wild-type KRAS was not associated with a significant effect on overall survival among all patients (hazard ratio [HR] = 1.17, P = .12; no significant heterogeneity among trials, P = .47),

KRAS Status and Selection for Lung Cancer Treatment ■ Overall, KRAS mutation status was not significantly associated with

prognosis or differential effects of adjuvant therapy vs observation on survival in early-stage resected non–small cell lung cancer.

■ Adjuvant chemotherapy was associated with significantly poorer outcome in the small group of patients with KRAS codon 13 mutations.

■ Risk for a second primary cancer was significantly increased in observation patients with KRAS mutations but nonsignificantly reduced in adjuvant chemotherapy patients.

2.23) and the subgroup with other nonadenocarcinomas (HR = 1.86, 95% CI = 1.22–2.82). Analyses by KRAS mutation subtypes vs wild-type KRAS showed no differences for codon 12 mutations, codon 13 mutations, or codon 12 mutation subgroups.

Mutation Status and Therapy There was no significant difference in risk for death in patients receiving adjuvant chemotherapy vs patients receiving observation among those with wild-type KRAS (HR = 0.89, P = .15) or mutant KRAS (HR = 1.05, P = .77; P = .37 for interaction; P = .52 for heterogeneity among trials). There was also no difference in risk when the analysis was restricted to patients with adenocarcinoma (HR = 0.88, P = .37, for wild type; HR = 0.92, P = .67, for mutant; P = .86 for interaction). Results were similar for disease-free survival. There was no significant difference in overall survival between chemotherapy and observation subgroups with codon 12 KRAS mutations (HR = 0.95, P = .77). However, adjuvant therapy was associated with significantly increased risk of death compared with observation in the subgroup of patients with codon 13 mutations (HR = 5.78, P < .001; P = .002 for interaction). Although differences were not significant, hazard ra-

tios for chemotherapy vs observation varied according to G12A or G12R (HR = 0.66, P = .48), G12C or G12V (HR = 0.94, P = .77), and G12D or G12S (HR 1.39, P = .49) subtypes of codon 12 mutation.

Risk of Second Cancers Second primary cancers were identified in 86 of 1,433 patients (data were not available from the ANITA trial). KRAS mutation was associated with a significantly increased risk of a second primary cancer among observation patients (HR = 2.76, P = .005), whereas chemotherapy patients with KRAS mutations had a nonsignificantly reduced risk (HR = 0.66, P = .40; P = .02 for interaction). The investigators noted that the finding of significantly increased risk of death in patients with codon 13 mutations who received adjuvant therapy needs to be interpreted with caution and validated in other studies, given the small number of patients (24) with codon 13 mutations in the current analysis. They also noted that the finding of reduced risk for second cancers in chemotherapy patients with KRAS mutations was unexpected. The investigators theorized that chemotherapy may have had a therapeutic effect on subclinical deposits of KRAS mutant cells in lung or other organs. The investigators concluded: KRAS is not a significant prognostic marker in patients with resected NSCLC. Overall, it is not significantly predictive of a differential benefit from adjuvant chemotherapy, particularly in patients with adenocarcinoma, and at this time, it cannot be recommended as a tool to select patients for adjuvant chemotherapy. Although our results suggest a potentially detrimental effect from chemotherapy in patients with codon 13 mutations, validation studies will be critical. n

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

Reference 1. Shepherd FA, Domerg C, Hainaut P, et al: Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. April 29, 2013 (early release online).

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Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations. Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination. Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing. 19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the Renal and urinary disorders As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. 3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go. 8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, 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 efďŹ cacy of XoďŹ go in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go. Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies. There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination. When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. ÂŠ 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: 05/2013 "3

The ASCO Post | JUNE 25, 2013

PAGE 34

Journal Spotlight Thoracic Oncology

Study Shows High Concordance of Recurrent Somatic Alterations in Primary and Matched Metastatic NSCLC By Matthew Stenger

n a study reported in Journal of Clinical Oncology, Stéphane Vignot, MD, of Institut National de la Santé et de la Recherche Medicale (INSERM) Unit 981, Paris, and Gustave Roussy Institute, Villejuif, France, and colleagues used next-generation sequencing to identify somatic alterations in archived primary tumors and matched metastatic tumor samples in patients with non–small cell lung cancer (NSCLC).1 They found a high concordance of recurrent alterations, suggesting that primary tumors may contain “much of the relevant genomic information required to guide treatment on recurrence.”

Study Details The study included 30 primary and matched metastatic tumor samples from 15 NSCLC patients who had undergone resection. Samples had to have tumor cellularity of greater than 50% (estimated median 70%). Histology was adenocarcinoma in 8 patients, squamous cell in 3, large-cell in 2, and basaloid in 2. No patient received molecular targeted therapy prior to biopsy of metastatic lesions. Patients ranged in age from 41 to 82 years; 13 were male, 14 had a history of smoking, 10 had not received chemotherapy for early-stage disease, 2 had synchronous metastasis, and metastasis was locoregional in 7. Genomic libraries were captured for 3,280 exons in 182 cancer-related genes and 37 introns from 14 genes

Mitigating the Anxiety over Tumor Heterogeneity By Jean-Charles Soria, MD, PhD

his collaborative study with Foundation Medicine (Cambridge, Massachusetts), using very sensitive deep sequencing, partially mitigates some of the anxiety generated by the identification of tumor heterogeneity. While our data in lung cancer confirm that such heterogeneity exists, they also indicate that there is a high level of concordance in recurrent driver mutations between primary tumors and their metastases. This is reassuring for clinicians when they make a therapeutic decision on Jean-Charles Soria, MD, PhD the basis of a molecular portrait. With regard to our future studies in this area, the matched primary tumors and metastases analyzed in the study were surgical samples. Therefore, there is a need to reproduce such a study in metastatic patients who present with multiple metastatic sites. To this end, multiple computed tomography–guided organ biopsies of the metastasis are necessary to harvest the relevant biologic material on which next-generation sequencing analysis can be performed. The acquisition of such material is ongoing at Institut Gustave Roussy under the umbrella of a prospective trial called MOSCATO (Molecular Screening for Cancer Treatment Optimization). Preliminary results of the trial were presented at the 2013 ASCO Annual Meeting by Dr. Antoine Hollebecque.1 n Disclosure: Dr. Soria reported no potential conflicts of interest.

Reference 1. Hollebecque A, Massard C, De Baere T, et al: Molecular screening for cancer treatment optimization (MOSCATO 01): A prospective molecular triage trial—interim results. 2013 ASCO Annual Meeting. Abstract 2512. Presented June 1, 2013. Dr. Soria is Chef du Service, Director of Site de Recherche Intégrée sur le Cancer (SIRIC) project Socrate, INSERM U981, Institut Gustave Roussy, Villejuif, France.

[O]ur results … [suggest] that genomic profiles of primary tumor reflect the genomic spectrum of the patient’s metastatic disease and can identify the key somatic alterations present in matched NSCLC metastases. —Stéphane Vignot, MD, and colleagues

often rearranged in cancer and were sequenced to high coverage (pairedend sequencing of 49 × 49 cycles). Tests for detecting alterations were validated to detect base substitutions at a ≥ 10% mutant allele frequency with ≥ 99% sensitivity and indels at a ≥ 0% mutant allele frequency with ≥ 95% 95% sensitivity and a false discovery rate of < 1%. Recurrent alterations were defined as those occurring in ≥ 5% of NSCLC samples in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported as amplified or deleted in ≥ 5% of samples in the literature; all other alterations were classified as “likely passenger alterations.”

quent recurrent alteration, found in 12 patients. Tumors had two to four recurrent alterations in 10 patients. Other mutations identified were those in GNAS (1), KRAS (3), NOTCH1 (1), PIK3CA (3), RB1 (1), SMARCA4 (2), and STK11 (3). One patient had an EGFR mutation in both the primary and metastatic tumors in association with TP53 mutation. No ALK rearrangements were identified. Large structural alterations consisted of CDKN2A deletion and amplification of FGFR1, MYC, and SOX2. Two patients had no recurrent alterations.

Overall Concordance

Analysis of 33 recurrent alterations and 159 likely passenger alterations showed concordance rates between primary and metastatic samples of 94% for recurrent alterations vs 63% for passenger alterations. Among mutations, concordance was 93% for recurrent mutations and 61% for passenger mutations. Among large structural alterations, concordance was 100% for recurrent alterations and 40% for passenger alterations. Limitations of the study include the relatively small size of the cohort and its heterogeneity in histologic subtypes and metastatic sites, with these factors limiting comparisons according to disease or treatment characteristics. As noted by the investigators, the study focused on patients with recurrence after surgery and not on patients who presented with metastatic disease or had biopsies taken from multiple sites simultaneously or sequentially after targeted treatment; such patients might

A total of 311 somatic alterations were identified among the 189 evaluated genes, including 161 in primary tumors and 150 in metastases. Tumors in one patient (who had large-cell carcinoma, a 30 pack-year history of smoking, and had received neoadjuvant chemotherapy) yielded no targeted alterations. Of the 311 alterations, 63 (20%) were known recurrent alterations (32 in primary tumors and 31 in metastases). Analysis of 170 unique mutations and 21 large structural alterations (irrespective of recurrent or passenger status) found in at least one of the paired tumor samples showed an overall rate of concordance between primary and metastatic tumors of 64% (64.5% for mutations and 59% for large structural changes). Overall, there were 26 different short alteration events (substitutions and indels) in nine genes and five large structural alterations (amplifications and deletions) in four genes. TP53 mutations were the most fre-

Concordance of Recurrent Alterations

continued on page 35

ASCOPost.com | JUNE 25, 2013

PAGE 35

News Issues In Oncology

National Institutes of Health Issues Projected Impact of Sequestration on Programs By Jo Cavallo

arlier this month, the National Institutes of Health (NIH) released its updated projections of reductions in programs due to the deficit-budget mechanism known as sequestration, which took effect on March 1, 2013. The sequestration law requires NIH to cut 5%, or $1.55 billion, of its fiscal year 2013 budget, and the cuts must apply evenly across all programs, projects, and activities. The result will mean that every area of medical research will be impacted.

The loss of revenue in research, said the report, is delaying progress in medical breakthroughs, including the development of more effective targeted cancer therapies. —NIH Fact Sheet

According to the fact sheet issued by the NIH, more than 80% of the agency’s budget goes to more than 300,000 research personnel at over 2,500 universities and research institutions nationwide. NIH also employs about 6,000 scientists in its own

NIH Updated Projections on Impact of Sequestration ■ The 5% sequestration cut to the National Institutes of Health 2013 fiscal

year budget will mean about 700 fewer competitive research project grants issued, approximately 750 fewer new patients admitted to the NIH Clinical Center, and no raise in stipends for National Research Service Award recipients.

■ According to NIH, all areas of scientific research are likely to be affected

by the budget cut, including the development of more effective cancer therapies.

■ 20,500 jobs in the life sciences and $3 billion in economic output are expected to be lost as a result of sequestration.

Somatic Alterations in NSCLC continued from page 34

have inherent genomic differences or differences that emerge under the selective pressure of targeted therapies. Overall, the findings indicate that the status of major alterations in oncogenesis in the primary tumor is “a robust surrogate” for status at first recurrence in the absence of molecular targeted therapy. The investigators concluded, “[O]ur results … reveal a high level of concordance for recurrent so-

Visit

matic alterations, suggesting that genomic profiles of primary tumor reflect the genomic spectrum of the patient’s metastatic disease and can identify the key somatic alterations

research laboratories, most of which are located on the NIH main campus in Bethesda, Maryland. The main campus also houses the NIH Clinical Center, the largest hospital in the world dedicated to clinical research, according to the agency.

Research Delays According to the report, the budget cuts will result in: • Approximately 700 fewer competitive grants issued • Approximately 750 fewer new patients admitted to the NIH Clinical Center—a decrease from 10,695 new patients in 2012 to about 9,945 new patients in 2013—although services to patients are not expected to be reduced present in matched NSCLC metastases. In these patients, biopsy of metastatic lesions can be hazardous, and samples are often limited in size. Our data indicate that archived primary

Genomics of Primary and Matched Metastatic Lung Cancer ■ Concordance of recurrent somatic alterations was 93% between the

primary tumor and matched metastasis in patients with non–small cell lung cancer.

■ Archived primary tumor may provide much of the relevant genomic information to guide treatment upon recurrence.

• No increase in stipends for National Research Service Award recipients in fiscal year 2013 The loss of revenue in research, said the report, is delaying progress in medical breakthroughs, including the development of more effective targeted cancer therapies; a universal flu vaccine that could be effective against every strain of influenza without the need for an annual shot; and a delay in the development of better treatments for common and rare diseases.

Economic Ramifications Although the budget reduction will affect all areas of research, NIH has no plans currently to furlough or lay off employees and will instead delay new hires and reduce administrative contracts. However, since NIH grant-funding spurs job creation and economic growth throughout the states, sequestration is expected to result in a loss of 20,500 jobs in the life sciences sector and $3 billion in economic output nationwide. According to NIH’s fact sheet, for every six applications submitted to the agency, only one will now be funded. n material could be a suitable specimen for clinical decision on development of metastatic disease.” n

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

Reference 1. Vignot S, Framptom GM, Soria J-C, et al: Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. April 29, 2013 (early release online).

website at ASCOPost.com

At first glAnCe, we sAw AChievement. with foCus, we see even more potentiAl. A closer look at targeting CD20 may bring new possibilities into view

CD20: A signifiCAnt tArget The advent of monoclonal antibody therapies has helped transform the treatment of hematologic malignancies.1 CD20 is an important target due to its unique features and presence on a majority of B cells.2 The success of targeting CD20 is due, in part, to the ability to activate cell death through a variety of potential mechanisms.2 In addition, CD20 is a stable antigen that is not typically down-regulated or shed upon antibody binding.2 Targeting CD20 is an important strategy for hematologic malignancies, including chronic lymphocytic leukemia (CLL).3 Despite clinical developments, certain patients with hematologic malignancies, including CLL, lack clear or effective treatment options and trade-offs between efficacy and tolerability are often made.3 To meet these needs, we continue to research anti-CD20 antibodies that optimize the potential of this target. ADvAnCements in tArgeting CD20 There is an opportunity to make additional clinical gains with new treatment options for a broader range of patients.3 As a leader in targeted treatments for B-cell malignancies, we remain committed to advancing the science of targeting CD20 in an effort to improve clinical outcomes for patients with hematologic malignancies, including CLL.

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

The ASCO Post | JUNE 25, 2013

PAGE 38

Journal Spotlight Pediatric Oncology

Reducing Unnecessary and High-dose Pediatric CT Scans Could Cut Future Cancers by More than Half

study examining trends in x-ray computed tomography (CT) use in children in the United States has found that reducing unnecessary scans and lowering the doses for the highest-dose scans could lower the overall lifetime risk of future imaging-related cancers by 62%. The research was published online in JAMA Pediatrics1 and accompanied by an editorial.2 The 4 million CT scans of the most commonly imaged organs conducted in children each year could result in approximately 4,870 future cancers, the study found. Reducing the highest 25% of radiation doses could prevent 2,090 (43%) of these future cancers. By also eliminating unnecessary imaging, 3,020 (62%) of cancers could be prevented, said Diana Miglioretti, PhD, lead study author and Dean’s Professor in Biostatistics in the Department of Public Health Sciences at UC Davis Health System. “There are potential harms from CT, meaning that there is a cancer risk, albeit very small in individual children, so it’s important to reduce this risk in two ways,” said Dr. Miglioretti, who is a member of the UC Davis Comprehensive Cancer Center. “The first is to only do a CT when it’s medically necessary, and use alternative imaging when possible. The second is to dose CT appropriately for children.” Dr. Miglioretti noted that the use of CT has increased dramatically because of the technology’s effectiveness and greater convenience over other imaging methods that do not involve ionizing radiation, such as magnetic resonance imaging (MRI), which requires that a child remain

still in a scanner for an extended period of time. Ultrasound imaging can be time-consuming. Radiation doses delivered by CT are 100 to 500 times higher than for conventional radiography, Dr. Miglioretti said.

Retrospective Study The retrospective study was conducted in diverse male and female children under 15 who were enrolled

There are potential harms from CT, meaning that there is a cancer risk, albeit very small in individual children, so it’s important to reduce this risk in two ways. The first is to only do a CT when it’s medically necessary, and use alternative imaging when possible. The second is to dose CT appropriately for children. — Diana Miglioretti, PhD

in seven integrated health-care systems: Group Health Cooperative in Washington; Kaiser Permanente in Colorado, Georgia, Hawaii, and the Northwest; and Marshfield Clinic in Wisconsin; as well as Henry Ford Health Systems in Michigan. The researchers examined CT utilization data from six of the health-care systems between 1996 and 2010. Radiation dosage and estimated cancer risk were calculated by examining 744 random CTs of the head, abdomen/pelvis, chest, and spine conducted from 2001 through 2011 at five of the health systems. The researchers said exams from these regions of the body account for

Computed Tomography in Pediatric Patients ■ A study found that the 4 million CT scans of the most commonly imaged

organs conducted in children each year could result in approximately 4,870 future cancers.

■ By reducing the highest 25% of radiation doses, 43% of these future

cancers could be prevented; by also eliminating uncessary imaging, 62% of cancers could be prevented.

■ The risk of radiation-induced leukemia and brain cancers were highest for head CT, the risk of radiation-induced solid cancer was highest for CTs of the abdomen and pelvis.

■ Dosage guidelines for imaging pediatric patients should be followed closely.

more than 95% of all CT scans. Estimated lifetime attributable risks of cancers were calculated using the Biological Effects of Ionizing Radiation (BEIR) VII report for breast, colon, liver, lung, ovarian, prostate, stomach, thyroid, bladder, and uterine cancers and leukemia, and using models developed with similar methods for oral, esophageal, rectal, pancreatic, kidney, and brain cancers,

which account for as much as 85% of all U.S. cancer incidence.

Radiation Risk Varies by Anatomic Region The study found that CT use increased between 1996 and 2005. Among children under age 5, CT use doubled from 11 in 1,000 in 1996 to 20 in 1,000 in 2005-2007, then decreased to 15.8 in 1,000 in 2010. Among children 5 to 14, CT use almost tripled, from 10.5 in 1,000 in 1996 to a peak of 27 in 1,000 in 2005 before decreasing to 23.9 in 1,000 in 2010. The researchers also found that patient radiation doses were highly variable for exams of the same anatomic region. The risk of radiation-induced leukemia and brain cancers are highest for head CT, the most commonly performed CT in children. Although the effective dose for head CT is relatively low, the brain and red bone marrow doses are relatively high for young children, resulting in the greatest risk of brain cancer and leukemia for imaged organs. The risk of radiation-induced solid cancer is highest for CTs of the abdomen and pelvis, which also had the most

dramatic increase in use, especially among older children. Breast, thyroid, and lung cancers and leukemia account for 68% of projected cancers in exposed girls; brain, lung, and colon cancer and leukemia account for 51% of future cancers in boys.

Dose-reducing Strategies Dr. Miglioretti explained that children’s organs are at an increased risk of cancer from CT scans because children still are growing and their cells are dividing rapidly. In addition, lifetime risk of cancer is greater among children because they are at the beginning of their lives—they have longer to live. She noted that physicians can reduce dosage amounts using a number of different strategies, including reducing scan length by focusing solely on the region requiring imaging. For example, when the zone of interest is the abdomen, physicians should avoid also scanning the pelvis. She said dosage guidelines for imaging pediatric patients should be followed closely. The Image Gently campaign, an initiative of the Alliance for Radiation Safety in Pediatric Imaging that encompasses the Society for Pediatric Radiology, American Association of Physicists in Medicine, American College of Radiology, and American Association of Radiologic Technicians, aims to change practice by increasing awareness of opportunities to promote radiation protection in medical imaging of children. “A smaller person needs a lower dose to come out of the machine to create an image of adequate quality for making a clinical diagnosis,” Dr. Miglioretti said. n

Disclosure: The research was supported by grant # U19CA79689 from the National Cancer Institute Cancer Research Network Across Health Care Systems, grant #R21CA131698 from the National Cancer Institute, and grant #K24CA125036.

References 1. Miglioretti DL, Johnson E, Williams A, et al: The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. JAMA Pediatr. June 10, 2013 (early release online). 2. Schroeder AR, Redberg RF: The harm in looking. JAMA Pediatr. June 10, 2013 (early release online).

MULTIPLE MYELOMA

NEVER

GIVES UP.

BUT NEITHER

DO WE. There is no cure for multiple myeloma. That’s why we’ve dedicated ourselves to three guiding principles: a relentless commitment to scientific advances, a persistent focus on patient needs, and a progressive approach to collaboration. Celgene has put these beliefs into practice for more than 15 years. And we’re not done yet.

02/13

US-CELG130012c

www.celgene.com

The ASCO Post | JUNE 25, 2013

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Direct from ASCO

In Memoriam: ASCO Remembers Founding Member Jane Cooke Wright, MD

arlier this year, ASCO and the oncology community at large lost a true pioneer, mentor, and renowned researcher. It is with great sadness that we mark the passing of Jane Cooke Wright, MD, one of seven founding members of ASCO—the only woman among the founders—and the Society’s first Secretary/Treasurer. Dr. Wright died on Tuesday, February 19, at the age of 93. In 2011, ASCO and the Conquer Cancer Foundation formally recognized Dr. Wright’s contributions to the field of oncology through the creation of the Jane C. Wright, MD, Young Investigator Award. Dr. Wright’s leadership at ASCO, her contributions to the field of oncology, and her dedication and passion for finding a cure for cancer were evident throughout her life and career. She graduated with honors from New York Medical College in 1945, interned at Bellevue Hospital, and completed her residency at Harlem Hospital. Following her residency, she continued on as a visiting physician at Harlem Hospital and was also hired as a staff physician with the New York City Public Schools.

Pioneer in Chemotherapy At a time when chemotherapy treatment was largely thought of as experimental, Dr. Wright pioneered the use of anticancer agents and developed new techniques for administering cancer chemotherapy. In 1949, she left the New York City Public School system to work with her father, who served as the Director of the Cancer Research Foundation at Harlem Hospital. Together, the two began testing a new agent on human leukemias and lymphomas, with some success. Several years later, Dr. Wright began her work at the New York University Medical Center as the Director of Cancer Chemotherapy Research. In 1964, President Lyndon B. Johnson appointed Dr. Wright to the President’s Commission on

Jane Cooke Wright, MD

Heart Disease, Cancer, and Stroke. That same year, in Chicago, seven oncologists, including Dr. Wright, assembled for lunch in the Edgewater Beach Hotel. This diverse group of physicians—who shared an interest in the fledging field of cancer chemotherapy with greater patient-related orientation—recognized the need for the creation of a separate society dedicated to issues unique to clinical oncology. It was the very first meeting of ASCO. From 1964 to 1967, Dr. Wright served as the Secretary/Treasurer of the newly formed Society. Together, the seven founding members developed a strong purpose and vision for ASCO, establishing the need for new methods to approaching the treatment of people with cancer. Much of their early meetings and discussions provided the framework for the Society’s current activities. During Dr. Wright’s tenure, membership of the Society grew to 175 members, and nearly every year since 1964, Dr. Wright attended what we know today as the ASCO Annual Meeting.

Changed the Face of Medicine Dr. Wright was a true trailblazer. At a time when African American women physicians numbered only a few hundred in the United States, she was the highest ranked African American woman at a nationally recognized medical institution. She was not only a

pioneer in the field of cancer research and treatment, but also a leader, opening minds and doors for those who would follow after her. During her 40-year career, Dr. Wright showed rigor towards scientific investigation with a keen tenderness and focus on patient care, and her contributions to the research of cancer chemotherapy have helped to change the face of medicine. If you would like to make a donation in honor of Dr. Wright and her lifetime of improving cancer care through research, you can do

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

so in support of the Jane C. Wright, MD, Conquer Cancer Foundation of ASCO Young Investigator Award. Please help us honor her memory by making a gift today: www.conquercancerfoundation .org/janewright. Dr. Wright will continue to be an inspiration for many generations to come and we will never forget the lasting impact she had on ASCO as one of our founding members. n © 2013. American Society of Clinical Oncology. All rights reserved.

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

What’s Hot in

JCO

JCO.org AVEREL: A Randomized Phase III Trial Evaluating Bevacizumab in Combination with Docetaxel and Trastuzumab as First-line Therapy for HER2-positive Locally Recurrent/Metastatic Breast Cancer by Luca Gianni, et al

Phase III, Multicenter, Randomized Trial of Maintenance Chemotherapy versus Observation in Patients with Metastatic Breast Cancer after Achieving Disease Control with Six Cycles of Gemcitabine Plus Paclitaxel as First-line Chemotherapy: KCSGBR07-02 by Yeon Hee Park, et al

Evolving Panorama of Treatment for Metastatic Pancreas Adenocarcinoma by Eileen M. O’Reilly

Randomized Phase III Study of Gemcitabine Plus S-1, S-1 Alone, or Gemcitabine Alone in Patients with Locally Advanced and Metastatic Pancreatic Cancer in Japan and Taiwan: GEST Study by Hideki Ueno, et al

Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade and Hormonal Therapy for the Treatment of Primary HER2-positive Breast Cancer: One More Step Toward Chemotherapy-free Therapy by Aleix Prat, et al

ASCOPost.com | JUNE 25, 2013

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Direct from ASCO

Philanthropy Spotlight Journal of Clinical Oncology Fosters the Development of Early-career Researchers through Support of Conquer Cancer Foundation Young Investigator Awards

he Conquer Cancer Foundation of the American Society of Clinical Oncology is dedicated to funding breakthrough research and sharing cutting-edge knowledge, and the Journal of Clinical Oncology (JCO) shares this commitment: It is ranked as the most widely read oncology journal worldwide, with a mission to serve readers as the most credible, authoritative resource for disseminating significant clinical oncology research. What may be surprising is that for more than a decade, JCO has joined the Foundation in its commitment to fund breakthrough research by annually supporting a Conquer Volume 31, Issue 15

May 20, 2013

Journal of CliniCal onCology Official Journal of the American Society of Clinical Oncology

SPECIAL SERIES The Era of Genomics-Driven Cancer Medicine Genomics-Driven Oncology: Framework for an Emerging Paradigm L.A. Garraway Clinical Analysis and Interpretation of Cancer Genome Data E.M. Van Allen et al Designing Transformative Clinical Trials in the Cancer Genome Era S. Sleijfer et al Ethical, Legal, and Counseling Challenges Surrounding the Return of Genetic Results in Oncology. M.P. Lolkema et al Genomic Medicine Frontier in Human Solid Tumors: Prospects and Challenges. R. Dienstmann et al Leveraging Cancer Genome Information in Hematologic Malignancies R. Rampal et al Future of Clinical Genomics in Pediatric Oncology. K.A. Janeway et al

www.jco.org

Cancer Foundation of ASCO Young Investigator Award.

Collaborating to Cultivate Oncology Research The Conquer Cancer Foundation of ASCO Young Investigator Award (YIA) is a 1-year grant designed to encourage and promote high-quality research in clinical oncology by providing funds to promising investigators during the transition from a fellowship program to a faculty appointment. The awards provide critical early-career research funding— an increasing rarity in the current research funding environment— and have served as a springboard for hundreds of productive and prolific oncology research careers since the first YIA was presented in 1984. JCO’s support of the YIA program began in 1997, sparked by a suggestion from George Canellos, MD, during his tenure as ASCO President as an opportunity for the Journal to encourage researchers at the beginning of their careers. “JCO prides itself in publishing the very best practice-changing research in oncology,” said Stephen A. Cannistra, MD, Editor-in-Chief of JCO. “There is no better way to ensure that such research continues than to foster the development

of early-career investigators who are dedicated to improving the lives of patients with cancer.” Supporting young investigators is a sort of cultivation, providing support for the next generation of oncologists to build a strong pipeline of Stephen A. Cannistra, MD Nancy R. Daly, MS, MPH quality research for the Metastatic Melanoma.” future, and the investment of JCO Dr. Postow hopes that the results and other YIA supporters is paying from this trial may help researchers off. A recent survey of past YIA and better understand the immunologic Career Development Award (CDA) effects of radiotherapy and how winners with 562 respondents (a therapeutic radiation may be best 70% response rate) showed that partnered with immunotherapy for the overwhelming majority—more patients with cancer. He officially rethan 99%—remain in research caceived his YIA at the Conquer Canreers, with more than 91% reporting cer Foundation Grants & Awards that their Conquer Cancer FoundaCeremony at the 2013 ASCO Antion grant was “Important” or “Very nual Meeting in Chicago during Important” to their careers. the celebration of the 30th anniverYIA Recipient Explores New sary of the Foundation’s Grants & Treatments for Melanoma Awards Program. Michael Postow, MD, is the Launchpad for Success 2013 recipient of the YIA supported JCO’s Young Investigator Award by Journal of Clinical Oncology. He has a track record of launching sucis currently a fellow in hematology cessful careers. The first recipient and oncology at Memorial Sloanin 1997 was Jeffrey Dome, MD, Kettering Cancer Center in New who is now the Chief of the DiviYork, and the title of his research sion of Oncology at Children’s Naproject is “Combining Ipilimumab continued on page 42 with Radiotherapy for Patients with

ASCO Issues Guideline Update and Videos on Fertility Preservation

SCO recently issued an update to its guideline on fertility preservation for people living with cancer, as well as two videos jointly produced with the LIVESTRONG Foundation. Both the guideline and videos are intended to raise awareness and understanding of this important area of cancer care.

Clarifications Added to Guideline The guideline, published in the Journal of Clinical Oncology, is an update to recommendations originally published in 2006 and

is based on a review of the evidence published since then. The guideline panel concluded that no major, substantive revisions to the 2006 ASCO recommendations were warranted, but clarifications were added. Specifically, the guideline further emphasizes that all oncology professionals should discuss the risk of infertility and fertility preservation options with patients with cancer in advance of their treatment. Although cancer treatment may impact fertility in both men and women, fertility preservation is frequently possible. Despite

this, fertility preservation is one of the least implemented services for young adults with cancer and many practices are currently falling short on discussing the risks of infertility and fertility preservation options. A recent analysis of self-reported data from ASCO’s Quality Oncology Practice Initiative (QOPI®) from 2006 to 2010 found that in a given collection round, practices documented fer-

tility preservation options discussion or referral to specialist for as few as 6% of patients of reproductive age.

Videos and Clinical Resources To help raise awareness on this important issue, ASCO and the LIVESTRONG Foundation worked together to produce two continued on page 43

The ASCO Post | JUNE 25, 2013

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Direct from ASCO

Early-career Researchers continued from page 41

tional Medical Center. The 2007 recipient, Donald Williams Parsons, MD, PhD, has the most cited YIA-funded research paper in the past 5 years (with over 1,000 citations) on his work identifying

IDH1 mutations in glioblastoma. The trend of success is continuing with more recent recipients, as well. TheB:8.25” 2010 recipient, Christopher Lieu, T:7.5”MD, received a 2013 Conquer S:6.75” Cancer Foundation of ASCO Career Development Award and the 2011 recipient, Samantha

Jaglowski, MD, presented her YIA research at an oral session at the 2012 ASCO Annual Meeting. “Supporting the developing careers of young researchers is vital to making advances in cancer care,” said Nancy R. Daly, MS, MPH, Executive Director of the Conquer Cancer

Cabozantinib is not approved for the use under investigation in this trial.

INVESTIGATIONAL PHASE 3 TRIAL CURRENTLY ACCRUING

Cabozantinib vs everolimus phase 3 trial in metastatic renal cell carcinoma (RCC) KEY ELIGIBILITY CRITERIA

Foundation. “As funding becomes increasingly scarce, we are grateful that our colleagues at JCO rise to the challenge each year to help establish another budding investigator’s career.” As Editor-in-Chief, Dr. Cannistra has an ambitious goal for the JCO-funded young investigators: “When JCO supports an earlycareer investigator through the Conquer Cancer Foundation, I not only see someone who will contribute to cancer research, but I see someone who may also produce work that will someday merit publication in one of the best oncology journals in the world, namely JCO,” said Dr. Cannistra. “The ability to be part of that process makes me very proud as Editor-in-Chief.” It’s certainly a strong possibility—since 2008 more than fifty research studies directly funded by Conquer Cancer Foundation grants have been published in JCO. n © 2013. American Society of Clinical -Oncology. All rights reserved.

• Diagnosis of RCC with a clear cell component

• Presence of measurable disease • Progression after prior treatment with a VEGFR-targeting tyrosine kinase inhibitor (TKI)

SECONDARY ENDPOINTS Overall Survival Objective Response Rate RCC (N=650) • Clear cell histology • Measurable disease (RECIST 1.1) • Progression after prior treatment with a VEGFR-targeting TKI

B:11.25”

PRIMARY ENDPOINT Progression-Free Survival

T:10.5”

S:9.75”

ASCO’s Guideline on Fertility Preservation

Cabozantinib 60 mg QD Randomization (1:1)

Global, randomized, open-label, controlled trial

Everolimus 10 mg QD

irect your patients to www. cancer.net/whattoknow so they can learn about ASCO’s recent guideline on fertility preservation, including what the recommendations mean for patients and a list of questions to ask the doctor. In addition, patients can view an infographic on ASCO’s recommendations for protecting their fertility before cancer treatment. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JUNE 25, 2013

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Direct from ASCO

Thirty Years of Advancing Cancer Research and Care

n the last 30 years, discoveries made through research have fueled great improvements in cancer prevention, treatment, and care. Major progress against cancer has been made, and steady investment both in scientific studies and in the careers of researchers has led to transformations in how doctors treat and prevent cancer today.

Since the first research grant given in 1984, the Conquer Cancer Foundation has been a staunch supporter of cancer research and progress through its ever-expanding Grants and Awards Program. The success of the Program, which celebrates its 30th anniversary this year, and the contributions to progress against cancer that have resulted from it are evident in the papers being published by Foundationfunded researchers in leading medical journals, the scientific presentations they’re giving at major cancer meetings, and the identification of their work as major advances in publications such as ASCO’s annual Clinical Cancer Advances report.

Highlighted Studies at the 2013 Annual Meeting Earlier this month, the excit-

Fertility Preservation continued from page 41

videos outlining the importance of discussing fertility preservation with patients. One video focuses on male fertility preservation; the other on female fertility preservation. The videos will be available on ASCO’s YouTube channel, www.youtube.com/ascocancer. The guideline, videos, and additional clinical tools and resources can all be found at: www.asco

ing work of several past and present Foundation grantees was highlighted in the official ASCO Annual Meeting press program. • Richard Carvajal, MD, received a 2010 Conquer Cancer Foundation of ASCO Career Development Award (CDA) to support his phase II study, which demonstrates that a new MEK inhibitor called selumetinib is the first drug to improve clinical outcomes in patients with advanced melanoma of the eye, a rare disease that affects only about 2,000 people in the United States. He is also the recipient of a 2008 Conquer Cancer Foundation of ASCO Young Investigator Award (YIA). • Marcia Brose, MD, PhD, recipient of a 2000 YIA, gave a prestigious plenary presentation on the results of a phase III clinical trial that shows that the targeted drug sorafenib (Nexavar) is likely the first effective therapy for a common form of advanced thyroid cancer that is resistant to standard treatments. This is the first time a kinase inhibitor like sorafenib has been evaluated in a phase III trial for this type of cancer. • Roy Herbst, MD, PhD, recipient of a 1997 YIA and 1999 CDA, presented findings on a phase I study that shows promising anticancer effects of an anti-PD-L1 drug in a variety .org/guidelines/fertility. In addition, there are courses that address fertility preservation in young men and women on ASCO University. The courses include practical case presentations based on real experiences and expert discussion, as well as access key references and resources. They can be found at: university.asco .org/focus-under-forty. n © 2013. American Society of Clinical Oncology. All rights reserved.

Richard Carvajal, MD

Marcia Brose, MD, PhD

of advanced cancers, with the strongest responses being seen in patients with non–small cell lung cancer, melanoma, and in patients who tested positive for the PD-L1 marker. Please join us in celebrating

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

Roy Herbst, MD, PhD

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

What’s Hot in

JOP

JCO.org Assessing Patient-centered Communication in Cancer Care: Stakeholder Perspectives by Kathleen M. Mazor, et al

Impact of Chemotherapy-induced Peripheral Neuropathy on Treatment Delivery in Nonmetastatic Breast Cancer by Rebecca M. Speck, et al

An Automated System for Detecting Nonadherence in Laboratory Testing and Monitoring for Myelosuppression in Patients Receiving Self-administered Oral Chemotherapy by Robert M. Morrell, et al

Hospital Management of Outpatient Oncology Treatment Decisions: A Survey to Identify Strategies and Concerns by Edward Li, et al

Patterns of Care in Palliative Radiotherapy: A Population-based Study by James D. Murphy, et al

To prevent SREs in patients with BREAST CANCER and bone metastases

vs zoledronic acid

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

27 26.4 At

Months (study end)

median time not yet reached

Months

XGEVA® 120 mg Q4W (n = 1,026)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

S:9.5”

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

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

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

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

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

RESPIRATORY Dyspnea Cough

21 15

18 15

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

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

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

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

ASCOPost.com | JUNE 25, 2013

PAGE 47

Journal Spotlight Thoracic Oncology

No Survival Benefit of ERCC1 and RRM1 Expression-based Chemotherapy in Patients with Advanced NSCLC Results may be false-negative—improved assays needed By Matthew Stenger

trial reported by Gerold Bepler, MD, PhD, of Karmanos Cancer Institute, Detroit, and colleagues in Journal of Clinical Oncology assessed whether chemotherapy selected on the basis of in situ ERCC1 and RRM1 protein levels could improve outcomes in patients with advanced non–small cell lung cancer (NSCLC).1

Study Details In this international phase III trial, 275 patients were randomly assigned 2:1 to an experimental or control arm. The experimental arm (n = 183) consisted of four groups according to ERCC1 and RRM1 status: patients with low-ERCC1 (≤ 66.0) and low-RRM1 (≤ 40.5) received gemcitabine at 1,250 mg/ m2 on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days (n = 56); those with low-RRM1/ high-ERCC1 received gemcitabine at 1,250 mg/m2 on days 1 and 8 and docetaxel at 40 mg/m2 on days 1 and 8 every 21 days (n = 37); those with high-RRM1/low-ERCC1 received docetaxel at 75 mg/m2 on day 1 and carboplatin AUC 6 on day 1 every 21 days (n = 26); and those with high-ERCC1/high-RRM1 received vinorelbine at 35 mg/m2 on days 1 and 15 and docetaxel at 50 mg/ m2 on days 1 and 15 every 28 days (n = 64). All patients in the control arm (n = 92) were treated with gemcitabine plus carboplatin regardless of protein levels. Among the 92 patients, profiles were low-RRM1/ low-ERCC1 in 33 patents, highRRM1/low-ERCC1 in 15, lowRRM1/high-ERCC1 in 19, and high-RRM1/high-ERCC1 in 25. There were no significant dif-

ferences between the experimental arm and the control arm with regard to baseline demographic or disease characteristics. The trial was powered to detect a 32% improvement in 6-month progression-free survival. Patients in both arms received a median of four treatment cycles, with there being no difference among the different treatment groups in the experimental arm in number of cycles received. Median follow-up times were 32.9 months in the experimental arm and 26.3 months in the control arm.

months in the docetaxel/vinorelbine group. By comparison, median progression-free survival durations in the four counterpart proteinexpression subgroups in the control arm were 8.1, 8.1, 6.0, and 6.3 months for the low-RRM1/lowERCC1, hihg-RRM1/lowERCC1, low-RRM1/high-ERCC1, and highRRM1/high-ERCC1 subgroups, respectively. The only significant difference in the subgroup comparisons was a prolonged progression-free survival in the low-RRM1/low-ERCC1 con-

[W]e believe that the survival results and possibly the disease response results are false negative. However, the trial clearly demonstrates feasibility of treatment assignment for patients with advanced NSCLC across countries and academic, nonacademic, and private practice settings. —Gerold Bepler, MD, PhD, and colleagues

Key Outcomes There were no significant differences in progression-free survival between the experimental arm and the control arm or among the different treatment groups in the experimental arm. The 6-month progression-free survival rate and median progression-free survival were 52.0% and 6.1 months in the experimental arm and 56.5% and 6.9 months in the control arm. Median progression-free survival durations in the experimental arm were 5.0 in the gemcitabine/carboplatin group, 6.5 in the docetaxel/ carboplatin group, 6.1 in the gemcitabine/docetaxel group, and 6.7

ERCC1 and RRM1 Expression in Non–Small Cell Lung Cancer ■ Chemotherapy selected on the basis of ERCC1 and RRM1 expression did

not improve progression-free survival in patients with advanced non–small cell lung cancer, but results may be false-negative.

■ The trial showed the feasibility of treatment assignment based on protein expression, but improved assays are needed before another trial is conducted.

trol subgroup vs the gemcitabine/ carboplatin group in the experimental arm. These two subgroups served as an internal control in the trial, since patients had the same protein expression profile and received the same treatment. The finding of a significant difference between them was thus unexpected, and, along with other considerations, raises the possibility the survival results of the trial are false-negative. There were no differences in overall survival between the experimental arm and the control arm, among treatment groups in the experimental arm, or between the experimental arm treatment groups and their counterpart protein expression subgroups in the control arm. Median overall survival was 11.0 months on the experimental arm and 11.3 months in the control arm. Objective response rates (all partial responses) were 38.8% in the experimental arm and 36.5% in the control arm. There were no significant differ-

ences in total adverse events, serious adverse events, or treatment discontinuation due to toxicity between the experimental and control arms or among the treatment groups in the experimental arm.

Approach Is Feasible In assessing the feasibility of protein analysis to guide chemotherapy selection, it was determined that the trial would meet its feasibility endpoint if more than two-thirds of registered patients had successful protein analysis. Of the 331 registered patients, protein levels were successfully determined in 301 (91%). The median time from informed consent to completed gene analysis was 11 days (range, 1–47 days). Rebiospsy for the specific purpose of gene expression analysis was required in 17% of patients. Of specimens used for protein analysis, 202 were histologic and 103 were cytologic, with no significant difference between procedures in successful vs unsuccessful initial protein analysis.

Reasons for False-negative Results As noted, the investigators believe that the survival results, and perhaps the disease response results, are false-negative, as suggested by the significantly better progression-free survival observed in the control subgroup of low/ low protein expression compared with the experimental group with low/low expression, both of which received gemcitabine/carboplatin. No differences in parameters known to affect survival were found between the two groups. A number of factors may have resulted in inaccurate protein expression measurements and inaccurate assignment of patients to protein expression groups and thus contributed to generation of false-negative results. No significant correlations between best disease response and protein or mRNA ERCC1 or RRM1 levels were observed in patients receiving gemcitabine/carboplatin, as continued on page 48

The ASCO Post | JUNE 25, 2013

PAGE 48

News

College of American Pathologists Issues Statement on Supreme Court Gene Patent Decision

n a statement released earlier this month, the College of American Pathologists applauded the unani-

“This is a landmark decision,” said the College’s President, Stanley Robboy MD, FCAP. “Genomic

medicine has the potential to be a cornerstone of medical testing, treatment, and clinical integration, but the question of ‘who owns your genes’ needed a definitive answer. Now we have it,” Dr. Robboy said. Until the Court’s recent decision, a woman could find out if she carried the mutated gene only from a test provided by Myriad at a cost of more than $3,000. The Court’s decision has now opened the door for other companies and researchers to create their own tests and conduct their own research on the previously patented genes. “The Supreme Court decision invalidating Myriad Genetics’ patents on BRCA1 and BRCA2, is a huge victory for patients,” said Debra Leonard, MD, PhD, FCAP, Chair of the College of American Pathologist’s Personalized Health Care Committee. “It

ment (monoclonal antibody 8F1) may detect other molecules of similar immunoreactivity and cellular localization as ERCC1. In contrast to earlier findings, data obtained from fresh-frozen tumor specimens showed no correlation of RRM1 protein and mRNA levels in the current trial. The investigators commented, “[We]believe that the survival results and possibly the disease response re-

sults are false negative. However, the trial clearly demonstrates feasibility of treatment assignment for patients with advanced NSCLC across countries and academic, nonacademic, and private practice settings.” They continued, “We conclude that further assay development with special attention to reagent specificity, day-today assay conditions, and site-specific specimen processing is desirable be-

ogists was a co-plaintiff in the case Association of Molecular Pathology et al vs Myriad Genetics, Inc, which

Genomic medicine has the potential to be a cornerstone of medical testing, treatment, and clinical integration, but the question of ‘who owns your genes’ needed a definitive answer. Now we have it. —Stanley Robboy MD, FCAP

mous Supreme Court decision invalidating the patents held by Myriad Genetics on the BRCA1 and BRCA2 genes, calling the decision “a victory for patients and for science.” The College of American Pathol-

ERCC1 and RRM1 Expression continued from page 47

has been previously reported. This finding may be related to interinstitutional variations in specimen collection and processing observed in the current trial and in other studies. There was also no correlation between ERCC1 protein and mRNA levels. This may be related to the fact that the reagent used for in situ measure-

the court decided on June 13, 2013.

Landmark Decision

Debra Leonard, MD, PhD, FCAP

will allow women to receive life saving, state-of-the-art genetic tests without being forced to trust one provider or one laboratory performing a single test to secure a diagnosis or inform treatment,” Dr. Leonard said. For more information, visit www. cap.org/advocacy. Plus, see next month’s issue of The ASCO Post for more on the recent Supreme Court decision. n fore another trial is launched.” n

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

Reference 1. Bepler G, Williams C, Schell MJ, et al: Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. May 20, 2013 (early release online).

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When hemoglobin falls...

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

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

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

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

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

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

RBC = red blood cell.

Hb = hemoglobin.

Q3W = once every three weeks.

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

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

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

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

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

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

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

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

"MM 1MBDFCP controlled Studies

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

DRUG INTERACTIONS

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

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

OVERDOSAGE

Aranesp overdosage can cause hemoglobin levels above the desired level, which TIPVME CF NBOBHFE XJUI EJTDPOUJOVBUJPO PS SFEVDUJPO PG "SBOFTQ EPTBHF BOE PS XJUI QIMFCPUPNZ BT DMJOJDBMMZ JOEJDBUFE $BTFT PG TFWFSF IZQFSUFOTJPO IBWF CFFO PCTFSWFE GPMMPXJOH PWFSEPTF XJUI &4"T

Aranesp Placebo Aranesp Placebo O O O O

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ASCOPost.com | JUNE 25, 2013

PAGE 53

Journal Spotlight Gastrointestinal Oncology

Similar Short-term Outcomes with Laparoscopic vs Open Surgery for Rectal Cancer By Matthew Stenger

s recently reported in Lancet Oncology by Martijn H.G.M. van der Pas, MD, of VU University Medical Center, Amsterdam, and colleagues, the phase III COLOR II trial has shown that laparoscopic surgery can produce similar safety outcomes, resection margins, and completeness of resection compared with open surgery in patients with rectal cancer, with laparoscopic surgery being associated with improved recovery.1 Results for locoregional recurrence, the primary endpoint of the trial, are expected by the end of 2013.

Study Details Between January 2004 and May 2010, 1,044 evaluable patients aged 18 years or older with rectal cancer within 15 cm from the anal verge without evidence of distant metastases were randomly assigned to laparoscopic surgery (n = 699) or open surgery (n = 345). Patients with rectal cancer invading adjacent tissues or organs, T4 tumors, or T3 tumors within 2 mm of the endopelvic fascia were excluded from the study. Analysis of outcomes was by modified intention to treat, excluding patients with postrandomization exclusion criteria and for whom data were not available. For the laparoscopic group and the open surgery group: 64% and 61% were male; mean ages were 67 and 66 years; 23%, 57%, 19%, and < 1% and 19%, 62%, 18%, and < 1% were in American Society of Anesthesiologists categories I, II, III, and IV, respectively; mean body mass index was 26.1 and 26.5 kg/m2; tumor loca-

tions were lower, middle, and upper rectum in 29%, 39%, and 32% and in 27%, 39%, and 34%, respectively; clinical stages were I, II, and III in 30%, 31%, and 38% and in 29%, 33%, and 38%, respectively; 59% and 58% had received preoperative radiotherapy; and 32% and 34% had received preoperative chemotherapy. The distribution of procedures performed was similar in the laparoscopic and open surgery groups, including resection with partial (10% and 10%)

dian, 200 mL vs 400 mL; P < .0001). There were no significant differences between groups with regard to intraoperative complications except for nerve injury, which occurred in none of the patients in the laparoscopic surgery group and in three patients in the open surgery group (P = .036). There were no significant differences between groups with regard to analgesic drug use on days 1 to 3, except for greater use of epidural medication in the open surgery group on days 2

[I]n selected patients treated by skilled surgeons, laparoscopic resection of rectal cancer provided oncologic radicality, using the pathology report as a proxy, similar to open surgery. —Martijn H.G.M. van der Pas, MD

or total (60% and 67%) mesorectal excision and abdominoperineal resection (29% and 23%). Hartmann procedures were performed in 5% and 7% of patients, and 35% and 38% of patients with an anastomosis had diverting ileostomies; of those with ileostomies, 33% and 38% were in the upper rectum, 49% and 54% were in the middle rectum, and 17% and 15% were in the lower rectum. Laparoscopic procedures were converted to open surgery in 17% of patients in the laparoscopic surgery group (intraoperatively in 16%).

Short-term Outcomes Laparoscopic procedures took significantly longer than open procedures (median, 240 vs 188 minutes; P < .0001) but were associated with significantly reduced blood loss (me-

Surgery for Rectal Cancer ■ In selected patients with rectal cancer treated by skilled surgeons,

laparoscopic surgery resulted in similar safety outcomes, resection margins, and completeness of resection compared with open surgery.

■ Laparoscopic surgery was associated with reduced blood loss and shorter hospital stay.

■ Findings on locoregional recurrence are expected by the end of the year.

(64% vs 51%, P = .0003) and 3 (38% vs 30%, P = .007). Bowel function returned significantly sooner after surgery in the laparoscopic surgery group (median, 2.0 vs 3.0 days; P < .0001). There was no difference between groups with regard to overall rate of postoperative complications (40% and 37%) or with regard to rates of cardiac complications, anastomotic leak, respiratory complications, abscess, wound infection, or ileus. Reintervention occurred in 16% of the laparoscopic surgery group and 15% of the open surgery group. Hospital stay was significantly reduced by 1 day in the laparoscopic surgery group (median 8.0 vs 9.0 days, P = .036). There There was no diff differerence between the two groups in 28day mortality (1% vs 2%, P = .409).

Pathology Outcomes With regard to pathology, resection was macroscopically complete in 88% of the laparoscopic surgery group and 92% of the open surgery group (P = .250). Incomplete resections occurred in patients in both groups, with incomplete resection specimens being more commonly from the upper rectum in the lapa-

roscopic surgery group (1% vs <1%, P = .026). There was no difference in proportion of patients (10% and 10%) with positive circumferential resection margins (< 2 mm); positive circumferential resection margins were more likely to be from the middle rectum in the laparoscopic surgery group (10% vs 3%, P = .068) and significantly more likely to be from the lower rectum in the open surgery group (22% vs 9%, P = .014). Neither median circumferential resection margin (1 cm in both groups) nor median tumor distance to distal resection margin (3 cm in both groups) differed between groups. There was no difference between groups with regard to number of harvested lymph nodes, pathology stage of tumors, or proportions of patients with no residual tumor after preoperative radiation or chemoradiation therapy. The authors noted that the findings of the study are not applicable to all patients with rectal cancer, since patients with T3 cancer within 2 mm from the endopelvic fascia or T4 cancers were excluded. They concluded, “[I]n selected patients treated by skilled surgeons, laparoscopic resection of rectal cancer provided oncologic radicality, using the pathology report as a proxy, similar to open surgery. In-hospital recovery after laparoscopic surgery was better than after open surgery. Long-term follow-up to assess local recurrence and survival is necessary to ascertain oncological safety of laparoscopic resection in patients with rectal cancer.” n Disclosure: Funding for the study was provided by Ethicon End-Surgery Europe, Swedish Cancer Foundation, West Gothia Region, Sahlgrenska University Hospital. The authors reported no potential conflicts of interest.

Reference 1. van der Pas MHG, Haglind E, Cuesta MA, et al: Laparoscopic versus open surgery for rectal cancer (COLOR II): Short-term outcomes of a randomized, phase 3 trial. Lancet Oncol 14:210218, 2013.

The ASCO Post | JUNE 25, 2013

PAGE 54

Journal Spotlight Hematology

Identification of Oncogenic Mutations in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia By Matthew Stenger

mong the hematologic cancers for which molecular causes remain unclear are chronic neutrophilic leukemia and atypical (BCRABL1–negative) chronic myeloid leukemia. Both disorders currently are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic factors known to occur in other myeloproliferative cancers. In a study recently reported in The New England Journal of Medicine, Julia E. Maxson, PhD, of Oregon Health & Science University, Portland, and colleagues identified activating mutations in the gene encoding for colony-stimulating factor 3 receptor (CSF3R) in a majority of patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia.1 Identification of these mutations may prove useful in diagnosis and in suggesting potential treatment strategies. To identify potential genetic drivers, the investigators used deep-sequencing analysis and screening of primary leukemia cells from chronic neutrophilic leukemia and atypical chronic myeloid leukemia patients against panels of tyrosine kinase–specific small interfering RNAs or smallmolecule kinase inhibitors. The candidate oncogenes were validated with in vitro transformation assays, and drug sensitivities were validated using primary cell colony assays.

CSF3R Mutations in 59% Enrichment of mutations in CSF3R were found in 16 (59%) of 27 patients with chronic neutrophilic leukemia or atypical chronic my-

The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of SRC family–TNK2 and JAK kinases and may provide a new avenue for therapy [in chronic neutrophilic leukemia and atypical chronic myeloid leukemia]. —Julia E. Maxson, PhD, and colleagues

eloid leukemia. Sequence variants included membrane proximal mutations (T615A and T618I) and several frameshift or nonsense mutations that truncate the cytoplasmic tail of CSF3R (D771fs, S783fs, Y752X, and W791X). The investigators noted that similar mutations that truncate the CSF3R cytoplasmic domain have been found in patients with congenital neutropenia that progresses to acute myeloid leukemia after long-term granulocyte colony-stimulating factor (filgrastim [Neupogen]) treatment. Five of the patients had both membrane proximal and truncation mutations, and it was found that these compound mutations can occur on the same CSF3R allele with no required order of mutation acquisition. In comparison, CSF3R mutations were found in only 3 (1%) of 292 patients with acute myeloid leukemia (including 2 of 200 in the Cancer Genome Atlas acute myeloid leukemia dataset), 0 of 8 with T-cell acute lymphoblastic leukemia, 1 of 3 with early T-cell precursor T-cell acute lymphoblastic leukemia, and 0 of 41 with B-cell acute lymphoblastic leukemia. As stated by the investigators, “Taken together, these data suggest that mutations in CSF3R are a defining molecular abnormality of [chronic neutrophilic leukemia]

CSF3R Mutations in Acute Leukemias ■ CSF3R mutations were found in 59% of patients with chronic neutrophilic leukemia or atypical chronic myeloid leukemia.

■ Membrane-proximal mutations resulted in dysregulation of JAK family

kinases and conferred sensitivity to JAK kinase inhibitors, whereas cytoplasmic domain truncation mutations resulted in dysregulation of SRC family–TNK2 kinases and sensitivity to inhibitors of these kinases.

■ A chronic neutrophilic leukemia patient with a JAK-activating mutation

had marked clinical improvement with treatment with the JAK1/2 inhibitor ruxolitinib.

and atypical [chronic myeloid leukemia], and testing for CSF3R mutations could aid in the diagnosis of these diseases.”

Characteristics of Two Mutation Types Analysis of cells from a small number of patients with either truncation mutations or membrane proximal mutations revealed important differences between the two types

of mutation with regard to downstream kinase signaling and sensitivity to kinase inhibitors. In particular, it was found that truncation mutations result in dysregulation of SRC family-TNK2 kinases and that membrane proximal mutations result in dysregulation of JAK family kinases. Truncation mutations conferred sensitivity to SRC family-TNK2 inhibition, including sensitivity to the multikinase inhibitor dasatinib (Sprycel) but not to JAK kinase inhibitors, whereas membrane-proximal mutations conferred sensitivity to JAK kinase inhibitors including ruxolitinib ( Jakafi) but not to SRC family-TNK2 inhibitors.

Response to Ruxolitinib Primary cells from a patient with continued on page 57

New Insights into Treatment for Two Types of Leukemia By Julia E. Maxson, PhD, and Jeffrey W. Tyner, PhD

he combination of functional and genomic screens has allowed us to accelerate the identification of oncogenes, as well as drug sensitivity that corresponds with those oncogenes. In the present study, we found Jeffrey W. Tyner, PhD Julia E. Maxson, PhD that CSF3R mutations define chronic neutrophilic leukemia and atypical chronic myeloid leukemia—two forms of leukemia that were not previously associated with any defining genetic lesions. Through our integrated approach of functional screening and genomic analysis on primary patient samples, we were able to demonstrate that CSF3R membrane-proximal mutations confer sensitivity to JAK kinase inhibitors, while CSF3R truncation mutations confer sensitivity to SRC inhibitors. This mechanism of differential drug sensitivity by two types of mutations within the same gene was significantly accelerated by the integrated functional genomic screening paradigm. Our next step will be to apply this functional genomic pipeline to other leukemias to match other genetic drivers with targeted therapies. n Disclosure: Drs. Maxson and Tyner reported no potential conflicts of interest.

Dr. Maxson is Postdoctoral Fellow and Dr. Tyner is Assistant Professor, Knight Cancer Institute and Cell & Developmental Biology Department, Oregon Health and Science University, Portland.

SUTENT® (sunitinib malate) is indicated for the treatment of advanced renal cell carcinoma (RCC).

With 11 months’ median PFS in 1st-line mRCC...

THIS IS NOT JUST ANOTHER SUNDAY. IT’S ANOTHER SUNDAY.

April: Follow-up scan

January: Started SUTENT

EX 7 PE YE RI AR EN S’ CE *

This moment

In the phase 3, randomized, 1st-line mRCC trial vs IFNα (N=750)...

SUTENT demonstrated 11 months’ median PFS

• 26.4 months vs 21.8 months with IFNα (HR=0.82; 95% CI: 0.673, 1.001; P =.051)

100

Nearly 40% of patients on SUTENT achieved an objective response

MONTHS

PFS probability (%)

SUTENT achieved more than 2 years’ median OS1

SUTENT (n=375) (95% CI: 9.8, 11.7)

(n=375)

(95% CI: 3.8, 5.5)

HR=0.42; 95% CI: 0.32, 0.54; P<.000001

0 0

• 28% vs 5% with IFNα (95% CI: 23.0, 32.3 and 3.3, 8.1, respectively; P<.001) in the ﬁrst analysis (November 2005)

SUTENT has a well-known safety profile

MONTHS

IFNα

• 39% vs 8% with IFNα (95% CI: 33.7, 43.8 and 5.2, 10.9, respectively; P<.001) in the ﬁnal analysis (March 2010)2

Time (months)

All data are from the large (N=750), phase 3, randomized, multicenter trial comparing SUTENT with IFNα in patients with treatment-naïve mRCC. Patients were treated with either 50-mg SUTENT once daily in cycles of 4 weeks on/2 weeks off, or 9 MIU IFNα 3 times per week until disease progression or study withdrawal. Primary endpoint was PFS. Secondary endpoints included ORR, OS, and safety. *Since FDA approval.

Important Safety Information Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Given the potential for serious ARs in nursing infants, a decision should be made whether to discontinue nursing or SUTENT. Cardiovascular events, including heart failure, myocardial disorders, and cardiomyopathy, some of which were fatal, have been reported. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies. SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered. Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled. There have been rare (<1%) nonfatal reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Hemorrhagic events, including tumor-related hemorrhage such as pulmonary hemorrhage, have occurred. Some of these events were fatal. Perform serial complete blood counts (CBCs) and physical examinations. Osteonecrosis of the jaw (ONJ) has been reported. Consider preventive dentistry prior to treatment with SUTENT. If possible, avoid invasive dental procedures, particularly in patients receiving bisphosphonates. Cases of tumor lysis syndrome (TLS) have been reported primarily in patients with high tumor burden. Monitor these patients closely and treat as clinically indicated. Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice. Cases of impaired wound healing have been reported. Temporary interruption of therapy with SUTENT is recommended in patients undergoing major surgical procedures.

• The most common ARs occurring in ≥20% of patients receiving SUTENT for treatment-naïve mRCC (all grades, vs IFNα) were diarrhea, fatigue, nausea, anorexia, altered taste, mucositis/stomatitis, pain in extremity/limb discomfort, vomiting, bleeding (all sites), hypertension, dyspepsia, arthralgia, abdominal pain, rash, hand-foot syndrome, back pain, cough, asthenia, dyspnea, skin discoloration/yellow skin, peripheral edema, headache, constipation, dry skin, fever, and hair color changes. The most common grade 3/4 ARs (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) were fatigue, hypertension, asthenia, diarrhea, hand-foot syndrome, dyspnea, nausea, back pain, pain in extremity/limb discomfort, vomiting, and abdominal pain • The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) included lymphocytes, lipase, neutrophils, uric acid, platelets, hemoglobin, sodium decreased, leukocytes, glucose increased, phosphorus, and amylase

Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection. CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT. Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers. The most common ARs occurring in ≥20% of patients receiving SUTENT for treatment-naïve mRCC (all grades, vs IFNα) were diarrhea (66% vs 21%), fatigue (62% vs 56%), nausea (58% vs 41%), anorexia (48% vs 42%), altered taste (47% vs 15%), mucositis/stomatitis (47% vs 5%), pain in extremity/limb discomfort (40% vs 30%), vomiting (39% vs 17%), bleeding, all sites (37% vs 10%), hypertension (34% vs 4%), dyspepsia (34% vs 4%), arthralgia (30% vs 19%), abdominal pain (30% vs 12%), rash (29% vs 11%), hand-foot syndrome (29% vs 1%), back pain (28% vs 14%), cough (27% vs 14%), asthenia (26% vs 22%), dyspnea (26% vs 20%), skin discoloration/yellow skin (25% vs 0%), peripheral edema (24% vs 5%), headache (23% vs 19%), constipation (23% vs 14%), dry skin (23% vs 7%), fever (22% vs 37%), and hair color changes (20% vs <1%). The most common grade 3/4 ARs (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) were fatigue (15% vs 15%), hypertension (13% vs <1%), asthenia (11% vs 6%), diarrhea (10% vs <1%), hand-foot syndrome (8% vs 0%), dyspnea (6% vs 4%), nausea (6% vs 2%), back pain (5% vs 2%), pain in extremity/limb discomfort (5% vs 2%), vomiting (5% vs 1%), and abdominal pain (5% vs 1%). The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) included lymphocytes (18% vs 26%), lipase (18% vs 8%), neutrophils (17% vs 9%), uric acid (14% vs 8%), platelets (9% vs 1%), hemoglobin (8% vs 5%), sodium decreased (8% vs 4%), leukocytes (8% vs 2%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and amylase (6% vs 3%). ARs=adverse reactions; mRCC=metastatic renal cell carcinoma; ORR=objective response rate; OS=overall survival; PFS=progression-free survival. References: 1. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584-3590. 2. Data on ﬁle. Pﬁzer Inc, New York, NY.

Please see Study Description and Brief Summary, including Boxed Warning, on the following pages.

Evidence. Experience. Every Day.

T:10” S:9.5”

Results of the phase 3, randomized, multicenter, international trial. 750 treatment-naïve patients were treated with either 50-mg SUTENT once daily in cycles of 4 weeks on/2 weeks off, or 9 MIU IFNα 3 times per week (administered subcutaneously) until disease progression or study withdrawal. Primary endpoint was progression-free survival, and secondary endpoints included objective response rate by Response Evaluation Criteria in Solid Tumors, overall survival, and safety. SUTENT® (SUNITINIB MALATE) CAPSULES, ORAL Brief Summary of Prescribing Information WARNING: HEPATOTOXICITY Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported. [See Warnings and Precautions] INDICATION AND USAGE: SUTENT is indicated for the treatment of advanced renal cell carcinoma (RCC). DOSAGE AND ADMINISTRATION Recommended Dose. The recommended dose of SUTENT for advanced RCC is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). SUTENT may be taken with or without food. Dose Modification. Dose interruption and/or dose modification in 12.5 mg increments or decrements is recommended based on individual safety and tolerability. A dose reduction for SUTENT to a minimum of 37.5 mg daily should be considered if SUTENT must be co-administered with a strong CYP3A4 inhibitor. A dose increase for SUTENT to a maximum of 87.5 mg daily should be considered if SUTENT must be co-administered with a CYP3A4 inducer. If dose is increased, the patient should be monitored carefully for toxicity. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hepatotoxicity. SUTENT has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 x ULN or, if due to liver metastases, >5.0 x ULN has not been established. Pregnancy. SUTENT can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of SUTENT should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of SUTENT in pregnant women. If the 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 avoid becoming pregnant while receiving treatment with SUTENT.

SUTT3X1782_A_10x13_Sutent_BS_2013_r4.indd 1

ADVERSE REACTIONS The data described below reflect exposure to SUTENT in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of gastrointestinal stromal tumor (GIST), an active-controlled trial (n=375) for the treatment of RCC or a placebo-controlled trial (n=83) for the treatment of pancreatic neuroendocrine tumors (pNET). The RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles. The most common adverse reactions (≥20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, and bleeding. The potentially serious adverse reactions of hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function are discussed in Warnings and Precautions. Other adverse reactions occurring in RCC studies are described below. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Treatment-Naïve RCC Study. The as-treated patient population for the treatment-naïve RCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 - 46.1) for SUTENT treatment and 4.1 months (range: 0.1 - 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on SUTENT and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on SUTENT and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for SUTENT and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on SUTENT versus IFN-α, respectively. The following table compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving SUTENT versus IFN-α. Adverse Reactions Reported in at Least 10% of Patients with RCC Who Received SUTENT or IFN-α*

SUTENT (n=375) IFN-α (n=360) Adverse Reaction, n (%) All Grades Grade 3/4a All Grades Grade 3/4b Any 372 (99) 290 (77) 355 (99) 197 (55) Constitutional Fatigue 233 (62) 55 (15) 202 (56) 54 (15) Asthenia 96 (26) 42 (11) 81 (22) 21 (6) Fever 84 (22) 3 (1) 134 (37) 1 (<1) Weight decreased 60 (16) 1 (<1) 60 (17) 3 (1) Chills 53 (14) 3 (1) 111 (31) 0 (0) Chest Pain 50 (13) 7 (2) 24 (7) 3 (1) Influenza like illness 18 (5) 0 (0) 54 (15) 1 (<1) Gastrointestinal Diarrhea 246 (66) 37 (10) 76 (21) 1 (<1) Nausea 216 (58) 21 (6) 147 (41) 6 (2) Mucositis/stomatitis 178 (47) 13 (3) 19 (5) 2 (<1) Vomiting 148 (39) 19 (5) 62 (17) 4 (1) Dyspepsia 128 (34) 8 (2) 16 (4) 0 (0) 113 (30) 20 (5) 42 (12) 5 (1) Abdominal painc Constipation 85 (23) 4 (1) 49 (14) 1 (<1) Dry mouth 50 (13) 0 (0) 27 (7) 1 (<1) GERD/reflux esophagitis 47 (12) 1 (<1) 3 (1) 0 (0) Flatulence 52 (14) 0 (0) 8 (2) 0 (0) Oral pain 54 (14) 2 (<1) 2 (1) 0 (0) Glossodynia 40 (11) 0 (0) 2 (1) 0 (0) Hemorrhoids 38 (10) 0 (0) 6 (2) 0 (0) Cardiac Hypertension 127 (34) 50 (13) 13 (4) 1 (<1) Edema, peripheral 91 (24) 7 (2) 17 (5) 2 (1) Ejection fraction decreased 61 (16) 10 (3) 19 (5) 6 (2) Dermatology Rash 109 (29) 6 (2) 39 (11) 1 (<1) Hand-foot syndrome 108 (29) 32 (8) 3 (1) 0 (0) Skin discoloration/ yellow skin 94 (25) 1 (<1) 0 (0) 0 (0) Dry skin 85 (23) 1 (<1) 26 (7) 0 (0) Hair color changes 75 (20) 0 (0) 1 (<1) 0 (0) Alopecia 51 (14) 0 (0) 34 (9) 0 (0) Erythema 46 (12) 2 (<1) 5 (1) 0 (0) Pruritus 44 (12) 1 (<1) 24 (7) 1 (<1) Neurology 178 (47) 1 (<1) 54 (15) 0 (0) Altered tasted Headache 86 (23) 4 (1) 69 (19) 0 (0) Dizziness 43 (11) 2 (<1) 50 (14) 2 (1) Musculoskeletal Back pain 105 (28) 19 (5) 52 (14) 7 (2) Arthralgia 111 (30) 10 (3) 69 (19) 4 (1) Pain in extremity/ limb discomfort 150 (40) 19 (5) 107 (30) 7 (2) Endocrine Hypothyroidism 61 (16) 6 (2) 3 (1) 0 (0) Respiratory Cough 100 (27) 3 (1) 51 (14) 1 (<1) Dyspnea 99 (26) 24 (6) 71 (20) 15 (4) Nasopharyngitis 54 (14) 0 (0) 8 (2) 0 (0) Oropharyngeal Pain 51 (14) 2 (<1) 9 (2) 0 (0) Upper respiratory tract infection 43 (11) 2 (<1) 9 (2) 0 (0) Metabolism/Nutrition e 182 (48) 11 (3) 153 (42) 7 (2) Anorexia Hemorrhage/Bleeding 35 (10) 3 (1) Bleeding, all sites 140 (37) 16 (4)f Psychiatric Insomnia 57 (15) 3 (<1) 37 (10) 0 (0) 40 (11) 0 (0) 51 (14) 5 (1) Depressiong *Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 a Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%) and rash (<1%). b Grade 4 ARs in patients on IFN-α included dyspnea (1%), fatigue (1%), abdominal pain (<1%) and depression (<1%). c Includes flank pain d Includes ageusia, hypogeusia and dysgeusia e Includes decreased appetite f Includes one patient with Grade 5 gastric hemorrhage g Includes depressed mood

Treatment-emergent Grade 3/4 laboratory abnormalities are presented below. Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve RCC Patients Who Received SUTENT or IFN-α

SUTENT (n=375) IFN-α (n=360) Laboratory All Grades* Grade 3/4*a All Grades* Grade 3/4*b Parameter, n (%) Gastrointestinal AST 211 (56) 6 (2) 136 (38) 8 (2) ALT 192 (51) 10 (3) 144 (40) 9 (2) Lipase 211 (56) 69 (18) 165 (46) 29 (8) Alkaline phosphatase 171 (46) 7 (2) 132 (37) 6 (2) Amylase 130 (35) 22 (6) 114 (32) 12 (3) Total bilirubin 75 (20) 3 (1) 8 (2) 0 (0) Indirect bilirubin 49 (13) 4 (1) 3 (1) 0 (0) Renal/Metabolic Creatinine 262 (70) 2 (<1) 183 (51) 1 (<1) Creatine kinase 183 (49) 9 (2) 40 (11) 4 (1) Uric acid 173 (46) 54 (14) 119 (33) 29 (8) Calcium decreased 156 (42) 4 (1) 145 (40) 4 (1) Phosphorus 116 (31) 22 (6) 87 (24) 23 (6) Albumin 106 (28) 4 (1) 72 (20) 0 (0) Glucose increased 86 (23) 21 (6) 55 (15) 22 (6) Sodium decreased 75 (20) 31 (8) 55 (15) 13 (4) Glucose decreased 65 (17) 0 (0) 43 (12) 1 (<1) Potassium increased 61 (16) 13 (3) 61 (17) 15 (4) Calcium increased 50 (13) 2 (<1) 35 (10) 5 (1) Potassium decreased 49 (13) 3 (1) 7 (2) 1 (<1) Sodium increased 48 (13) 0 (0) 38 (10) 0 (0) Hematology Neutrophils 289 (77) 65 (17) 178 (49) 31 (9) Hemoglobin 298 (79) 29 (8) 250 (69) 18 (5) Platelets 255 (68) 35 (9) 85 (24) 2 (1) Lymphocytes 256 (68) 66 (18) 245 (68) 93 (26) Leukocytes 293 (78) 29 (8) 202 (56) 8 (2) *Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 a Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%). b Grade 4 laboratory abnormalities in patients on IFN-α included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%) and hemoglobin (<1%). Venous Thromboembolic Events. Thirteen (3%) patients receiving SUTENT for treatmentnaïve RCC had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from SUTENT due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. Reversible Posterior Leukoencephalopathy Syndrome. There have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these subjects had a fatal outcome to the event. Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician. Pancreatic and Hepatic Function. If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued. Pancreatitis was observed in 5 (1%) patients receiving SUTENT for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Hepatotoxicity was observed in patients receiving SUTENT [See Boxed Warning and Warnings and Precautions]. Post-marketing Experience. The following adverse reactions have been identified during post-approval use of SUTENT. 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. Blood and lymphatic system disorders: thrombotic microangiopathy; hemorrhage associated with thrombocytopenia*. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician. Immune system disorders: hypersensitivity reactions, including angioedema. Infections and infestations: serious infection (with or without neutropenia)*; necrotizing fasciitis, including of the perineum*. The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections and sepsis. Metabolism and nutrition disorders: TLS* [see Warnings and Precautions]. Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression*; ONJ [see Warnings and Precautions]; myopathy and/or rhabdomyolysis with or without acute renal failure*. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice. Renal and urinary disorders: renal impairment and/or failure*; proteinuria; rare cases of nephrotic syndrome. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue SUTENT in patients with nephrotic syndrome. Respiratory disorders: pulmonary embolism*; pulmonary hemorrhage* [see Warnings and Precautions] Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive dechallenges Vascular disorders: arterial thromboembolic events*. The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction. *including some fatalities DRUG INTERACTIONS/CYP3A4 Inhibitors. Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors [see Dosage and Administration]. CYP3A4 Inducers. CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s Wort) may decrease sunitinib concentrations. St. John’s Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John’s Wort concomitantly. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers [see Dosage and Administration]. In Vitro Studies of CYP Inhibition and Induction. In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

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Left Ventricular Dysfunction In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of SUTENT is recommended. The dose of SUTENT should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline. Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience. More patients treated with SUTENT experienced decline in left ventricular ejection fraction (LVEF) than patients receiving interferon-α (IFN-α). In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on SUTENT (7%) and seven on IFN-α (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received SUTENT. Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as myocardial infarction (including severe/unstable angina), coronary/ peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from SUTENT clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered. QT Interval Prolongation and Torsade de Pointes. SUTENT has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of SUTENT-exposed patients. SUTENT should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using SUTENT, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of SUTENT should be considered [see Dosage and Administration]. Hypertension. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled. Of patients receiving SUTENT for treatment-naïve RCC, 127/375 patients (34%) receiving SUTENT compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on SUTENT compared to 1/360 patients (<1%) on IFN-α. No Grade 4 hypertension was reported. SUTENT dosing was reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naïve RCC study. Four treatment-naïve RCC patients, including one with malignant hypertension, discontinued treatment due to hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 32/375 treatment-naïve RCC patients (9%) on SUTENT and 3/360 patients (1%) on IFN-α. Hemorrhagic Events. Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving SUTENT in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Epistaxis was the most common hemorrhagic adverse event reported. Less common bleeding events included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve patient. Tumor-related hemorrhage has been observed in patients treated with SUTENT. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with SUTENT. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations. Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with SUTENT. Osteonecrosis of the Jaw (ONJ). ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients treated with SUTENT. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease, may increase the risk of osteonecrosis of the jaw. Tumor Lysis Syndrome (TLS). Cases of TLS, some fatal, have occurred in patients treated with SUTENT. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated. Thyroid Dysfunction. Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of SUTENT treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on SUTENT treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on SUTENT in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.

Wound Healing. Cases of impaired wound healing have been reported during SUTENT therapy. Temporary interruption of SUTENT therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery. Adrenal Function. Physicians prescribing SUTENT are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection. Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of SUTENT demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of SUTENT. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with SUTENT. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12-16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency. Laboratory Tests. CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

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USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic exposure [combined AUC of sunitinib + primary active metabolite] in patients administered the recommended daily doses [RDD]). Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while developmental effects were observed at ≥1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in patients administered the RDD). Neither fetal loss nor malformations were observed in rats dosed at ≤3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥1 mg/kg/day but no maternal reproductive toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). At the high dose of 3 mg/kg/day, reduced body weights were observed at birth and persisted for offspring of both sexes during the pre-weaning period and in males during post-weaning period. No other developmental toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). Nursing Mothers. Sunitinib and its metabolites are excreted in rat milk. In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were extensively excreted in milk at concentrations up to 12-fold higher than in plasma. It is not known whether this drug or its primary active metabolite are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SUTENT, 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 efficacy of SUTENT in pediatric patients have not been established. Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated for ≥ 3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) with sunitinib at doses that were >0.4 times the RDD based on systemic exposure (AUC). In developing rats treated continuously for 3 months (1.5, 5.0 and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥ 5 mg/kg (approximately 10 times the RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment; however, findings in the teeth were not. A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no effect level in bones was ≤ 2 mg/kg/day. Geriatric Use. Of 825 GIST and RCC patients who received SUTENT on clinical studies, 277 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients. Hepatic Impairment. No dose adjustment to the starting dose is required when administering SUTENT to patients with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of SUTENT were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5 x ULN or, if due to liver metastases, >5.0 x ULN. Renal Impairment. No adjustment to the starting dose is required when administering SUTENT to patients with mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on safety and tolerability [see Dose Modification]. In patients with end-stage renal disease (ESRD) on hemodialysis, no adjustment to the starting dose is required. However, compared to subjects with normal renal function, the sunitinib exposure is 47% lower in subjects with ESRD on hemodialysis. Therefore, the subsequent doses may be increased gradually up to 2 fold based on safety and tolerability.

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Journal Spotlight

Oncogenic Mutations in Leukemia continued from page 54

chronic neutrophilic leukemia with a membrane proximal (T618I) CSF3R mutation showed in vitro hypersensitivity to ruxolitinib. Treatment of this patient with oral ruxolitinib at 10 mg twice daily resulted in a marked reduction in white blood cell and absolute neutrophil counts, with an increase in ruxolitinib dose to 15 mg twice daily providing further reductions in both. Treatment concurrently resulted in normalization of the patient’s platelet count. The investigators concluded, “[T]he presence of CSF3R mutations identified a distinct diagnos-

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NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. The carcinogenic potential of sunitinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at doses of ≥25 mg/kg/day following daily dose administration of sunitinib in studies of 1- or 6-months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC in patients given the RDD of 50 mg/day). At the high dose of 3 mg/kg/day (approximately 7.8 times the AUC in patients at the RDD of 50 mg/day) the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal medulla. Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test. Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (≥ 5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (≥ 0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was ≥ 0.8 times the AUC in patients administered the RDD). A no effect level was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months. Although fertility was not affected in rats, SUTENT may impair fertility in humans. In female rats, no fertility effects were observed at doses of ≤5.0 mg/kg/day [(0.5, 1.5, 5.0 mg/kg/day) administered for 21 days up to gestational day 7; the 5.0 mg/kg dose produced an AUC that was ≥ 5 times the AUC in patients administered the RDD], however significant embryolethality was observed at the 5.0 mg/kg dose. No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day (the 10 mg/kg/day dose produced a mean AUC that was ≥ 25.8 times the AUC in patients administered the RDD).

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OVERDOSAGE Treatment of overdose with SUTENT should consist of general supportive measures. There is no specific antidote for overdosage with SUTENT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. A few cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of SUTENT, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,500 mg of SUTENT in an attempted suicide was reported without adverse reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

ASCOPost.com | JUNE 25, 2013

tic subgroup of more than 50% of patients with [chronic neutrophilic leukemia or atypical chronic myeloid leukemia] in our study. The oncogenic CSF3R mutations are molecular markers of sensitivity to inhibitors of SRC family–TNK2 and JAK kinases and may provide a new avenue for therapy.” n

Disclosure: The study was funded by the Leukemia and Lymphoma Society and others. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Maxson JE, Gotlib J, Pollyea DA, et al: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 368:17811790, 2013. Survivorship

Celebrations Nationwide Recognize Cancer Survivorship in June

mong the celebrations held nationwide recognizing survivorship day in June, there was a special program held on June 10, 2013, at Memorial Sloan-Kettering Cancer Center in New York. Mary McCabe, RN, MS, Director, Survivorship Program, at MSKCC, moderated the program. The evening celebration included several talks along with a keynote address by actor and activist

Rob Lowe. Mr. Lowe shared his perspective on the importance of screening and discussed the impact of cancer on his own mother and grandmother. Following the talks, informative sessions were held on dermatology, exercise, integrative medicine, nutrition, research highlights, and young adult networking, for all in attendance, including patients, survivors, caregivers, and family members. n

PATIENT COUNSELING INFORMATION Gastrointestinal Disorders. Gastrointestinal disorders such as diarrhea, nausea, stomatitis, dyspepsia, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received SUTENT. Supportive care for gastrointestinal adverse events requiring treatment may include anti-emetic or anti-diarrheal medication. Skin Effects. Skin discoloration possibly due to the drug color (yellow) occurred in approximately one third of patients. Patients should be advised that depigmentation of the hair or skin may occur during treatment with SUTENT. Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Other Common Events. Other commonly reported adverse events included fatigue, high blood pressure, bleeding, swelling, mouth pain/irritation and taste disturbance. Musculoskeletal Disorders. Prior to treatment with SUTENT, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with SUTENT, who have previously received or are receiving bisphosphonates, invasive dental procedures should be avoided, if possible. Concomitant Medications. Patients should be advised to inform their health care providers of all concomitant medications, including over-the-counter medications and dietary supplements [see Drug Interactions]. Rx only

Revised: November 2012

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Mary McCabe, RN, MS, Director, Survivorship Program, at MSKCC, and actor and activist Rob Lowe.

The ASCO Post | JUNE 25, 2013

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Expert’s Corner Psychosocial Oncology

Treating Both the Physical and Psychological Symptoms of Cancer A Conversation with Jon Levenson, MD By Jo Cavallo

Jon Levenson, MD

growing number of people with cancer are being treated on an outpatient basis. At the Herbert Irving Comprehensive Cancer Center of New York-Presbyterian Hospital/Columbia University Medical Center in New York, to ensure that the psychosocial and psychiatric needs of these patients were being met, Jon Levenson, MD, Associate Clinical Professor of Psychiatry and Attending Physician, and colleagues helped launch the hospital’s Cancer Support and Counseling Outpatient Service in 2007. A specialist in a subfield of psychiatry known as consultation-liaison psychiatry, or psychosomatic medicine, Dr. Levenson is part of the interdisciplinary oncology team at the Herbert Irving Comprehensive Cancer Center. He addresses the psychiatric disorders, such as depression and anxiety, patients may experience following a cancer diagnosis and through longterm survivorship. Prior to 2007, the consultation-liaison psychiatry service at the cancer center was primarily an inpatient-provided program. “Cancer care has dramatically changed over the past few years and is now nearly all conducted on an outpatient basis. We had to adjust to the development of cancer as an outpatient disease,” said Dr. Levenson. He is also a past President of both the American Psychosocial Oncology Society and the Society for Liaison Psychiatry. The ASCO Post talked with Dr. Levenson about how a cancer diagnosis, cancer pain syndromes, and even long-term survivorship are contributing to the psychological distress felt by many people.

Multidisciplinary Collaboration Is there a greater recognition now in oncology about the importance of working col-

laboratively with mental health specialists to treat both the disease and psychological symptoms patients may experience? Absolutely. In addition to the three programs I’m programmatically involved with—for breast cancer, gynecologic oncology, and neuro-oncology—I also often attend tumor board meetings and provide input when the oncology team is discussing treatment for patients. For example, if the patient is a woman newly diagnosed with breast cancer and there is a family history of a psychiatric illness or if she has a past psychiatric history, I’ll be able to immediately work with the oncology team to develop an individualized treatment plan, which will usually include direct consultation between the patient and me. The American Psychosocial Oncology Society (APOS) is an interdisciplinary organization consisting

cause they are preoccupied with the medical news and predicament they now find themselves in. It is important for oncology teams to engage with patients to see if their symptoms develop into a formal type of depression or anxiety disorder. Not all patients experience these psychiatric complications, but a significant minority will develop them, and we need to prescribe formalized treatment when they do. Many patients will have sub-threshold symptoms of depression and anxiety. While they may not meet the diagnostic criteria for major depression or an anxiety disorder, these patients will benefit from some kind of ongoing psychosocial support, which might include support that the oncologist and the nurse practitioner provide. This support might include an ongoing psychoeducational

It is important for oncology teams to engage with patients to see if their symptoms develop into a formal type of depression or anxiety disorder. Not all patients experience these psychiatric complications, but a significant minority will develop them, and we need to prescribe formalized treatment when they do. —Jon Levenson, MD

of psychiatrists, psychologists, social workers, nurses, chaplains, patients, and oncologists. So it really represents the multidisciplinary nature of providing comprehensive care for patients with cancer and families. APOS has a toll-free helpline from which patients and caregivers can obtain psycho-oncology referrals in their home communities (1 866 APOS 4 HELP).

Psychological Symptoms What are some common psychological symptoms patients with cancer may experience? Many newly diagnosed patients develop acute emotional symptoms that abate within 2 weeks. Most of the time, that is a normal reaction to learning about having a serious medical condition. Commonly, people may experience transient sleep disturbance or some anxiety symptoms, and have intermittent trouble concentrating be-

approach to reviewing the patient’s diagnosis and treatment plans. It could also entail strategies to minimize the distress of the initial staging, such as frequent contact to combat demoralization, and the judicious use of benzodiazepines (such as lorazepam) to help with insomnia and imaging-related claustrophobia (MRI scanning). Newly diagnosed patients often benefit from joining cancer support groups, which is true for family members, too. Cancer advocacy organizations with support group programs include CancerCare, Gilda’s Club, and the American Cancer Society, as well as site-specific groups such as PanCan (pancreatic cancer), Lung Cancer Alliance, and SHARE (for women with breast or ovarian cancer). An outstanding resource for adult patients with school-age children is the website Parenting at a Challenging Time (mghpact.org). The program,

which was developed at the Massachusetts General Hospital Cancer Center, provides specialized support for patients with cancer, partners or spouses, and their children, and can be very helpful to families dealing with the stress of cancer and treatment.

Post-traumatic Stress Disorder Researchers at your institution found that 23% of newly diagnosed patients with breast cancer have post-traumatic stress disorder (PTSD),1 and other studies have shown PTSD onset in other cancer types. Is PTSD becoming a more common problem among patients with cancer? I don’t think post-traumatic stress disorder is becoming more common, but we are getting better at recognizing its signs and symptoms, which can develop with aggressive treatment regimens. PTSD appears to be particularly common in the setting of breast cancer treatment. For example, over the course of a year, many women will have a significant surgery—and often more than one procedure—as well as radiation therapy, systemic chemotherapy, and hormonal therapy if the tumor is estrogen receptor–positive, so the potential for side effects from these multimodal treatments is significant. Patients with breast cancer are especially vulnerable to being traumatized by the type of surgery they have (mastectomy vs lumpectomy, for example) or by complications from reconstructive surgery that delay healing. Contributing factors for PTSD also include the patient’s prior psychiatric history of anxiety or depression. What are some of the symptoms of posttraumatic stress disorder? Patients may relive the cancer experience in nightmares during sleep or in flashbacks during waking hours, and they may be in a continuous state of fearfulness and irritability. Other symptoms can include an altered startle response and emotional numbing. The symptoms are different for each person. PTSD can be effectively treated with a combination approach of psychotherapy and psychopharmacology.

Distress in Survivors Do long-term survivors encounter psychological distress from their diagnosis? Increasingly, cancers are being caught

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Expert’s Corner

at an early stage, which for some people may lead to a cure of their disease. Even for people whose cancer is incurable, it is now possible for them to live a long time with cancer as a chronic illness. However, living longer is not always associated with improved quality of life. Many people living with cancer as a chronic disease need continuous cancer treatment and may have ongoing side effects from their cancer and treatment, and that can negatively impact quality of life and raise the likelihood of feeling distressed and anxious. Once patients are identified as having a significant level of distress, we can further determine whether they have a depressive disorder like major depression or an anxiety disorder, like generalized anxiety disorder or post-traumatic stress disorder, or whether they are suffering from psychiatric complications related to a poorly controlled cancer pain syndrome and its management. For example, patients may have neuropsychiatric side effects from pain medications like opioids. Opioids are effective at relieving pain, but their side effects might be intolerable and can include confusion, which we also call delirium. That said, we can provide these patients with effective support, which may include individual psychotherapy, cancer support group involvement, and pharmacologic therapy. And long-term cancer survivors who have achieved cure often have good quality of life with minimal distress. Conversely, we know that some of these long-term survivors are quietly symptomatic with fatigue states, sexual dysfunction, and a condition called Damocles’ syndrome, which refers to survivors feeling like a sword is always hanging over their head. Thus, it is critical for oncology teams to serially evaluate how long-term survivors are coping because they may benefit from psychosocial oncology services.

Evaluating Distress How can oncologists evaluate a patient’s level of mental distress? Jimmie C. Holland, MD [Wayne E. Chapman Chair in Psychiatric Oncology at Memorial Sloan-Kettering Cancer Center] developed a “distress thermometer,” which measures a patient’s level of distress on a 0-to-10 scale. If a patient scores 4 or higher, her level of distress is considered significant and she should be further evaluated by a mental health specialist to see if psychotherapy is warranted. Also, some cancer treatments, such as high-dose interferon and the corticosteroid dexamethasone, are associated with

causing depression or anxiety. We have new evidence showing that some patients on interferon may benefit from being ‘pretreated’ with antidepressants like selective serotonin-reuptake inhibitors. Studies have shown that pretreatment with one of these agents before a patient receives high-dose cytokine treatment can greatly reduce the incidence of depression.

One caveat I’ll mention is that some commonly prescribed antidepressants such as fluoxetine and paroxetine may interfere with the effectiveness of certain chemotherapies like tamoxifen, so it is important for physicians and patients to understand that some antidepressants may not be advisable. n

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

Reference 1. Vin-Raviv N, Hillyer GC, Hershman DL, et al: Racial disparities in posttraumatic stress after diagnosis of localized breast cancer: The BQUAL study. J Natl Cancer Inst 105:563-572, 2013.

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Expert’s Corner Neuro-oncology

Improving Treatment and Care for Patients with Primary Brain Cancers A Conversation with Steven Brem, MD By Jo Cavallo

Steven Brem, MD

espite advances in neuroimaging, the development of focused radiation therapy, and more effective chemotherapy, life expectancy for patients with primary malignant tumors of the brain and spinal cord remains stubbornly low at between 15 and 18 months. However, there are significant advances on the horizon that could improve patients’ quality of life and lead to significant increases in survival rates in the near future, said Steven Brem, MD, Co-Director of the Penn Brain Tumor Center, Professor of Neurosurgery, and Chief of Neurosurgical Oncology in the Department of Neurosurgery at the Hospital of the University of Pennsylvania in Philadelphia. A student of Dr. Judah Folkman’s at Harvard Medical School, Dr. Brem has been a leader in research in angiosuppressive agents in the treatment of malignant brain tumors and is a cofounder of the Adult Brain Tumor Consortium (ABTC), an initiative of the National Cancer Institute. Dr. Brem has performed more than 3,500 brain tumor surgeries and chaired the National Comprehensive Cancer Network (NCCN) committee that developed guidelines for the treatment of brain tumors. The ASCO Post talked with Dr. Brem about the causes of this deadly cancer and the major shifts in the care of patients with malignant brain tumors.

Survival Statistics Survival for high-grade gliomas remains low. Is progress being made in extending overall survival rates? Patients with malignant gliomas

are living longer than ever before and they have better quality of life. Overall survival used to be 9 months, and now the average is 15 to 18 months. It’s not a spectacular improvement, but the trend is unmistakable. And there is a definite subgroup—perhaps 20% of patients—who are living over 3 years, with an occasional long-term survivor. So there are definitely reasons to be hopeful. The combination of temozolomide chemotherapy and radiation therapy in the upfront setting has proved to be a major benefit to patients. The use of bevacizumab (Avastin) in the treatment of recurrent glioblastomas is exciting and has changed the landscape of neuro-oncology because patients experience a significant increase in progression-

infections, have improved patient outcomes. But while historic progress has been made, major challenges remain.

Current Research What research might lead to improved overall survival in the near future. There are several areas of research we are pursuing. The field of cancer genomics, including pediatric brain tumors, and the advent of personalized medicine will have a tremendous impact on patient outcomes. Glioblastomas were among the first malignant tumors to be decoded by The Cancer Genome Atlas Research Network. These tumors are known to have four distinct molecular subtypes, and we are studying the path-

We will see more progress [in managing brain tumors] over the next 10 years than we’ve seen over the past 30 or 40 years because we have all the new tools based on genomics and neuroimaging. —Steven Brem, MD

free survival and enhancement in quality of life. Bevacizumab starves the tumor of its blood supply, shrinks the size of the tumor, and decreases brain edema. Its discovery revolutionized neuro-oncology—the previous dogma was that large molecules, such as a monoclonal antibody, would be ineffective in the brain because of the blood-brain barrier. The effectiveness of the molecule provided “proof of principle” that a targeted therapy can be highly effective in the brain. Today, there is great interest in developing additional targeted therapies for brain tumors. The development of high-quality cancer centers housing integrated teams of highly trained nurses and clinicians following NCCN guidelines (and where patients have access to clinical trials) has also led to increased survival. The intensity of overall medical care at these centers with close attention focused on preventing side effects, such as seizures, deep-vein thrombosis, and

ways that determine the specific malignant behaviors. The Abramson Cancer Center of the University of Pennsylvania has created a Neuro-Oncology Translational Center of Excellence with high-impact projects underway. For example, my colleagues, including Donald M. O’Rourke, MD, Associate Professor of Neurosurgery, and Carl H. June, MD, Richard W. Vague Professor in Immunotherapy, are working to find more effective immunologic therapies for brain tumors. Dr. June published landmark studies in chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. The Penn Brain Tumor Center is working to develop a protocol using T-cell chimeric antigen receptor technology for patients with glioblastomas. Furthermore, following the advances of the NIH Human Connectome Project [a 5-year endeavor to link brain connectivity to human behavior], we are deciphering the human connectome by mapping the

neural pathways in the brain and incorporating the technology into the operating room. Using advanced mathematical modeling, surgeons can visualize what was formerly invisible to the eye, and even invisible under the microscope—the brain’s “wiring diagram.” In this way, we can tailor our surgery precisely to the region of the tumor boundary, reducing the risk of neurologic complications, such as cognitive impairment, paralysis, or language deficit. Also, since glioblastoma cells follow the white fiber matter pathways, we can better predict tumor growth and strategically plan therapy using newer mathematical models that provide a roadmap of each tumor.

Management Challenges Is it possible to manage malignant brain tumors in such a way that longterm survival is possible? Hopefully, we will be able to control glioblastoma growth so that long-term survival becomes commonplace. Glioblastoma is a wily beast, and while we have been able to tame the beast with safer surgery, radiation, and antiangiogenic therapy, brain tumors are a genetically heterogeneous group. Glioblastomas are particularly intractable because, while they do not metastasize throughout the rest of the body, they can spread throughout the entire brain and, therefore, recurrences are inevitable. The biochemical redundancy of the metabolic pathways enables the cells to escape targeted therapies, and resistant cells can invade the surrounding brain.

Underlying Causes What is research showing about the causes of malignant brain tumors? Our current research is investigating the root causes of these tumors. For example, it is well known that as we age, we are more likely to be struck by cancer, and this is particularly true of brain cancer. At the Moffitt Cancer Center, I was part of a team that looked at the DNA gene expression of over 5,000 patients with 10 major types of macontinued on page 62

The case for Vectibix® QQ2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

660-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

PPremedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

NNo loading dose1

– No loading dose is required

IInfusion reactions1

– Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

DDermatologic toxicity1

– Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy – Withhold Vectibix® for dermatologic toxicities that are ≥ grade 3 or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix® – If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than 2 doses of Vectibix®, treatment may be resumed at 50% of the original dose - If toxicities recur, permanently discontinue Vectibix® - If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached

INDICATION:

Vectibix® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®. Vectibix® is not indicated for the treatment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. IMPORTANT SAFETY INFORMATION WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of interstitial lung disease (ILD), including fatalities, have been reported in patients treated with Vectibix®. Interrupt Vectibix® therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix® therapy if ILD is confirmed. In a randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment (eg, oral or intravenous electrolyte repletion) as needed. Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months after the last dose. Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis. Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be transmitted from the mother to the developing fetus and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix®. The most common adverse reactions (≥ 20%) of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, diarrhea, including diarrhea resulting in dehydration, and constipation. The most serious adverse reactions of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling. Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix® administration. Terminate the infusion for severe infusion reactions. Vectibix® is not indicated for use in combination with chemotherapy. In a phase 3 study of patients with KRAS mutation-positive mCRC (n = 440) evaluating Vectibix® in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR = 1.24, 95% CI: 0.98–1.57). Please see brief summary of Prescribing Information on next page. In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% Reference: 1. Vectibix® (panitumumab) vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- prescribing information, Amgen. treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/ mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). 04-13 NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs ©2013 Amgen Inc. All rights reserved. G61228-R2-V2 61007-R2-V2 4%) and included fatal events in three (< 1%) Vectibix®-treated patients.

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Expert’s Corner

Steven Brem, MD, on Primary Brain Cancers

Looking Ahead are programmed to become harmless incidence, and aggressiveness Publication: of ma- ASCOPost Brand: Vectibix Do you foresee improvements in surand senescent. lignant brain tumors. Client:However, AMGEN if these same Issue: 2013-May15_IP4C-PI Job#: Trim: 7.875in vival x 10.75in continued from page 60 rates in malignant brain tumors cells are in an 10109634 inflammatory environOur laboratory is also focused 10109634_AMGEN-Vectibix_ASCOPost_2013-May15_IP4C-PI.pdf Bleed: 7.875in x 10.75in lignant tumors, including melanoma over the next decade? ment or have gene mutations, they on drug discovery and development and breast, colon, lung, and prostate Yes, absolutely. We will see more can “switch” to malignancy, as shown of novel peptides aimed at blocking cancers. We compared the DNA of progress over the next 10 years than by an independent group led by Juglioma invasion and angiogenesis, as young patients with older patients to we’ve seen over the past 30 or 40 dith Campisi, PhD. These findings well as the molecular pathways that T: 7.875” see if there were senescence-associatyears because we have all the new highlight a possible cause of cancer drive the spread of malignant cells ed genes. As individual cells age, they tools based on genomics and neuroand may explain the link between age, throughout the brain. imaging (based on the emerging field of connectomics, which combines neural imaging and histologic techTable 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Vectibix (panitumumab) Injection for intravenous Infusion niques to map the neural connecPatients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Brief Summary of Prescribing Information. For complete prescribing information consult Grade* official package insert. tions of the nervous system). There Body System All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Body as a Whole Fatigue 26 4 15 3 WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS is also a realization now that knowGeneral Deterioration 11 8 4 3 Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients Digestive Abdominal Pain 25 7 17 5 receiving Vectibix monotherapy [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. ing a cancer cell’s mutational status Nausea 23 1 16 <1 Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in Diarrhea 21 2 11 0 postmarketing experience [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)]. Constipation 21 3 9 1 can inform successful treatment and Vomiting 19 2 12 1 INDICATIONS AND USAGE Stomatitis 7 0 1 0 guide therapy, building on the tradiVectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) Mucosal Inflammation 6 <1 1 0 with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14.1) Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 in Full Prescribing Information]. tional classification of tumors, based Peripheral Edema 12 1 6 <1 The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionRespiratory Cough 14 <1 7 0 free survival [see Clinical Studies (14.1) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related on morphology and location. This is symptoms or increased survival with Vectibix. Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Vectibix is not indicated for the tratment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Skin 90 14 6 0 indeed an exciting time for the study Erythema 65 5 1 0 Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13 [see Warnings and Precautions, Clinical Pharmacology (12.1) and Clinical Studies (14.3) in Full Prescribing Information]. Dermatitis Acneiform 57 7 1 0 and treatment of malignant brain Pruritus 57 2 2 0 DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion Nail 29 2 0 0 cancer. n over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration (2.2) Paronychia 25 2 0 0 in Full Prescribing Information]. ®

Skin Exfoliation 25 2 0 Rash 22 1 1 Skin Fissures 20 1 <1 Eye 15 <1 2 Acne 13 1 0 Dry Skin 10 0 0 Other Nail Disorder 9 0 0 Hair 9 0 1 Growth of Eyelashes 6 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

0 0 0 0 0 0 0 0 0

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported. Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration]. Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. As monotherapy: The incidence of binding antibodies (excluding pre-existing and transient positive patients) was 0.4% (3/717), as detected by the acid dissociation ELISA, and 3.8% (27/717) as detected by the Biacore® assay. The incidence of neutralizing antibodies (excluding pre-existing and transient positive patients) was 1% (7/717). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix. In combination with irinotecan- or oxaliplatin-based chemotherapy: The incidence of binding antibodies (excluding pre-existing positive patients) was 1% (11/1124) as detected by the acid dissociation ELISA and 0.8% (9/1123) as detected by the Biacore assay. The incidence of neutralizing antibodies (excluding pre-existing positive patients) was 0.2 % (2/1124). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions has been identified during post-approval use of Vectibix. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Skin necrosis, angioedema [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology (13.3) in Full Prescribing Information]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll. Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients. Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients. OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions, and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations]. This brief summary is based on the Vectibix® prescribing information v17, 03/2013 Rx Only Patent: http://pat.amgen.com/vectibix/ ©2006-2013 Amgen Inc.All rights reserved.

73846-R1-V1

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

Contact

The ASCO Post Editorial Correspondence T: 10.75”

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions. Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. • Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix. Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix. • If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose. – If toxicities recur, permanently discontinue Vectibix. – If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached. Do not administer Vectibix as an intravenous push or bolus. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix. Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning, and Adverse Reactions]. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling [see Dosage and Administration]. Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3-4). Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration]. Increased Mortality or Toxicity with Vectibix in Combination with Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In a randomized, open-label study enrolling 440 patients with KRAS mutation-positive mCRC; evaluating Vectibix in combination with infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) compared to FOLFOX alone as first-line therapy for mCRC, shortened overall survival time was observed in the mutant KRAS mCRC population after 294 deaths (HR=1.24, 95% CI: 0.98-1.57). In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCICTC grade 3 diarrhea was 25%. Severe diarrhea and dehydration, which may lead to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy. Pulmonary Fibrosis/Interstitial Lung Disease (ILD): Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Patients with a history or evidence of interstitial pneumonitis, pulmonary fibrosis, were excluded from most clinical trials. Therefore, the estimated risk in a general population that includes such patients is uncertain. Cases of ILD, including fatalities, have been reported in patients treated with Vectibix. Interrupt Vectibix therapy for the acute onset or worsening of pulmonary symptoms. Discontinue Vectibix therapy if ILD is confirmed. Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed. Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix. Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis. EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Mortality or Toxicity of Vectibix in Combination with Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis/ILD [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions]. The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

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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PAGE 63

In the Clinic Melanoma

Dabrafenib for Unresectable or Metastatic Melanoma with BRAF V600E Mutation By Matthew Stenger

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

Indication On May 29, 2013, dabrafenib (Tafinlar) was approved for treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by a U.S. Food and Drug Administration (FDA)-approved test.1,2 Concurrent with this approval, FDA approved the THxID BRAF assay (bioMérieux, Inc) for detection of BRAF V600E mutations. Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma, due to the potential risk of tumor promotion. Approval of dabrafenib was based on improved progression-free survival in an international, open-label trial in 250 patients with previously untreated, histologically confirmed, unresectable stage III or IV melanoma determined to be BRAF V600E mutation–positive based on centralized testing.2,3 Patients were randomized to receive either dabrafenib at 150 mg orally twice daily (n = 187) or dacarbazine at 1,000 mg/m2 IV once every 3 weeks (n = 63). At the time of disease progression, 28 dacarbazine patients received dabrafenib.

OF NOTE Dabrafenib carries warnings/precautions for cutaneous malignancies, tumor promotion in BRAF wild-type melanoma, febrile drug reactions, hyperglycemia, uveitis and iritis, G6PD deficiency, and embryo-fetal toxicity. Overall, patients had a median age of 52 years, 60% were male, 67% had ECOG performance status of 0, and 66% had M1c disease. The trial excluded patients with abnormal left-ventricular ejection fraction or cardiac valve morphology (≥ grade 2), corrected QT interval ≥ 480 480 milliseconds on electrocardiogram, or a known history of glucose-6 phosphate dehydrogenase deficiency.

Dabrafenib significantly reduced investigator-assessed progression by 67% (median progression-free survival = 5.1 vs 2.7 months, hazard ratio = 0.33, P < .0001). A progression-free survival analysis based on blinded independent central review was consistent with the investigator results. Objective response rates were 52% in the dabrafenib group (including complete response in 3%) and 17% in the dacarbazine group. Median duration of response was approximately 5 months in both groups. There was no statistically significant difference in overall survival between the two groups.

How It Works Dabrafenib is an inhibitor of some mutated forms of BRAF kinases. Some mutations in the BRAF gene, including

OF NOTE Dabrafenib is an inhibitor of some mutated forms of BRAF kinases that can stimulate tumor cell growth. inducers of CYP3A4 or CYP2C8 (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort) is not recommended, and concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 (eg, midazolam, omeprazole, lansoprazole, rosiglitazone, warfarin) may result in loss of efficacy of these agents. Drugs that increase gastric pH (eg, proton pump inhibitors and H2-receptor blockers) may decrease dabrafenib concentrations. Appropriate doses have not been

Dabrafenib to Treat Advanced Melanoma ■ Dabrafenib (Tafinlar) was approved for treatment of unresectable or

metastatic melanoma with BRAF V600E mutation as detected by an FDAapproved test.

■ The recommended dose for dabrafenib is 150 mg orally twice daily, at

least 1 hour before or 2 hours after a meal, until disease progression or unacceptable toxicity.

those that result in the BRAF V600E enzyme, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Dabrafenib inhibits BRAF V600 mutation–positive melanoma cell growth in vitro and in vivo. Dabrafenib also inhibits wild-type BRAF and CRAF kinases (and other kinases, such as SIK1, NEK11, and LIMK1). However, in vitro experiments have shown paradoxical activation of MAP kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors.

How It Is Given The recommended dose for dabrafenib is 150 mg orally twice daily, at least 1 hour before or 2 hours after a meal, until disease progression or unacceptable toxicity. Dose modification or discontinuation is required for febrile drug reactions. No dose modifications are recommended for new primary cutaneous malignancies. Concurrent administration of strong inhibitors or strong

established for patients with moderate to severe hepatic impairment or severe renal impairment. The presence of BRAF V600E mutation in tumor specimens must be confirmed prior to initiation of dabrafenib treatment. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/ CompanionDiagnostics.

Safety Profile The most common (≥ 20%) adverse events of any grade in dabrafenib patients were hyperkeratosis (37% vs 0% with dacarbazine), headache (32% vs 8%), pyrexia (28% vs 10%), arthralgia (27% vs 2%), papilloma (27% vs 2%), alopecia (22% vs 2%), and palmar-plantar erythrodysesthesia syndrome (20% vs 2%). The most common grade 3 or 4 adverse events were cutaneous squamous cell carcinoma (4% vs 0%), pyrexia (3% vs 0%), and back pain (3% vs 0%). Laboratory abnormalities more common in dabrafenib patients were

hyperglycemia (50% vs 43%, grade 3 or 4 in 6% vs 0%), hypophosphatemia (37% vs 14%, grade 3 or 4 in 6% vs 2%), increased alkaline phosphatase (19% vs 14%, grade 3 or 4 in 0% vs 2%), and hyponatremia (8% vs 3%, grade 3 or 4 in 2% vs 0%). Adverse events resulted in permanent discontinuation of study medication in 3% of both groups. The most frequent adverse events leading to dabrafenib dose reduction were pyrexia (9%), palmar-plantar erythrodysesthesia syndrome (3%), chills (3%), fatigue (2%), and headache (2%). Serious adverse events in dabrafenib patients consisted of development of new primary skin cancers (cutaneous squamous cell carcinoma, new primary melanomas, and keratoacanthomas), febrile drug reactions requiring hospitalization, hyperglycemia, and uveitis/iritis. Dabrafenib carries warnings/precautions for new primary cutaneous malignancies, tumor promotion in BRAF wild-type melanoma, serious febrile drug reactions, hyperglycemia, uveitis and iritis, glucose-6-phosphate dehydrogenase deficiency, and embryo-fetal toxicity. Patients should undergo dermatologic evaluation prior to treatment, every 2 months during treatment, and for up to 6 months after stopping treatment. Serum glucose levels should be monitored in patients with preexisting diabetes or hyperglycemia. Patients should be monitored routinely for visual symptoms. Female patients should be advised to use highly effective contraception during treatment and for 4 weeks after stopping treatment and males should be advised of the potential risk for impaired spermatogenesis. Since dabrafenib may reduce the effectiveness of hormonal contraceptives, an alternative method of contraception should be used. Nursing mothers should discontinue dabrafenib treatment or discontinue nursing. n References 1. U.S. Food and Drug Administration: Dabrafenib. Available at www.fda.gov. Accessed June 11, 2013. 2. TAFINLAR® (dabrafenib) capsules prescribing information, GlaxoSmithKline, May 2013. Available at www.accessdata.fda. gov. Accessed June 11, 2013. 3. Hauschild A, Grob JJ, Demidov LV, et al: Dabrafenib in BRAF-mutated metastatic melanoma. Lancet 380:358-365, 2012.

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase

chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Iclusig (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients ™

IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. • Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity. Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusigtreated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver

function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated. Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients.

C H R O N I C P H A S E C M L (C P - C M L ) More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

44%

(144/267)

MCyR 95% CI: 48-60 (118/267)

CCyR 95% CI: 38-50 Most patients who achieved MCyR also achieved CCyR.

Median duration of follow-up was 10 months.1

Efficacy in T315I 70% of CP-CML patients with the T315I mutation (45/64) achieved MCyR (95% CI: 58-81), and 66% (42/64) achieved CCyR (95% CI: 53-77). Iclusig is a 45 mg oral tablet taken once daily with or without food.

Learn more about Iclusig’s efficacy in patients with the T315I mutation and all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Tablet is not shown at actual size. Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning. Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012. Reference: 1. Data on file.

BRIEFBRIEF SUMMARY SUMMARY IclusigIclusig (ponatinib) (ponatinib) Rx only Rx only PleasePlease consult full Prescribing Information, including BoxedBoxed Warning, consult full Prescribing Information, including Warning, available at Iclusig.com. available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical serious arterial thrombosis occurred of Iclusig-treated patients. Interrupt trials,trials, serious arterial thrombosis occurred in 8%inof8% Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic and consider discontinuation of Iclusig in patients who develop arterial thrombotic [see Dosage and Administration (2.3)Warnings and Warnings and Precautions eventsevents [see Dosage and Administration (2.3) and and Precautions (5.1)]. (5.1)].

required required urgenturgent clinicalclinical intervention intervention for hypertension for hypertension associated associated with confusion, with confusion, headache, headache, chest chest pain, or pain, shortness or shortness of breath. of breath. Treatment-emergent Treatment-emergent hypertension hypertension occurred occurred in 67%inof67% patients of patients (300/449) (300/449) [see Adverse [see Adverse Reactions Reactions (6)]. In(6)]. patients In patients with baseline with baseline systolic systolic BP<140 BP<140 mm Hgmm andHgbaseline and baseline diastolic diastolic BP<90mm BP<90mm Hg, 78% Hg,(220/282) 78% (220/282) experienced experienced treatment-emergent treatment-emergent hypertension; hypertension; 49% (139/282) 49% (139/282) developed developed Stage Stage 1 hypertension 1 hypertension (defined (defined as systolic as systolic BP≥140 BP≥140 mm Hgmm or Hg diastolic or diastolic BP≥90BP≥90 mm mm Hg) while Hg) 29% whiledeveloped 29% developed Stage Stage 2 hypertension 2 hypertension (defined (defined as systolic as systolic BP≥160 BP≥160 mm Hgmm or Hg diastolic or diastolic BP≥100 BP≥100 mm Hg). mmInHg). 131Inpatients 131 patients with Stage with Stage 1 hypertension 1 hypertension at baseline, at baseline, 61% (80/131) 61% (80/131) developed developed Stage Stage 2 hypertension. 2 hypertension. Monitor Monitor and manage and manage blood blood pressure pressure elevations. elevations. 5.5

ClinicalClinical pancreatitis pancreatitis occurred occurred in 6% in(28/449) 6% (28/449) of patients of patients (5% grade (5% grade 3) treated 3) treated with Iclusig. with Iclusig. Pancreatitis Pancreatitis resulted resulted in discontinuation in discontinuation or treatment or treatment interruption interruption in 6% inof6% patients of patients (25/449). (25/449). Twenty-two Twenty-two of the of 28the cases 28 cases of pancreatitis of pancreatitis resolved resolved withinwithin 2 weeks 2 weeks with dose with interruption dose interruption or or reduction. reduction. The incidence The incidence of treatment-emergent of treatment-emergent lipase lipase elevation elevation was 41%. was 41%. CheckCheck serumserum lipase lipase every every 2 weeks 2 weeks for thefor first the2 first months 2 months and then andmonthly then monthly thereafter thereafter or as or as clinically clinically indicated. indicated. Consider Consider additional additional serumserum lipase lipase monitoring monitoring in patients in patients with awith history a history of of pancreatitis pancreatitis or alcohol or alcohol abuse.abuse. Dose interruption Dose interruption or reduction or reduction may bemay required. be required. In cases In cases wherewhere lipase lipase elevations elevations are accompanied are accompanied by abdominal by abdominal symptoms, symptoms, interrupt interrupt treatment treatment with Iclusig with Iclusig and evaluate and evaluate patients patients for pancreatitis for pancreatitis [see Dosage [see Dosage and Administration and Administration (2.3)]. (2.3)]. Do notDo consider not consider restarting restarting IclusigIclusig until patients until patients have complete have complete resolution resolution of symptoms of symptoms and lipase and lipase levels levels are less are less than 1.5 than x ULN. 1.5 x ULN.

Hepatotoxicity: Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior and during treatment. Interrupt and reduce then reduce or discontinue hepatic function prior to andtoduring treatment. Interrupt and then or discontinue for hepatotoxicity [see Dosage and Administration (2.3)Warnings and Warnings IclusigIclusig for hepatotoxicity [see Dosage and Administration (2.3) and and and Precautions Precautions (5.2)].(5.2)]. 1

1INDICATIONS INDICATIONS AND USAGE AND USAGE

5.6

™ ™ IclusigIclusig (ponatinib) (ponatinib) is indicated is indicated for thefor treatment the treatment of adult ofpatients adult patients with chronic with chronic phase,phase, accelerated accelerated phase,phase, or blast or phase blast phase chronic chronic myeloid myeloid leukemia leukemia (CML)(CML) that isthat resistant is resistant or intolerant or intolerant to priorto prior tyrosine tyrosine kinasekinase inhibitor inhibitor therapy therapy or Philadelphia or Philadelphia chromosome chromosome positive positive acute acute lymphoblastic lymphoblastic leukemia leukemia (Ph+ ALL) (Ph+that ALL)isthat resistant is resistant or intolerant or intolerant to priortotyrosine prior tyrosine kinasekinase inhibitor inhibitor therapy. therapy.

This indication This indication is based is based upon response upon response rate [see rateClinical [see Clinical Studies Studies (14)]. There (14)]. There are noare trials no trials verifying verifying an improvement an improvement in disease-related in disease-related symptoms symptoms or increased or increased survival survival with Iclusig. with Iclusig. 4

4CONTRAINDICATIONS CONTRAINDICATIONS

5.7

None None 5

5WARNINGS WARNINGS AND PRECAUTIONS AND PRECAUTIONS

5.1

5.1 Thrombosis Thrombosis and Thromboembolism and Thromboembolism

5.5 Pancreatitis Pancreatitis

Arterial Arterial Thrombosis Thrombosis Cardiovascular, Cardiovascular, cerebrovascular, cerebrovascular, and peripheral and peripheral vascular vascular thrombosis, thrombosis, including including fatal myocardial fatal myocardial infarction infarction and stroke and stroke have occurred have occurred in Iclusig-treated in Iclusig-treated patients. patients. SeriousSerious arterialarterial thrombosis thrombosis occurred occurred in 8% in (34/449) 8% (34/449) of Iclusig-treated of Iclusig-treated patients. patients. Twenty-one Twenty-one patients patients5.8 required required a revascularization a revascularization procedure procedure (16 patients (16 patients with coronary with coronary revascularization, revascularization, 4 patients 4 patients with peripheral with peripheral arterialarterial revascularization, revascularization, and 1 and patient 1 patient with cerebrovascular with cerebrovascular revascularization). revascularization). Overall, Overall, fifty-one fifty-one patients patients (11%) (11%) experienced experienced an arterial an arterial thrombosis thrombosis event event of anyofgrade. any grade. Myocardial Myocardial infarction infarction or worsening or worsening coronary coronary arteryartery disease disease was the was most the common most common arterialarterial thrombosis thrombosis event event and occurred and occurred in 21 patients in 21 patients (5%) of(5%) Iclusig-treated of Iclusig-treated patients. patients. ElevenEleven of of these these patients patients developed developed congestive congestive heart failure heart failure concurrent concurrent or subsequent or subsequent to the to myocardial the myocardial ischemic ischemic event.event. Serious Serious cerebrovascular cerebrovascular eventsevents were reported were reported in 2% in(8/449) 2% (8/449) of Iclusig-treated of Iclusig-treated patients. patients. Two Two patients patients experienced experienced hemorrhagic hemorrhagic conversion conversion of the of initial the ischemic initial ischemic event.event. Four patients Four patients developed developed stenosis stenosis of large of arterial large arterial vessels vessels of the of brain the (e.g., brain carotid, (e.g., carotid, vertebral, vertebral, middlemiddle cerebral cerebral artery).artery). Serious Serious peripheral peripheral arterialarterial eventsevents were reported were reported in 2% in(7/449) 2% (7/449) of Iclusig-treated of Iclusig-treated patients. patients. Three Three5.9 patients patients developed developed digitaldigital or distal or distal extremity extremity necrosis; necrosis; 2 of these 2 of these patients patients had diabetes had diabetes mellitus mellitus and peripheral and peripheral arterialarterial disease disease and required and required amputations. amputations.

5.6 Hemorrhage Hemorrhage Serious Serious bleeding bleeding events,events, occurred occurred in 5% in (22/449) 5% (22/449) of patients of patients treatedtreated with Iclusig, with Iclusig, including including fatalities. fatalities. Hemorrhagic Hemorrhagic eventsevents occurred occurred in 24%inof24% patients. of patients. The incidence The incidence of serious of serious bleeding bleeding eventsevents was higher was higher in patients in patients with AP-CML, with AP-CML, BP-CML, BP-CML, and Ph+ andALL. Ph+Cerebral ALL. Cerebral hemorrhage hemorrhage and gastrointestinal and gastrointestinal hemorrhage hemorrhage were the were most the commonly most commonly reported reported seriousserious bleeding bleeding events.events. Most hemorrhagic Most hemorrhagic eventsevents occurred occurred in patients in patients with grade with grade 4 thrombocytopenia 4 thrombocytopenia [see Warnings [see Warnings and Precautions and Precautions (5.9)]. (5.9)]. Interrupt Interrupt IclusigIclusig for serious for serious or severe or severe hemorrhage hemorrhage [see Dosage [see Dosage and and Administration Administration (2.3)]. (2.3)]. 5.7 Fluid Retention Fluid Retention Fluid retention Fluid retention eventsevents judgedjudged as serious as serious occurred occurred in 3% in(13/449) 3% (13/449) of patients of patients treatedtreated with Iclusig. with Iclusig. One instance One instance of brain of edema brain edema was fatal. was Serious fatal. Serious fluid retention fluid retention eventsevents in more in than more1than patient 1 patient included: included: pericardial pericardial effusion effusion (6/449,(6/449, 1%), pleural 1%), pleural effusion effusion (5/449,(5/449, 1%), and 1%),ascites and ascites (2/449,(2/449, <1%).<1%). In total, In fluid total,retention fluid retention occurred occurred in 23%inof23% the of patients. the patients. The most The common most common fluid retention fluid retention eventsevents were peripheral were peripheral edemaedema (16%),(16%), pleuralpleural effusion effusion (7%), (7%), and pericardial and pericardial effusion effusion (3%). (3%). Monitor Monitor patients patients for fluid forretention fluid retention and manage and manage patients patients as clinically as clinically indicated. indicated. Interrupt, Interrupt, reduce, reduce, or discontinue or discontinue IclusigIclusig as clinically as clinically indicated indicated [see Dosage [see Dosage and Administration and Administration (2.3)]. (2.3)]. 5.8 Cardiac Cardiac Arrhythmias Arrhythmias Symptomatic Symptomatic bradyarrhythmias bradyarrhythmias that led that to led a requirement to a requirement for pacemaker for pacemaker implantation implantation occurred occurred in 3 (1%) in 3Iclusig-treated (1%) Iclusig-treated patients. patients. The cardiac The cardiac rhythms rhythms (1 case(1each) case each) identified identified were complete were complete heart block, heart block, sick sinus sick syndrome, sinus syndrome, and atrial and fibrillation atrial fibrillation with bradycardia with bradycardia and pauses. and pauses. AdviseAdvise patients patients to report to report signs and signssymptoms and symptoms suggestive suggestive of slowofheart slow rate heart(fainting, rate (fainting, dizziness, dizziness, or or chest chest pain). pain). Supraventricular Supraventricular tachyarrhythmias tachyarrhythmias occurred occurred in 25 (5%) in 25Iclusig-treated (5%) Iclusig-treated patients. patients. Atrial fibrillation Atrial fibrillation was the was most the common most common supraventricular supraventricular tachyarrhythmia tachyarrhythmia and occurred and occurred in 20 patients. in 20 patients. The other The other supraventricular supraventricular tachyarrhythmias tachyarrhythmias were atrial were flutter atrial flutter (4 patients), (4 patients), supraventricular supraventricular tachycardia tachycardia (4 patients), (4 patients), and atrial and tachycardia atrial tachycardia (1 patient). (1 patient). For 13For patients, 13 patients, the event the event led to led hospitalization. to hospitalization. AdviseAdvise patients patients to report to report signs and signssymptoms and symptoms of rapid of heart rapid rate heart(palpitations, rate (palpitations, dizziness). dizziness). 5.9 Myelosuppression Myelosuppression SevereSevere (grade(grade 3 or 4)3myelosuppression or 4) myelosuppression occurred occurred in 48%in(215/449) 48% (215/449) of patients of patients treatedtreated with Iclusig. with Iclusig. The incidence The incidence of these of these eventsevents was greater was greater in patients in patients with accelerated with accelerated phasephase CML (AP-CML), CML (AP-CML), blast phase blast phase CML (BP-CML) CML (BP-CML) and Ph+ andALL Ph+than ALLinthan patients in patients with chronic with chronic phasephase CML (CP-CML). CML (CP-CML). ObtainObtain complete complete blood blood countscounts every every 2 weeks 2 weeks for thefor first the3 first months 3 months and then andmonthly then monthly or as or as clinically clinically indicated, indicated, and adjust and adjust the dose the as dose recommended as recommended [see Dosage [see Dosage and Administration and Administration (2.2)]. (2.2)].

Thirty Thirty of 34 Iclusig-treated of 34 Iclusig-treated patients patients who experienced who experienced a serious a serious arterialarterial thrombosis thrombosis event event had had one orone more or cardiovascular more cardiovascular risk factors risk factors (e.g., myocardial (e.g., myocardial infarction, infarction, coronary coronary arteryartery disease, disease, angina, angina, stroke,stroke, transient transient ischemic ischemic attack,attack, hypertension, hypertension, diabetes diabetes mellitus, mellitus, hyperlipidemia, hyperlipidemia, and and smoking). smoking). Patients Patients with cardiovascular with cardiovascular risk factors risk factors are at are increased at increased risk forrisk arterial for arterial thrombosis thrombosis5.10 5.10 TumorTumor Lysis Lysis Syndrome Syndrome with Iclusig. with Iclusig. Interrupt Interrupt and consider and consider discontinuation discontinuation of Iclusig of Iclusig in patients in patients who develop who develop arterialarterial Two patients Two patients (<1%)(<1%) treatedtreated with Iclusig with Iclusig developed developed seriousserious tumortumor lysis syndrome. lysis syndrome. Both cases Both cases thrombotic thrombotic eventsevents [see Dosage [see Dosage and Administration and Administration (2.3)]. (2.3)]. occurred occurred in patients in patients with advanced with advanced CML. Hyperuricemia CML. Hyperuricemia occurred occurred in 7% in(30/449) 7% (30/449) of patients, of patients, VenousVenous Thromboembolism Thromboembolism the majority the majority had chronic had chronic phasephase CML (19 CML patients). (19 patients). Due toDue the to potential the potential for tumor for tumor lysis syndrome lysis syndrome in patients in patients with advanced with advanced disease disease (AP-CML, (AP-CML, BP-CML, BP-CML, or Ph+orALL), Ph+ ensure ALL), ensure adequate adequate hydration hydration VenousVenous thromboembolic thromboembolic eventsevents occurred occurred in 3% inof3% Iclusig-treated of Iclusig-treated patients, patients, including including deep deep and treat andhigh treaturic highacid uriclevels acid levels prior toprior initiating to initiating therapy therapy with Iclusig. with Iclusig. venousvenous thrombosis thrombosis (9 patients), (9 patients), pulmonary pulmonary embolism embolism (4 patients), (4 patients), and 1 and case1each case of each portal of portal vein vein thrombosis, thrombosis, and retinal and retinal vein thrombosis. vein thrombosis. Consider Consider dose modification dose modification or discontinuation or discontinuation of Iclusig of Iclusig 5.11 5.11 Compromised Compromised Wound Wound Healing Healing and Gastrointestinal and Gastrointestinal Perforation Perforation in patients in patients who develop who develop seriousserious venousvenous thromboembolism thromboembolism [see Dosage [see Dosage and Administration and Administration (2.3)]. (2.3)]. No formal No formal studiesstudies of the of effect the effect of Iclusig of Iclusig on wound on wound healinghealing have been have conducted. been conducted. BasedBased on theon the 5.2 5.2 Hepatotoxicity Hepatotoxicity mechanism mechanism of action of action [see Clinical [see Clinical Pharmacology Pharmacology (12.1)],(12.1)], IclusigIclusig could compromise could compromise woundwound healing. healing. Serious Serious gastrointestinal gastrointestinal perforation perforation (fistula) (fistula) occurred occurred in one in patient one patient 38 days 38 post-cholecystectomy. days post-cholecystectomy. Hepatotoxicity Hepatotoxicity that has thatresulted has resulted in liverinfailure liver failure and death and death occurred occurred in Iclusig-treated in Iclusig-treated patients. patients. Fulminant Fulminant hepatichepatic failurefailure leadingleading to death to death occurred occurred in an Iclusig-treated in an Iclusig-treated patientpatient withinwithin one week one of week of Interrupt Interrupt IclusigIclusig for at least for at 1least week1 week prior toprior major to major surgery. surgery. The decision The decision when when to resume to resume IclusigIclusig starting starting Iclusig.Iclusig. Two additional Two additional fatal cases fatal cases of acute of acute liver failure liver failure also occurred. also occurred. The fatal Thecases fatal cases after surgery after surgery shouldshould be based be based on clinical on clinical judgment judgment of adequate of adequate woundwound healing. healing. occurred occurred in patients in patients with BP-CML with BP-CML or Ph+orALL. Ph+Severe ALL. Severe hepatotoxicity hepatotoxicity occurred occurred in all disease in all disease cohorts. cohorts. 5.12 5.12 Embryo-Fetal Embryo-Fetal Toxicity Toxicity The incidence The incidence of aspartate of aspartate aminotransferase aminotransferase (AST) (AST) or alanine or alanine aminotransferase aminotransferase (ALT) elevation (ALT) elevation Iclusig Iclusig can cause can cause fetal harm fetal when harm when administered administered to a pregnant to a pregnant woman woman basedbased on its on mechanism its mechanism was 56% was(all 56% grades) (all grades) and 8% and(grade 8% (grade 3 or 4).3 Iclusig or 4). Iclusig treatment treatment may result may result in elevation in elevation in ALT,in ALT, of action of action and findings and findings in animals. in animals. Ponatinib Ponatinib caused caused embryo-fetal embryo-fetal toxicity toxicity in rats in at rats exposures at exposures AST, orAST, both. or ALT both.orALT ASTorelevation AST elevation was not was reversed not reversed by theby date theofdate lastoffollow-up last follow-up in 5% in of 5% patients. of patients. lower lower than human than human exposures exposures at the at recommended the recommended humanhuman dose. dose. If this Ifdrug thisisdrug usedis during used during Monitor Monitor liver function liver function tests at tests baseline, at baseline, at least at monthly least monthly or as clinically or as clinically indicated. indicated. Interrupt, Interrupt, pregnancy, pregnancy, or if the or patient if the patient becomes becomes pregnant pregnant while taking while taking this drug, this the drug, patient the patient shouldshould be be reducereduce or discontinue or discontinue IclusigIclusig as clinically as clinically indicated indicated [see Dosage [see Dosage and Administration and Administration (2.3)]. (2.3)]. apprised apprised of the of potential the potential hazardhazard to the to fetus. the fetus. AdviseAdvise women women to avoid to pregnancy avoid pregnancy while taking while taking IclusigIclusig [see Use [seeinUse Specific in Specific Populations Populations (8.1)]. (8.1)]. 5.3 5.3 Congestive Congestive Heart Heart Failure Failure 6 6 ADVERSE ADVERSE REACTIONS REACTIONS TwentyTwenty patients patients treatedtreated with Iclusig with Iclusig (4%) experienced (4%) experienced seriousserious congestive congestive heart failure heart failure or or left ventricular left ventricular dysfunction, dysfunction, with 4with fatalities. 4 fatalities. Thirty-three Thirty-three patients patients treatedtreated with Iclusig with Iclusig (7%) (7%) Because Because clinicalclinical trials are trials conducted are conducted under under widelywidely varying varying conditions, conditions, adverse adverse reaction reaction rates rates experienced experienced any grade any grade of congestive of congestive heart failure heart failure or leftor ventricular left ventricular dysfunction. dysfunction. Monitor Monitor observed observed in the in clinical the clinical trials of trials a drug of acannot drug cannot be directly be directly compared compared with rates with in rates the in clinical the clinical patients patients for signs for or signs symptoms or symptoms consistent consistent with congestive with congestive heart failure heart failure and treat andas treat clinically as clinically trials of trials another of another drug and drugmay andnot may reflect not reflect the rates the observed rates observed in clinical in clinical practice. practice. indicated, indicated, including including interruption interruption of Iclusig. of Iclusig. Consider Consider discontinuation discontinuation of Iclusig of Iclusig in patients in patients who who The following The following adverse adverse reactions reactions are discussed are discussed in greater in greater detail detail in other in sections other sections of the of the develop develop seriousserious congestive congestive heart failure heart failure [see Dosage [see Dosage and Administration and Administration (2.3)]. (2.3)]. prescribing prescribing information: information: 5.4 5.4 Hypertension Hypertension • Thrombosis • Thrombosis and Thromboembolism and Thromboembolism [see Warnings [see Warnings and Precautions and Precautions (5.1)] (5.1)] Eight patients Eight patients treatedtreated with Iclusig with Iclusig (2%) experienced (2%) experienced treatment-emergent treatment-emergent symptomatic symptomatic • Hepatotoxicity • Hepatotoxicity [see Warnings [see Warnings and Precautions and Precautions (5.2) and (5.2)Dosage and Dosage and Administration and Administration (2.3)] (2.3)] hypertension hypertension as a serious as a serious adverse adverse reaction, reaction, including including hypertensive hypertensive crisis.crisis. TheseThese patients patients • Congestive • Congestive Heart Heart FailureFailure [see Warnings [see Warnings and Precautions and Precautions (5.3)] (5.3)]

AdverseAdverse drug reactions, drug reactions, reportedreported using MedDRA using MedDRA and graded and graded using NCI-CTC-AE using NCI-CTC-AE v 4.0 (NCI v 4.0 Common (NCI Common Terminology Terminology Criteria Criteria for for • Hypertension [see Warnings and Precautions (5.4)] (5.4)] • Hypertension [see Warnings and Precautions AdverseAdverse Events) Events) for assessment for assessment of toxicity. of toxicity. • Pancreatitis [see Dosage and Administration (2.3) and and Precautions (5.5)] (5.5)] • Pancreatitis [see Dosage and Administration (2.3)Warnings and Warnings and Precautions Treatment-emergent, Treatment-emergent, all causality all causality events events • Hemorrhage [see Warnings and Precautions (5.6)] (5.6)] • Hemorrhage [see Warnings and Precautions (a) derived (a) derived from blood frompressure blood pressure (BP) measurement (BP) measurement recorded recorded monthlymonthly while onwhile trial on trial • Fluid• Retention [see Warnings and Precautions (5.7)] (5.7)] Fluid Retention [see Warnings and Precautions • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] (5.8)] • Cardiac Arrhythmias [see Warnings and Precautions (b) includes (b) includes cardiac,cardiac, central central nervousnervous system,system, and peripheral and peripheral arterial arterial ischemia ischemia • Myelosuppression [see Dosage and Administration (2.2) and and Precautions (5.9)] (5.9)] (c) includes • Myelosuppression [see Dosage and Administration (2.2)Warnings and Warnings and Precautions (c) includes cardiac cardiac failure, cardiac failure, cardiac failure congestive, failure congestive, cardiogenic cardiogenic shock, cardiopulmonary shock, cardiopulmonary failure, ejection failure, ejection fractionfraction decreased, decreased, pulmonary pulmonary edema, edema, right ventricular right ventricular failure failure

The adverse reactions described in thisinsection were identified in a single-arm, open-label, The adverse reactions described this section were identified in a single-arm, open-label, (d) includes (d) includes abdominal abdominal pain, abdominal pain, abdominal pain upper, painabdominal upper, abdominal pain lower, painabdominal lower, abdominal discomfort discomfort international, multicenter trial intrial 449inpatients with CML Ph+orALL disease was was international, multicenter 449 patients withorCML Ph+whose ALL whose disease (e) includes aphthous aphthous stomatitis, stomatitis, lip blister, lip mouth blister,ulceration, mouth ulceration, oral mucosal oral mucosal eruption, eruption, oral pain, oral oropharyngeal pain, oropharyngeal pain, pharyngeal pain, pharyngeal considered to be resistant or intolerant to priortotyrosine kinasekinase inhibitor (TKI) therapy including considered to be resistant or intolerant prior tyrosine inhibitor (TKI) therapy including (e) includes ulceration, ulceration, stomatitis, stomatitis, tongue ulceration tongue ulceration those those with the BCR-ABL T315I T315I mutation. All patients received a starting dose of 45 mg Iclusig with the BCR-ABL mutation. All patients received a starting dose of 45 mg Iclusig (f) includes gastric hemorrhage, gastric hemorrhage, gastric ulcer gastric hemorrhage, ulcer hemorrhage, hemorrhagic hemorrhagic gastritis,gastritis, gastrointestinal gastrointestinal hemorrhage, hemorrhage, hematemesis, hematemesis, once daily. the At time analysis, the median duration of treatment with Iclusig was 337 once At daily. theoftime of analysis, the median duration of treatment with Iclusig wasdays 337 days (f) includes hematochezia, hematochezia, hemorrhoidal hemorrhoidal hemorrhage, hemorrhage, intra-abdominal intra-abdominal hemorrhage, hemorrhage, melena,melena, rectal hemorrhage, rectal hemorrhage, and upper andgastrointestinal upper gastrointestinal in patients with CP-CML, 362 days patients with AP-CML, 89 days patients with BP-CML, in patients with CP-CML, 362indays in patients with AP-CML, 89indays in patients with BP-CML, hemorrhage hemorrhage and 81and days patients with Ph+ dose intensity was 37was mg,37ormg, 83%, of the of the (g) includes 81indays in patients withALL. Ph+The ALL.median The median dose intensity or 83%, (g) includes burningburning sensation, sensation, hyperesthesia, hyperesthesia, hypoesthesia, hypoesthesia, neuralgia, neuralgia, neuropathy neuropathy peripheral, peripheral, paresthesia, paresthesia, peripheral peripheral expected 45 mg45 dose. expected mg dose. sensorimotor sensorimotor neuropathy, neuropathy, polyneuropathy polyneuropathy Adverse reactions reported in more all patients treatedtreated with Iclusig in thisintrial Adverse reactions reported in than more10% thanof10% of all patients with Iclusig thisare trial are presented in Table Overall, the most non-hematologic adverse reactions (≥ 20%) presented in 4. Table 4. Overall, the common most common non-hematologic adverse reactions (≥ 20%) Table 5: Table Serious 5: Serious Adverse Adverse Reactions Reactions (SAR) (SAR) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, arthralgia, were hypertension, rash, abdominal pain, fatigue, headache, dry constipation, skin, constipation, arthralgia, nausea, and pyrexia. nausea, and pyrexia. Cardiovascular Cardiovascular disorders disorders ArterialArterial ischemic ischemic event event The rates treatment-emergent adverse eventsevents resulting in discontinuation were 13% CP-in CPThe of rates of treatment-emergent adverse resulting in discontinuation werein13% Myocardial Myocardial infarction infarction or worsening or worsening coronary coronary artery disease artery disease CML, 11% AP-CML, 15% in15% BP-CML, and 9% Ph+inALL. adverse eventsevents CML,in11% in AP-CML, in BP-CML, andin 9% Ph+The ALL.most The common most common adverse Stroke Stroke or TIA or TIA that led to led treatment discontinuation were thrombocytopenia (4%) and (1%). (1%). that to treatment discontinuation were thrombocytopenia (4%)infections and infections Peripheral Peripheral arterialarterial diseasedisease Hemorrhage Dose modifications (dose (dose delaysdelays or dose due todue adverse reactions occurred in 74%inof74% of Hemorrhage Dose modifications or reduction) dose reduction) to adverse reactions occurred CNS hemorrhage CNS hemorrhage the patients. The most adverse reactions (≥5%)(≥5%) that led to led dose includeinclude the patients. The common most common adverse reactions that to modifications dose modifications Gastrointestinal Gastrointestinal hemorrhage hemorrhage thrombocytopenia (30%),(30%), neutropenia (13%),(13%), lipase lipase increased (12%),(12%), rash (11%), abdominal pain pain thrombocytopenia neutropenia increased rash (11%), abdominal CardiacCardiac failure failure (11%),(11%), pancreatitis (6%), and GGTorincreased (6%). (6%). pancreatitis (6%),ALT, andAST, ALT,orAST, GGT increased Effusions* Effusions*

N (%) N (%) 34 (8%)34 (8%) 21 (5%)21 (5%) 8 (2%)8 (2%) 7 (2%)7 (2%) 22 (4%)22 (4%) 10 (2%)10 (2%) 10 (2%)10 (2%) 20 (4%)20 (4%) 13 (3%)13 (3%) 11 (2%)11 (2%) 10 (2%)10 (2%) 8 (2%)8 (2%)

Atrial fibrillation Atrial fibrillation thromboembolism VenousVenous thromboembolism Table 4: Table Adverse 4: Adverse Reactions Reactions Occurring Occurring in >10% in >10% of Patients, of Patients, Any Group Any Group Hypertension Hypertension Gastrointestinal disorders Gastrointestinal disorders CP-CML CP-CML AP-CML AP-CML BP-CML BP-CML Ph+ ALL Ph+ ALL Pancreatitis Pancreatitis 23 (5%)23 (5%) (N=270) (N=270) (N=85)(N=85) (N=62)(N=62) (N=32)(N=32) Abdominal Abdominal pain pain 17 (4%)17 (4%) SystemSystem Organ Organ Class Class Any Any CTCAECTCAE Any Any CTCAECTCAE Any Any CTCAECTCAE Any Any CTCAECTCAE and lymphatic disorders and lymphatic systemsystem disorders Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Blood Blood neutropenia FebrileFebrile neutropenia 13 (3%)13 (3%) (%) (%) 3 / 4 3 /(%) 4 (%) 3 / 4 3 /(%) 4 (%) 3 / 4 3 /(%) 4 (%) 3/4 3/4 Thrombocytopenia Thrombocytopenia 13 (3%)13 (3%) (%) (%) (%) (%) (%) (%) (%) (%) AnemiaAnemia 12 (2%)12 (2%) Cardiac Cardiac or Vascular or Vascular disorders disorders Infections Infections Pneumonia Pneumonia 24 (4%)24 (4%) Hypertension Hypertension (a) (a) 68 6839 3971 7136 3665 6526 2653 5331 31 SepsisSepsis 11 (2%)11 (2%) ArterialArterial ischemia ischemia (b) (b) 13 137 712 126 68 85 53 30 0 General General CardiacCardiac FailureFailure (c) 64 46 62 215 1511 116 66 6 (c) 6 PyrexiaPyrexia 14 (3%)14 (3%) Gastrointestinal disorders Gastrointestinal disorders *includes*includes pericardial pericardial effusion,effusion, pleural effusion, pleural effusion, and ascites and ascites Abdominal 834 346 644 446 6 Abdominal pain (d)pain (d) 49 4910 1040 408 Constipation 224 242 226 260 047 473 3 Constipation 37 372 Laboratory Abnormalities Laboratory Abnormalities 127 270 032 322 222 220 0 NauseaNausea 23 231 Diarrhea 126 260 018 183 313 133 3 Diarrhea 16 161 Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 3 or 4 Myelosuppression was commonly reported in all patient populations. The frequency of grade Vomiting 224 240 023 232 222 220 0 Vomiting 13 132 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ patients with CP-CML (see Table andALL Ph+than ALLinthan in patients with CP-CML (see 6). Table 6). Oral mucositis (e) 115 151 123 230 09 93 3 Oral mucositis (e) 10 101 GI hemorrhage (f) 2<1 <18 81 111 115 59 96 6 GI hemorrhage (f) 2 and lymphatic disorders Blood Blood and lymphatic systemsystem disorders Table 6: Table Incidence 6: Incidence of Clinically of Clinically Relevant Relevant Grade Grade 3/4* Hematologic 3/4* Hematologic Abnormalities Abnormalities neutropenia 1<1 <14 44 411 1111 1125 2525 25 Laboratory FebrileFebrile neutropenia 1 Laboratory Test Test CP-CML CP-CML AP-CML AP-CML BP-CML BP-CML Ph+ ALL Ph+ ALL (N=270) (N=270) (N=85)(N=85) (N=62)(N=62) (N=32)(N=32) Infections and infestations Infections and infestations (%) (%) (%) (%) (%) (%) (%) (%) 11 15 55 58 88 822 2222 22 SepsisSepsis 1 Hematology Hematology Pneumonia 32 211 119 913 1311 119 93 3 Pneumonia 3 Thrombocytopenia Thrombocytopenia tract infection 71 112 121 10 00 09 90 0 UrinaryUrinary tract infection 7 36 36 47 47 57 57 47 47 (platelet (platelet count decreased) count decreased) Upper respiratory tract infection 18 80 011 112 20 00 0 Upper respiratory tract infection 11 111 Neutropenia Neutropenia (ANC decreased) (ANC decreased) 24 24 51 51 55 55 63 63 Leukopenia Leukopenia (WBC decreased) (WBC decreased) 14 14 35 35 53 53 63 63 Nasopharyngitis 90 012 120 03 30 03 30 0 Nasopharyngitis 9 AnemiaAnemia (Hgb decreased) (Hgb decreased) 9 9 26 26 55 55 34 34 Cellulitis 21 14 42 211 113 30 00 0 Cellulitis 2 Lymphopenia Lymphopenia 10 10 26 26 37 37 22 22 Nervous disorders Nervous systemsystem disorders ANC=absolute ANC=absolute neutrophil neutrophil count, Hgb=hemoglobin, count, Hgb=hemoglobin, WBC=white WBC=white blood cellblood countcell count Headache 328 280 031 313 325 250 0 Headache 39 393 *Reported *Reported using NCI-CTC-AE using NCI-CTC-AE v 4.0 v 4.0 Peripheral neuropathy 28 80 08 80 06 60 0 Peripheral neuropathy (g) (g) 13 132 Dizziness 05 50 05 50 03 30 0 Dizziness 11 110 Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Respiratory, thoracic, Respiratory, thoracic, Laboratory Test Test SafetySafety Population Laboratory Population and mediastinal disorders and mediastinal disorders N=449N=449 effusion 31 111 112 213 130 019 193 3 PleuralPleural effusion 3 017 170 018 180 06 60 0 Cough Cough 12 120 Any Grade* Grade Grade 3/4 3/4 Any Grade* Dyspnea 215 152 221 217 76 60 0 Dyspnea 11 112 (%) (%) (%) (%) Skin and subcutaneous disorders Skin and subcutaneous tissue tissue disorders Liver function tests tests Liver function Rash and related conditions 548 488 839 395 534 346 6 Rash and related conditions 54 545 ALT increased 53 53 8 ALT increased 8 Dry skin 227 271 124 242 225 250 0 Dry skin 39 392 AST increased 41 41 4 AST increased 4 Musculoskeletal and connective Musculoskeletal and connective AlkalineAlkaline phosphatase increased 37 37 2 phosphatase increased 2 disorders tissue tissue disorders Albumin decreased 28 28 1 Albumin decreased 1 Arthralgia 231 311 119 190 013 130 0 Arthralgia 26 262 Bilirubin increased 19 19 1 Bilirubin increased 1 120 200 016 160 06 60 0 MyalgiaMyalgia 22 221 Pancreatic enzymes Pancreatic enzymes in extremity 217 170 013 130 09 90 0 Pain inPain extremity 17 172 LipaseLipase increased 41 41 15 15 increased Back pain 111 112 216 162 213 130 0 Back pain 15 151 Amylase increased 3 <1 <1 Amylase increased 3 05 50 05 50 013 130 0 MuscleMuscle spasmsspasms 12 120 Chemistry Chemistry Bone pain 111 113 39 93 3 Bone pain 12 12<1 <112 121 GlucoseGlucose increased 58 58 6 increased 6 Phosphorus decreased 57 57 8 Phosphorus decreased 8 General disorders and administration General disorders and administration Calcium decreased 52 52 1 Calcium decreased 1 site conditions site conditions SodiumSodium decreased 29 29 5 decreased 5 or asthenia 336 366 635 355 531 313 3 FatigueFatigue or asthenia 39 393 GlucoseGlucose decreased 24 24 0 decreased 0 131 315 532 323 325 250 0 PyrexiaPyrexia 23 231 Potassium decreased 16 16 2 Potassium decreased 2 peripheral 013 130 022 220 0 Edema,Edema, peripheral 13 13<1 <119 190 Potassium increased 15 15 2 Potassium increased 2 8<1 <17 70 016 163 36 63 3 Pain Pain 8 SodiumSodium increased 10 10 <1 <1 increased 70 011 110 013 132 29 90 0 Chills Chills 7 Bicarbonate decreased 11 11 <1 <1 Bicarbonate decreased Metabolism and nutrition disorders Metabolism and nutrition disorders Creatinine increased 7 <1 <1 Creatinine increased 7 Decreased appetite 8<1 <112 121 18 80 031 310 0 Decreased appetite 8 Calcium increased 5 0 Calcium increased 5 0 Investigations Investigations Triglycerides increased 3 <1 <1 Triglycerides increased 3 decreased 6<1 <17 70 05 50 013 130 0 WeightWeight decreased 6 ALT=alanine ALT=alanine aminotransferase, aminotransferase, AST=aspartate AST=aspartate aminotransferase. aminotransferase. Psychiatric disorders Psychiatric disorders 012 120 08 80 09 90 0 *Graded*Graded Insomnia 70 Insomnia 7 using NCI-CTC-AE using NCI-CTC-AE v 4.0 v 4.0

DRUG INTERACTIONS

8.7

Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)]. 7.1

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/ day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3

Nursing Mothers It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Renal Impairment

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally selfadministered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234

For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0513/0019/US

ASCOPost.com | JUNE 25, 2013

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Dermatologic Events in Oncology How to Recognize and Manage Hand-Foot Syndrome Due to Capecitabine or Doxorubicin By Beth McLellan, MD

lso known as palmar-plantar erythrodysesthesia, hand-foot syndrome is a common adverse event caused by many cytotoxic agents.

from excretion of the chemotherapy in the sweat. Development of the condition may be a surrogate marker of capecitabine efficacy, as there is a significant correlation between capecitabine-induced hand-foot syndrome and efficacy biomarkers in patients with metastatic breast cancer.

Treatment Recommendations

Beth McLellan, MD

Two of the most common causative medications are capecitabine (Xeloda, adverse events of all grades occur in 56%–63% and grade 3 events occur in 11%–24%) and liposomal doxorubicin (all grades occur in 40% and grade 3 events occur in 1%–20%). The symptoms begin an average of 2 to 12 days after drug administration, beginning with redness and swelling of the palms and soles, which may progress to dryness, scaling, pain, itching, and sometimes blisters and ulceration (Fig. 1). Hand-foot syndrome affects the palms more frequently than the soles. Although several hypotheses exist, the precise mechanism underlying the development of the syndrome is unknown. The presence of liposomal doxorubicin has been demonstrated in the skin surrounding eccrine glands, so it is possible that this toxicity comes Dr. McLellan is Assistant Professor in the Ronald O. Perelman Department of Dermatology at New York University School of Medicine and NYU Langone Medical Center, New York.

Visit

Patients with hand-foot syndrome should avoid excessive friction or trauma on the hands and feet, and they should use protective gloves and socks when performing activities, especially during the first 2 months of chemotherapy. Pain is the predominant symptom of hand-foot syndrome. Consequently, analgesia with opioids or nonsteroidal anti-inflammatory drugs should be instituted if necessary. Treatment with twice daily applications of high-potency topical steroid creams (clobetasol, betamethasone) for erythematous or painful areas is recommended, as well as keratolytic moisturizers such as ammonium lactate (lactic acid) 12% or salicylic acid 6% for hyperkeratotic areas. Systemic premedication with dexamethasone (8 mg twice daily on days 1–4; 4 mg twice daily on day 5; 4 mg on day 6) has demonstrated benefit in uncontrolled studies of patients treated with liposomal doxorubicin. Celecoxib (Celebrex), 200 mg twice daily, has been shown to delay the onset and decrease the incidence of grade 1/2 hand-foot syndrome from capecitabine. Regional cooling of the hands and feet during liposomal doxorubicin infusion decreases the frequency and severity of hand-foot syndrome, but presents logistical challenges in busy

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, an Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments and the author of many publications, including the recently published Skin Care Guide for People Living With Cancer. The series is intended to offer oncologists guidance in recognizing and treating the skin toxicities associated with anticancer agents.

chemotherapy suites. In cases where these interventions are not effective, decreasing or interrupting doses may lead to improvement in symptoms. Early recognition

and treatment of hand-foot syndrome may help prevent the need for changes in drug regimen. n

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

Fig. 1: Palmar-plantar erythrodysesthesia is a common adverse event often caused by capecitabine and liposomal doxorubicin in addition to other cytotoxic agents.

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The ASCO Post | JUNE 25, 2013

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Integrative Oncology Vitamin D and Cancer: A Uniform Dose Is Unlikely to Fit All Patients By Kathleen M. Wesa, MD, and Barrie R. Cassileth, MS, PhD, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center, New York

echnically, vitamin D is a secosteroid hormone, not a vitamin. Increasing evidence indicates that vitamin D exerts effects beyond calcium homeostasis. Importantly, for example, higher serum vitamin D levels are associated with better cancer outcomes, including survival.1-3 The protective effects of vitamin D result from its role as a nuclear transcription factor that regulates cell growth,4 differentiation,5 and a wide range of cellular mechanisms crucial to the development and progression of cancer. Vitamin D acts as an immunomodulator through multiple pathways and enhances immune tolerance.6 Serum vitamin D levels influence both gene expression and regulation in hundreds of genes.7 Vitamin D activates the Wnt-cadherin pathway, and vitamin D deficiency permits increased colon cancer cell growth.8 Vitamin D increases aromatase inhibition9 and decreases both VEGF and IL-8 synthesis.6 New evidence indicates that vitamin D plays a role in BRCA1-mediated cancers and may modulate triple-negative breast cancer by preventing cathepsin L–mediated degradation of 53BP1.10 BRCA1 deficiency induces increased degradation of 53BP1 in breast cancer cells, facilitating unregulated cellular growth. Because administration of vitamin D reverses the 53BP1 degradation, thus enhancing serum vitamin D levels, therapeutic benefits in triple-negative breast cancer and other BRCA1-mediated cancers may result.10

Vitamin D Synthesis Vitamin D is predominantly synthesized in two steps: First, calcidiol (25-hydroxy vitamin D) is formed from ergocalciferol (D2) or cholecalciferol (D3) via 25-hydroxylation in the liver by CYP2R1, CYP27A1, or CYP3A4. Calcidiol then undergoes 1α-hydroxylation primarily in the kidney via CYP27B1, resulting in its active form, calcitriol (1, 25-dihydroxy vitamin D). Local calcitriol tissue synthesis

vitamin D are likely secondary to local synthesis, enhancing serum vitamin D levels may provide tissue-specific protective effects.

Vitamin D and Cancer Prevention The strongest and most consistent evidence for vitamin D’s protective effects is seen in patients with colorectal14 and breast cancer.1 Some epidemiologic studies suggest that vitamin D levels

To overcome genetic variability in receptors, monitoring vitamin D levels and titrating supplementation to achieve target levels may be more prudent than administering a single vitamin D dose to all patients. Large randomized controlled trials designed to address specific oncology-relevant endpoints are warranted to define optimal vitamin D level(s) in oncology. —Kathleen M. Wesa, MD, (top), and Barrie R. Cassileth, MS, PhD

Prostate cancer data are inconsistent.18 Prostate cells can lose their vitamin D receptor as they become more anaplastic, rendering cells resistant to vitamin D’s antiproliferative effects.13 This vitamin D receptor loss provides insight into potential mechanisms behind U-shaped survival curves, where both higher and lower serum vitamin D levels show worse survival. Similar mechanisms may be in effect for pancreatic and other cancers, as higher levels were associated with poorer outcomes in the Vitamin D Pooling Project.19 Two prospective trials that are underway address whether vitamin D3 supplementation helps prevent cancer. The VITamin D and OmegA-3 TriaL (VITAL) uses a 2×2 factorial design with vitamin D3 at 2,000 IU daily with or without omega-3 fatty acid supplementation to assess cancer and cardiovascular disease incidence in 20,000 subjects. The three-armed FINnish Vitamin D (FIND) trial administers vitamin D3 at 1,600 or 3,200 IU daily vs placebo and will study the incidence of cardiovascular disease and cancer in 18,000 participants.

Different Doses May Achieve Similar Serum Levels also occurs through activation of the vitamin D receptor, driven by the serum concentration of calcidiol. Local calcitriol synthesis also has been demonstrated in cancerous cell lines in colorectal,11 breast,12 and prostate13 tissues. Because extraskeletal benefits of

of approximately 30 ng/mL may protect against breast cancer15; while metaanalyses conclude at least 50 ng/mL is required to decrease risk by 50%.16 Meta-analyses find a 50% decreased incidence of colorectal cancer with serum vitamin D levels ≥ 33 ng/mL.17

Vitamin D receptor genetics may contribute to the detrimental effects of low vitamin D.20 Receptor variability and medications can alter vitamin D metabolism, affecting daily vitamin D requirements needed to maintain steady serum levels. Vitamins D3 and

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Herbs, Botanicals, & Other Products Visit the About Herbs website at

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ASCOPost.com | JUNE 25, 2013

PAGE 71

Integrative Oncology D2 are fat-soluble; therefore, coadministration with resin binders such as cholestyramine or clinical malabsorption syndromes decrease vitamin D absorption. Vitamin D2 has a shorter half-life and is approximately 80% less potent than vitamin D3. Calcidiol is synthesized by CYP3A4, and calcitriol induces CYP3A4. Thus, there is theoretical potential for serum drug alterations in medications that utilize the CYP3A4 pathway. That said, a recent review21 concluded there was insufficient evidence regarding most interactions.

Breast Cancer and Aromatase Inhibitors Aromatase inhibitors utilize CYP3A4, which may increase the vitamin D daily requirement. Higher serum vitamin D levels than typically achieved with most vitamin D3 maintenance doses may be required to decrease aromatase inhibitor treatment–related side effects. Vitamin D has tissue-selective aromatase inhibitor action9 and may also modulate aromatase inhibi-

D2 administration, which dissipated once dose was decreased to 50,000 IU monthly.24 Larger confirmatory randomized controlled trials are needed.

Conflicting Recommendations The Institute of Medicine (IOM),25 U.S. Preventive Services Task Force,26,27 and Endocrine Society28 published conflicting recommendations regarding vitamin D sufficiency. A 2011 IOM report recommends at least 20 ng/mL for skeletal health, whereas the Endocrine Society requires > 30 ng/mL. Neither may be applicable to the oncology setting. Long-term vitamin D3 use of 10,000 IU daily has been shown safe,29 and risk of toxicity even with serum levels of 150 ng/mL is minimal.30 Most intervention trials have not reported vitamin D levels > 60 ng/mL; thus, the overall risk-benefit ratio of enhanced serum levels remains undefined. Population-based screening for vitamin D deficiency is not recommended, but determining vitamin D levels in patients at risk for falls, osteoporo-

Monitoring vitamin D levels and titrating supplementation to achieve target levels may be more prudent than administering a single vitamin D dose to all patients. —Kathleen M. Wesa, MD, and Barrie R. Cassileth, PhD

tor–associated osteoporosis. The B-ABLE study of 232 women on aromatase inhibitors for early breast cancer showed significantly decreased aromatase inhibitor–associated bone density loss after 1 year of aromatase inhibitor treatment in women with serum vitamin D levels ≥ 40 ng/mL22 compared with levels < 30 ng/mL. Women with vitamin D ≥ 40 ng/mL at 3 months post–aromatase inhibitor initiation had reduced bone loss of 1.7% (P = .005) compared to women with levels < 30 ng/mL. Phase II trials using vitamin D supplementation to prevent aromatase inhibitor–associated arthralgias showed increased arthralgias with vitamin D < 40 ng/mL. A pilot trial using cholecalciferol (vitamin D3) supplementation showed significantly decreased aromatase inhibitor–associated arthralgias with vitamin D levels > 66 ng/mL.23 Another randomized controlled trial using 50,000 IU of vitamin D2 showed significant reduction in arthralgias with weekly vitamin

sis, or other complications of vitamin D deficiency is appropriate. Vitamin D testing does not ensure adequate vitamin D levels, given the inconsistency in responses to vitamin D supplementation and the wide variability in overthe-counter product potency.31

Concluding Thoughts The IOM guidelines do not appear to be useful in the oncology setting. More aggressive vitamin D3 administration may be required to achieve serum vitamin D levels in a range adequate to determine risk-benefit ratio, especially for patients receiving aromatase inhibitors. To overcome genetic variability in receptors, monitoring vitamin D levels and titrating supplementation to achieve target levels may be more prudent than administering a single vitamin D dose to all patients. Large randomized controlled trials designed to address specific oncology-relevant endpoints are warranted to define optimal vitamin D level(s) in oncology. n

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan-Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc. org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. Disclosure: Drs. Wesa and Cassileth reported no potential conflicts of interest.

References 1. Goodwin PJ, Ennis M, Pritchard KI, et al: Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol 27:3757-3763, 2009. 2. Ng K, Meyerhardt JA, Wu K, et al: Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer. J Clin Oncol 26:2984-2991, 2008. 3. Peiris AN, Bailey BA, Manning T: Relationship of vitamin D monitoring and status to bladder cancer survival in veterans. South Med J 106:126-130, 2013. 4. Holt PR, Arber N, Halmos B, et al: Colonic epitheliam cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D. Cancer Epidemiol Biomarkers Prev 11:113-119, 2002. 5. Murillo G, Matusiak D, Benya RV, et al: Chemopreventive efficacy of 25-hydroxyvitamin D3 in colon cancer. J Steroid Biochem Mol Biol 103:763-767, 2007. 6. Krishnan AV, Feldman D: Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 51:311-336, 2011. 7. Pike JW, Meyer MB: The vitamin D receptor: New paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D3. Rheum Dis Clin North Am 38:1327, 2012. 8. Larriba MJ, Ordóñez-Morán P, Chicote I, et al: Vitamin D receptor deficiency enhances Wnt/beta-catenin signaling and tumor burden in colon cancer. PLoS One 6:e23524, 2011. 9. Krishnan AV, Swami S, Peng L, et al: Tissue-selective regulation of aromatase expression by calcitriol: Implications for breast cancer therapy. Endocrinology 151:32-42, 2010. 10. Grotsky DA, Gonzalez-Suarez I, Novell A, et al: BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells. J Cell Biol 200:187-202, 2013. 11. Tangpricha V, Flanagan JN, Whit-

latch LW, et al: 25-hydroxyvitamin D-1αhydroxylase in normal and malignant colon tissue. Lancet 357:1673-1674, 2001. 12. Friedrich M, Diesing D, Cordes T, et al: Analysis of 25-hydroxyvitamin D3-1alpha-hydroxylase in normal and malignant breast tissue. Anticancer Res 26(4A):26152620, 2006. 13. Chen TC, Wang L, Whitlatch LW, et al: Prostatic 25-hydroxyvitamin D-1alphahydroxylase and its implication in prostate cancer. J Cellular Biochem 88:315-322, 2003. 14. Giovannucci E: Epidemiology of vitamin D and colorectal cancer: Casual or causal link? J Steroid Biochem Mol Biol 121:349-354, 2010. 15. Bertone-Johnson ER, Chen WY, Holick MF, et al: Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14:1991-1997, 2005. 16. Garland CF, Gorham ED, Mohr SB, et al: Vitamin D and prevention of breast cancer: Pooled analysis. J Steroid Biochem Mol Biol 103:708-711, 2007. 17. Gorham ED, Garland CF, Garland FC, et al: Optimal vitamin D status for colorectal cancer prevention: A quantitative meta analysis. Am J Prev Med 32:210-216, 2007. 18. Gilbert R, Martin RM, Beynon R, et al: Associations of circulating and dietary vitamin D with prostate cancer risk: A systematic review and dose-response meta-analysis. Cancer Causes Control 22:319-340, 2011. 19. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al: Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort consortium Vitamin D Pooling Project of rarer cancers. Am J Epidemiol 172:81-93, 2010. 20. Martineau AR, Jolliffe DA: Genetic variants modifying the influence of vitamin D. JAMA 309:872-873, 2013. 21. Robien K, Oppeneer SJ, Kelly JA, et al: Drug-vitamin D interactions: A systematic review of the literature. Nutr Clin Pract 28:194-208, 2013. 22. Prieto-Alhambra D, Servitja S, Javaid MK, et al: Vitamin D threshold to prevent continued on page 72

The ASCO Post | JUNE 25, 2013

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FDA Update

Orphan Drug Status Granted for Novel Targeted Therapy to Treat Rare Hematologic Cancer

he U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation to Stemline Therapeutics’ SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm, a rare and aggressive hematologic malignancy for which there is no effective treatment. SL401 also has Orphan Drug status for the treatment of acute myeloid leukemia (AML). SL-401 is a novel targeted therapy directed to the interleukin-3 receptor present on tumor bulk and cancer stem cells of multiple hematologic cancers. The agent has demonstrated singleagent clinical activity in patients with

advanced hematologic cancers, including blastic plasmacytoid dendritic cell neoplasm, AML, and myelodysplastic syndrome.

Blastic plasmacytoid dendritic cell neoplasm was previously known as blastic NK cell lymphoma and agranular CD4+/CD56+ hematodermic neo-

plasm. The disease most commonly affects middle-aged and older patients and is approximately three times more common in men than women. n

Vitamin D and Cancer continued from page 71

aromatase inhibitor-related bone loss: The B-ABLE prospective cohort study. Breast Cancer Res Treat 133:1159-1167, 2012. 23. Khan QJ, Reddy PS, Kimler BF, et al: Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 119:111-118, 2010. 24. Rastelli AL, Taylor ME, Gao F, et al: Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): A phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat 129:107-116, 2011. 25. Ross AC, Manson JE, Abrams SA, et al: The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 96:53-58, 2011. 26. Kuehn BM: USPSTF: Taking vitamin D and calcium doesn’t prevent fractures in older women. JAMA 308:225-226, 2012. 27. Moyer VA, US Preventive Services Task Force: Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 157:197-197, 2012. 28. Holick MF, Binkley NC, BischoffFerrari HA, et al: Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911-1930, 2011. 29. Veith R: Vitamin D and cancer minisymposium: The risk of additional vitamin D. Ann Epidemiol 19:441-445, 2009. 30. Jones G, Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88:582S-586S, 2008. 31. Walker T: Vitamin D potency varies widely in dietary supplements. Formulary. February 28, 2013.

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

Boxed Warning And Additional Important Safety Information Boxed Warning And Additional Embryo-Fetal Death and Severe Birth Defects Important Safety Information

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

ASCOPost.com | JUNE 25, 2013

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Announcements

Partnership Seeks to Accelerate Development of Innovative Therapies

he Leukemia & Lymphoma Society (LLS) recently joined the Dana-Farber Cancer Institute in Boston to establish a network of sites for clinical trial testing of innovative blood cancer therapies in community oncol-

ogy settings across the country. This Blood Cancer Research Partnership (BCRP) will bring clinical trials closer to where patients live and as a result make it easier for more patients to take part in trials.

“Having to travel long distances from home to a major medical center is a major deterrent to patients’ participation in cancer clinical trials,” said Leukemia & Lymphoma Society Chief Mission Officer Louis J. DeGennaro,

TRANSFORM THE TREATMENT OF TRANSFORM THE TREATMENT OF DIFFICULT ADVANCED BASAL CELL DIFFICULT ADVANCED CARCINOMA ((aBCC) BASAL CELL CARCINOMA ((aBCC) (Not actual size)

ERIVEDGE IS A UNIQUE ORAL THERAPY ERIVEDGE IS A UNIQUE ORAL THERAPY

• Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, and invasiveness), some patients may not be candidates for surgery or radiation1,2 • Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, • and Erivedge is an oral some treatment option dosed ascandidates a 150-mg capsule once until1,2 invasiveness), patients may not be for surgery or daily radiation disease progression or unacceptable toxicity3 • Erivedge is an oral treatment option dosed as a1,3 150-mg capsule once daily until • disease Erivedgeprogression reduced lesions in patients with aBCC 3 or unacceptable toxicity

(Not actual size)

1,3 • Erivedge reduced lesions in patients withby aBCC Objective response rates (ORR) IR from ERIVANCE1,3*

(n=63) mBCC (n=33) Objective response rates (ORR) bylaBCC IR from ERIVANCE1,3* ORR 43% (n=27) 30% (n=10) laBCC (n=63) mBCC (n=33) (95% CI) (30.5-56.0) (15.6-48.2) ORR 43% (n=27) 30% (n=10) Complete response 21% (n=13) 0% (95% CI) (30.5-56.0) (15.6-48.2) Partial response 22% (n=14) 30%0% (n=10) Complete response 21% (n=13) 7.6 7.6 Median duration of response (months) Partial response 22% (n=14) 30% (n=10) (5.7-9.7) (5.6-NE) (95% CI) 7.6 7.6 Median duration of response (months) (5.7-9.7) (5.6-NE) (95% CI)

Indication Erivedge® (vismodegib) capsule is a hedgehog pathway inhibitor indicated for the treatment Indication

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

Adverse Reactions • The most common adverse reactions (≥10%) were Adverse Reactions muscle spasms, alopecia, dysgeusia, weight loss, • The most common adverse reactions (≥10%) were fatigue, nausea, diarrhea, decreased appetite, muscle spasms, alopecia, dysgeusia, weight loss, constipation, arthralgias, vomiting, and ageusia fatigue, nausea, diarrhea, decreased appetite, • constipation, In clinical trials, a total ofvomiting, 3 of 10 premenopausal arthralgias, and ageusia women developed amenorrhea while receiving Erivedge • In clinical trials, a total of 3 of 10 premenopausal • women Treatment-emergent grade 3 laboratory abnormalities developed amenorrhea while receiving Erivedge observed in clinical trials were hyponatremia in • Treatment-emergent grade 3 laboratory abnormalities 6 patients (4%), hypokalemia in 2 patients (1%), observed in clinical trials were hyponatremia in and azotemia in 3 patients (2%) 6 patients (4%), hypokalemia in 2 patients (1%), You may report side the FDA at and azotemia in 3 effects patientsto(2%) (800) FDA-1088 or www.fda.gov/medwatch. You may report side effects to the FDA at You may also report side effects to Genentech (800) FDA-1088 or www.fda.gov/medwatch. at (888) 835-2555. You may also report side effects to Genentech Please Brief Summary of Prescribing Information on at (888)see 835-2555. following page. Please see Brief Summary of Prescribing Information on following page.

See what you can offer your patients with aBCC at www.Erivedge.com See what you can offer your patients with aBCC at www.Erivedge.com References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med.

2012;366:2171-2179. 2. Walling HW, et al. Cancer Metastasis Rev. 2004;23:389-402. 3. A, Erivedge capsule Prescribing References: 1. Sekulic Migden® (vismodegib) MR, Oro AE, et al. N Engl J Med. Information. Genentech,2.Inc. January 2012;366:2171-2179. Walling HW,2012. et al. Cancer Metastasis Rev. 2004;23:389-402. 3. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012.

PhD. “Most cancer patients are treated by oncologists in their local community. This partnership will bring trials closer to where patients live. We are optimistic that this program will increase continued on page 74

The ASCO Post | JUNE 25, 2013

PAGE 74

Announcements

Innovative Therapies

Georgia, Colorado, Illinois, California, Florida, Texas, Kansas, Tennessee, New Jersey, and Washington State. The Leukemia & Lymphoma Society is investing $1,050,000 in the 3-year project. The Leukemia & Lymphoma Society will have two seats on the steering committee formed to determine which trials will be conducted by the

continued from page 73

trial enrollment, more rapidly advance innovative blood cancer therapies ,and save lives,” Dr. DeGennaro said.

Eleven Trial Sites Eleven potential sites have been identified for the trials - in New York,

network. The agreement requires that certain milestones be met, including the number of trials initiated and number of patients accrued for each trial. The trials will be either Phase I or II, with patient accrual taking place over an 18-month period. Dana-Farber is the lead institute for the Blood Cancer Research Partnership and each of the community sites

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

MedDRA Preferred Term

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

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

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

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

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

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

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

Safety:10"

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

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

will follow the clinical trial protocols established by one centralized agreement.

Novel Partnership “This novel partnership between Dana-Farber Cancer Institute and Leukemia & Lymphoma Society supports the mission of both organizations - to bring cutting-edge clinical research to a wider spectrum of patients with blood cancers today in order to change the paradigms of clinical care for patients tomorrow,” said Blood Cancer Research Program Co-Director Robert Soiffer, MD. Dr. Soiffer is the Chief of the Division of Hematologic Malignancies at Dana-Farber. “The BCRP consortium will provide the opportunity for the Division of Hematologic Malignancies to extend clinical research trials to patients who are outside our regional area and do not have the capacity to come to Dana-Farber,” Dr. Soiffer said. A number of different clinical trial proposals are currently under consideration - including several for chronic lymphocytic leukemia, myeloma, and stem cell transplant. “I believe this partnership provides a unique opportunity to deliver innovative clinical trials to patients closer to home,” says Blood Cancer Research Program Co-Director Irene Ghobrial, MD. Dr. Ghobrial is a medical oncologist in the Division of Hematologic Malignancies at DanaFarber. “It also creates a new pathway of collaboration between community oncologists, academic centers and foundations to improve cancer therapy for patients throughout the United States,” she said. n

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

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2013

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

Indiana Oncology Society Fall Membership Conference July 25 • Indianapolis, Indiana For more information: www.accc-cancer.org/ossn_network/ IN/INevents.asp 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org

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

Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

July

Second Annual 2013 World Cutaneous Malignancies Congress July 26-28 • San Diego, California For more information: www.cutaneousmalignancies.com

ASCO Palliative Care Training July 1-5 • Accra, Ghana For more information: www.asco.org/palliativecare 2nd International Michelangelo Conference on Promises and Challenges of Developing New Drugs in Oncology July 4-5 • Milan, Italy For more information: www.fondazionemichelangelo.org WIN 2013 Symposium: Personalized Cancer Therapy: From Innovation to Implementation July 10-12 • Paris, France For more information: www.winsymposium.org 12th International Congress on the Future of Breast Cancer July 18-20 • Huntington Beach, California For more information: www.gotoper.com/conferences Georgia Society of Clinical Oncology Debates and Didactics in Hematology and Oncology July 24 • Sea Island, Georgia For more information: www.gasco.us/meetings.php

August Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org South Carolina Oncology Society Fall 2013 Membership Conference August 9-10 • Charleston, South Carolina For more information: www.scosonline.com Hematology and Medical Oncology Best Practices August 15-22 • Arlington, Virginia For more information: www.gwumc.edu/cehp/ hemoncbestpractices/ Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna

Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org North Carolina Oncology Association Fall Membership Conference August 24 • Greensboro, North Carolina For more information: www.ncoa-northcarolina.com 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

September George Society of Clinical Oncology 2013 GASCO Annual Meeting September 6 • Atlanta, Georgia For more information: www.gasco.us SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/ Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

9th Scientific Meeting of the Australasian Society for Breast Disease September 12-14 • Cairns, Queensland, Australia For more information: www.asbd.org.au International Liver Cancer Association Seventh Annual Conference September 13-15 • Washington, DC For more information: www.ilca2013.org/ Inflammation, Microbiota, and Cancer September 19-20 • Bethesda, Maryland For more information: ncifrederick.cancer.gov/events/ microbiota/agenda.asp Continuum Cancer Centers of New York Conference on Quality of Care in Oncology September 20 • New York, New York For more information: www.chpnet. org/cme Tennessee Oncology Practice Society 2013 Membership Conference September 20 • Nashville, Tennessee For more information www.tops-tennessee.com Michigan Society of Hematology and Oncology Annual Meeting September 20-21 • Traverse City, Michigan For more information: www.msho.org NCCN 8th Annual Congress: Hematologic Malignancies September 20-21, 2013 New York, New York For more information: www.nccn.org

Minnesota Society of Clinical Oncology - MSCO Fall Membership Conference September 10 • Minneapolis, Minnesota For more information: www.msco-minnesota.com/ Rocky Mountain Oncology Society Fall Membership Conference September 12 • Denver, Colorado For more information: www.rmos-colorado.com

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences continued on page 76

The ASCO Post | JUNE 25, 2013

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2013

2013 Oncology Meetings continued from page 75

2013 ASH State-of-the-Art Symposium September 27-28 • Chicago, Illinois For more information: www.hematology.org ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October The 2nd International Multidisciplinary Forum on Palliative Care (IMFPC 2013) October 3-6 • Sofia, Bulgaria For more information: www.imfpc.org Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences Second Annual Conference Global Biomarkers Consortium October 4-6 • Boston, Massachusetts For more information: www.globalbiomarkersconsortium. com

For more information: www.cancereducationconsortium. org/programs_paaw.html 9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/ International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

Merrill J. Egorin Workshop in Cancer Therapeutics and Drug Development October 11-14 • Leesburg, Virginia

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

November Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu

Virginia Association of Hematologists and Oncologists Fall Membership Conference October 11 • Virginia Beach, Virginia For more information: www.vah-o.org 4th International Breast Cancer Prevention Symposium: Genes, the Environment, and Breast Cancer Risks October 11-13 • Beirut, Lebanon For more information: www.purdue.edu/breastcancer/

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com

Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/

SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013 SITC Primer on Tumor Immunology and Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information:www.abclisbon.org/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences Academy of Oncology Nurse Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: http://aonnonline.org/conference African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org 36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

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 | JUNE 25, 2013

PAGE 78

In the Clinic Melanoma

Trametinib in Unresectable or Metastatic Melanoma with BRAF V600E or BRAF V600K Mutation In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication On May 29, 2013, trametinib (Mekinist) was approved by the U.S. Food and Drug Administration (FDA) for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test.1,2 Concurrent with this approval, FDA approved the THxID BRAF assay (bioMérieux, Inc) for detection of BRAF V600E and V600K mutations. Trametinib is not indicated for treatment of patients who have received prior BRAF inhibitor therapy.

Pivotal Trial Approval was based on improved progression-free survival in an international open-label trial in 322 patients with histologically confirmed stage IIIC or IV melanoma determined to be BRAF V600E or V600K mutation–

OF NOTE Trametinib carries warnings/ precautions for cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, serious skin toxicity, and embryo-fetal toxicity. positive based on centralized testing.3 Patients were randomized to receive either trametinib at 2 mg orally once daily (n = 214) or chemotherapy consisting of either IV dacarbazine at 1,000 mg/m2 or paclitaxel at 175 mg/m2 every 3 weeks (n = 108). No more than one prior chemotherapy regimen was permitted, and patients with prior exposure to BRAF inhibitors or MEK inhibitors were excluded from the trial. Patients with abnormal left-ventricular ejection fraction, history of acute coronary syndrome within 6 months, or current evidence of class II or greater congestive heart failure were also excluded. Among all patients, median age was

54 years, 54% were male, all had ECOG performance status of 0 or 1, and 64% had M1c disease. All patients had tumor tissue with mutations in BRAF V600E (87%), V600K (12%), or both (< 1%). At the time of disease progression, 51 chemotherapy patients (47%) received trametinib. Trametinib treatment was associated with a significant 53% reduction in risk of progression (median progression-free survival, 4.8 vs 1.5 months, hazard ratio = 0.47, P < .0001). .0001). Progression-free survival analysis based on blinded independent central review was consistent with the investigator results. Objective response rates were 22% in the trametinib group and 8% in the chemotherapy arm. Overall survival data are not yet mature. In a separate single-arm trial in 40 patients with BRAF V600E or V600K mutation–positive unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor, trametinib showed no evidence of antitumor activity (no confirmed partial or complete responses).

How It Works Trametinib is a reversible inhibitor of MEK1 and MEK2 activation and MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the ERK pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation–positive melanoma cell growth in vitro and in vivo.

How It Is Given The recommended dose of trametinib is 2 mg orally once daily, at least 1 hour before or 2 hours after a meal, until disease progression or unacceptable toxicity. Dose modification or discontinuation is required for cutaneous, cardiac (reduced left-ventricular ejection fraction, symptomatic congestive heart failure), ocular (retinal pigment epithelial detachment, retinal vein occlusion), and pulmonary (interstitial lung disease, pneumonitis) toxicities. Appropriate doses have not been established for patients with moderate to severe hepatic impairment or severe renal impairment. The presence of BRAF V600E or V600K mutation in tumor specimens

Trametinib for Advanced Melanoma ■ Trametinib (Mekinist) has been approved by the FDA to treat patients

with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test.

■ The recommended dose of trametinib is 2 mg orally once daily, at

least 1 hour before or 2 hours after a meal, until disease progression or unacceptable toxicity.

must be confirmed prior to initiation of trametinib treatment. Information on approved tests for the detection of BRAF V600 mutations in melanoma is available from the FDA.4

Safety Profile The most frequent (≥ 20%) adverse events of any grade in the trametinib group were rash (57% vs 10% in the chemotherapy group), diarrhea (43% vs 16%), and lymphedema (32% vs 4%). The most frequent grade 3 or 4 adverse events in the trametinib group were hypertension (12%) and rash (8%). The most common laboratory abnormalities of any grade in trametinib patients were increased AST (60% vs 16%), hypoalbuminemia (42% vs 23%), increased ALT (39% vs 20%), and anemia (38% vs 26%); grade 3 adverse events in these categories occurred in 2% to 3% of trametinib patients. Adverse events led to discontinuation of trametinib treatment in 9% of patients, with the most common reasons being decreased left-ventricular ejection fraction, pneumonitis, renal failure, diarrhea, and rash, and to dose reduction in 27% of patients, with the most common reasons being rash and reduced left-ventricular ejection fraction. Serious adverse events in trametinib recipients included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, intersti-

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).

tial lung disease, and serious skin toxicity. Trametinib carries warnings/precautions for cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, serious skin toxicity, and embryo-fetal toxicity. Left-ventricular ejection fraction must be assessed prior to treatment and after 1 month and every 2 to 3 months thereafter. Ophthalmologic exams

OF NOTE Trametinib inhibits MEK1 and MEK2 activation and kinase activity, thereby inhibiting BRAF V600 mutation–positive melanoma cell growth. should be performed for any visual disturbance, and patients should be monitored for pulmonary symptoms and skin toxicities and secondary infections. Women should be advised on pregnancy planning and contraception, and men should be advised on potential impairment of fertility. Nursing mothers should discontinue trametinib or discontinue nursing. n References 1. U.S. Food and Drug Administration: Trametinib. Available at http://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm354478.htm. Accessed June 11, 2013. 2. MEKINISTTM (trametinib) tablets prescribing information, GlaxoSmithKline, May 2013. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2013/204114s000lbl.pdf 3. Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107-114, 2012. 4. U.S. Food and Drug Administration: Medical devices: Companion diagnostic devices: In vitro and imaging tools. Available at http://www.fda.gov/CompanionDiagnostics. Accessed June 11, 2013.

The ASCO Post | JUNE 25, 2013

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ASCO State Affiliates Focus on the Georgia Society of Clinical Oncology By Jo Cavallo

Hillary Hahm, MD

ith a roster of over 600 members that includes community and institutional oncologists, administrators, registered nurses, and patient navigators, the Georgia Society of Clinical Oncology (GASCO) is one of ASCO’s largest State Affiliates. Founded in 1986, the Atlanta-based Society is active in developing new programs to serve its members and ensure patient accessibility to cancer care throughout the state. In 2010, with a $10,000 State Affiliate Grant from ASCO, GASCO established a patient navigator society, Cancer Patient Navigators of Georgia, to improve the effectiveness of cancer screenings and patient followup services. Two years later, GASCO received another State Affiliate Grant to implement the new survivorship care standards recommended by the American College of Surgeons Commission on Cancer. The program includes a process to develop and disseminate a comprehensive care summary and follow-up

plan to patients with cancer who are completing their treatment by 2015. To reach a demographically diverse patient population, GASCO identified three sites in Northwest, West Central, and Southeast Georgia, and is currently testing and evaluating the survivorship care plan template for effectiveness and physician and patient compliance. The ASCO Post talked with GASCO’s President, Hillary Hahm, MD, about the success of the patient navigator program, the launch

We are giving our patients information regarding the impact of the cuts to Medicare reimbursements and are asking them to make their voices heard with their legislators if they have concerns about how the reductions are affecting their care. —Hillary Hahm, MD

of an e-tumor board, and how the sequester budget cuts to Medicare are impacting oncology practices and patient care in Georgia.

Patient Navigator Society How has the formation of a patient navigator affiliate improved patient care in Georgia? The fact that there is now a uni-

Fast Facts ■ ■ ■ ■

fied patient navigator society in which navigators can be supported by GASCO resources has already resulted in increased navigator availability to provide assistance to patients and their families and has improved care for our patients. Now, navigators from community-

The Georgia Society of Clinical Oncology was founded in 1986. The current President is Hillary Hahm, MD. The Society has over 600 members. The Society’s mission is to serve the needs of oncology providers, to ensure delivery of the highest quality of compassionate cancer care. The Society is committed to enhancing access to clinical care, improving access to clinical trials, encouraging an environment of collaboration among colleagues, and providing services that meet the needs of its members.

■ The Society’s annual meeting is being held in September 2013 and will be

combined with programs from the Best of ASCO®. In addition to its annual meeting, GASCO holds quarterly meetings with its Board members and an Administrator’s Association Meeting in the spring; has meetings to present highlights from the San Antonio Breast Cancer Symposium and American Society of Hematology Annual Meeting; and holds educational sessions for the Cancer Patient Navigators of Georgia, including programs on complementary and integrative medicine.

or hospital-based settings and from both urban and rural parts of the state can more easily interact with each other and determine which patient navigator programs work best in each environment.

Web-based Tumor Board What was the impetus for the development of GASCO’s new Webbased oncology tumor board? We received an ASCO State Affiliate Grant to launch an e-tumor board that is being piloted at a few sites throughout the state. The program is being driven through Georgia Regents University, which is part of the Medical College of Georgia and Georgia Health Sciences University, in Augusta. GASCO purchased Web-based cameras for some test site community practices in Rome and Dublin, Georgia, so oncologists can share radiology images and case discussions of specific tumor types, including colon and pancreatic cancers and glioblastoma, with disease-specific tumor board members at Georgia Regents University.

The ability for community practices to be able to collaborate and network with experts in these cancers is invaluable. Our hope is to eventually have multiple practices across the state linked with the tumor board, but finding funding to expand this project and others is difficult. Our Society is starting a foundation so we can attract funds to support these sorts of important projects. The more we have the ability to communicate across the state, the more we can work together as an association.

Impact of Sequestration In April, an additional 2% cut to Medicare went into effect as part of the federal budget reduction known as sequestration. How is the reduction in physician reimbursement impacting your members? It is having a major impact. Even before the sequester took effect, previous reductions in Medicare reimbursement were causing many community practices to send patients being treated in the office to other facilities because they could no longer afford to treat these patients. Fortunately, we are still able to deliver high-quality care in hospital settings, but any disruption in cancer care or change in location can be very difficult for patients. There is a huge financial stress on oncology practices today, and any reduction in reimbursements has the potential to push more practices either out of business altogether or to join hospital-based systems. We are giving our patients information regarding the impact of the cuts to Medicare reimbursements and are asking them to make their voices heard with their legislators if they have concerns about how the reductions are affecting their care.

ASCOPost.com | JUNE 25, 2013

PAGE 81

ASCO State Affiliates Are you currently sending your patients to other medical facilities for oncology care? Yes. Patients that I previously treated in my office I’m now sending to a hospital I’m affiliated with. It’s a disruption of our care and it’s very, very difficult for patients, but I can no longer afford to treat all Medicare patients in my office. We can ride this out for a while, but if this is the new normal of how care is going to be delivered, then I think it will adversely affect more and more community practices and more and more patients.

Advocacy Activities Is GASCO active on a local and national level to advocate for the needs of its members and patients? We have a wonderful lobbyist who represents our association with our state legislature and representatives, as we try to educate our legislators about the impact of decisions like the reduction to Medicare reimbursements. We are doctors, but we are also small business owners and part of the financial engine of the state, so keeping our practices viable is critical to the state’s economy. In addition to trying to reinstate Medicare reimbursement levels and add our assistance to what ASCO is doing nationally, we are also active in two other major areas: Georgia

has one of the lowest sales taxes on tobacco products in the nation, and we are involved in lobbying for a tobacco sales tax increase. Georgia is also one of the states without an Oral Chemotherapy Parity law, and we are seeing major problems in our community practices as a result. We have effective oral drugs, but be-

cause the pharmacy benefit portion of insurance drug plans requires that patients pay a certain percentage of the drug cost, patients are having a hard time affording the copays. In my practice, we employ a full-time person just to coordinate drug assistance programs to help patients with drug copays.

As a Society, we try to be active legislatively and make our voices heard, but when it comes to impacting legislation, sometimes you have to keep sending the same message over a long period of time before you get results. n

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

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The ASCO Post | JUNE 25, 2013

PAGE 82

Patient’s Corner

Living Without Fear

Despite having an incurable disease, I’m not letting colon cancer stop me from living my life. By Patrick Yaklin, as told to Jo Cavallo

ven before I had a colonoscopy to determine the cause of abdominal pains I had been having, I instinctively knew that the news wouldn’t be good. A colonoscopy and subsequent pathology report confirmed stage IIIC colorectal cancer. Because I was just 47 years old at the time of my diagnosis and had no family history of the disease, my doctor suggested that I have genetic testing, which showed that I have the MLH1 unclassified gene variant with the genetic marker for Lynch syndrome. Since this gene mutation is inherited, my doctor suggested that my siblings and children also get genetic testing. I’m happy to say my brother and sister do not have the gene mutation and my children, who are 22 and 19, will be tested when they reach 25. Because I was so young and in such excellent health when I was diagnosed nearly a year ago, my oncologist said my prognosis looked pretty good. I underwent a surgical resection to remove as much of the tumor as possible and reconnect my colon, and I was prescribed FOLFOX (leucovorin, fluorouracil [5-FU], and oxaliplatin) to shrink the remaining

tumor and kill any errant malignant cells. But because the chemotherapy regimen caused my while blood cell and platelet count to drop precipitously, my doctor switched me to five cycles of capecitabine (Xeloda). Still, at the end of my chemotherapy,

cancer is terminal. Despite this dire prediction, I consider myself a cancer survivor and I’m doing what I can to stay positive and enjoy my life every day. I’m fortunate to have a wonderful family and a supportive group

I’m fortunate to have a wonderful oncologist, who puts me at ease at every office visit and helps me understand what is happening to me.

Looking Toward the Future

—Patrick Yaklin

I fully expected to be cancer-free. However, 6 months of chemotherapy failed to rid me of my cancer and, in fact, a CT scan at the end of my treatment showed that the cancer had metastasized to the lymph nodes in my mediastinum, neck, and abdomen.

Confronting Mortality I am now receiving therapy with FOLFIRI (leucovorin, 5-FU, and irinotecan), but understand that my

my treatment and includes what he expects to happen over time. He also reassures me that there are still treatments to try after FOLFIRI to give me more time. Most of all, he responds quickly when I leave a voicemail message with questions I forgot to ask in person, and that makes me feel confident that I’m not alone in this cancer struggle.

of friends I can rely on and draw strength from, so I don’t have a lot of fear surrounding my prognosis. I’m fortunate, too, to have a wonderful oncologist, who puts me at ease at every office visit and helps me understand what is happening to me by drawing a picture of my body and showing me the location of my tumor and where it has spread. He writes down details of the progression of the cancer and the result of

Although I try to keep a positive attitude, I admit I’m not always successful, and I occasionally succumb to feelings of depression. For the most part, though, I have my sights set on the next big events in my life—like my son’s college graduation—that give me joy. Instead of looking back on my life to see what I could have done differently, my attention is on the future and all the things I want to do. Most importantly, I’m relishing every moment I have with my family and friends, and I’m determined to live not just a purposeful life, but also one without fear. n Patrick Yaklin is a claims team manager in Bakersfield, California.

Don’t Miss These Important Reports in This Issue of The ASCO Post Richard D. Carvajal, MD, and Michael A. Davies, MD, PhD, on Metastatic Uveal Melanoma see page 10

Wyndham Wilson, MD, PhD, and Kieron Dunleavy, MD, on Doseadjusted EPOCH-Rituximab for Primary Mediastinal B-cell Lymphoma see page 23

Stephane Vignot, MD, and JeanCharles Soria, MD, PhD, on Somatic Alterations in Primary and Matched Metastic NSCLC see page 34

Julia E. Maxson, PhD, and Jeffrey W. Tyner, PhD, on New Insights into Treatment for Two Types of Leukemia see page 54

Visit The ASCO Post online at ASCOPost.com

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. 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 • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages. To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120044a(1)

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FDA Update Hematology

FDA Approves Lenalidomide for Relapsed/Refractory Mantle Cell Lymphoma

he U.S. Food and Drug Administration has approved lenalidomide (Revlimid) for the treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies,

one of which included bortezomib (Velcade).

Clinical Trial The approval was based on the results of a phase II, single-arm, multi-

center clinical trial enrolling 134 patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. All patients received prior treatment with bortezomib, and 60%

were documented to have disease refractory to bortezomib therapy. Patients received a median of four prior therapies for mantle cell lymphoma. The median age was 67 years, 81% were male, 96% were Caucasian, and 61% had mantle

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This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

Toxicity

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FDA Update

cell lymphoma for at least 3 years. The primary endpoints of the study were overall response rate and duration of response. In the 133 patients who were evaluable for efficacy, the overall response rate was 26% (95% confidence interval [CI] = 18.4– 33.9). Complete response or complete response unconfirmed was achieved

by 9 patients (7%), and 25 patients (19%) achieved a partial response.

complete response, complete response unconfirmed, or partial response was 16.6 months (95% CI = 7.7–26.7).

Adverse Effects The median duration of response for the 34 patients who achieved a

Safety data were evaluated in 134 patients who received at least one dose of lenalidomide. The median duration of therapy was 95 days (range,

1–1,002), and 78 patients (58%) received three or more cycles of therapy. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events. n

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(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%). Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112). Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction. Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%). Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112). Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

The ASCO Post | JUNE 25, 2013

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Lab Notes

Ongoing Molecular Research in the Science of Oncology BIOMARKERS Circulating Tumor Cells with ALK Rearrangement in ALK-positive NSCLC

The diagnostic test for ALK rearrangement in non–small cell lung cancer (NSCLC) for crizotinib (Xalkori) treatment currently uses biopsy or fine-needle aspiration. Pailler and colleagues assessed

whether ALK rearrangement could be detected using circulating tumor cells. They analyzed circulating tumor cells in 18 ALK-positive and 14 ALK-negative patients using a filtration enrichment technique and

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day. In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females. 17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide). Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. • Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. • Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation. Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown. Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). • The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water. • Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed. Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)]. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved. POMBSv.001a 02/13

Cosmos Communications

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

filter-adapted fluorescence in situ hybridization. All ALK-positive patients had four or more ALK-rearranged circulating tumor cells per 1 mL of blood, whereas ALK-negative patients had no or one ALK-rearranged circulating tumor cell. ALK-rearranged circulating tumor cells harbored a unique (3’5’) split pattern, whereas tumors exhibited heterogeneous split patterns (3’5’, only 3’). The ALK-rearranged circulating tumor cells also expressed a mesenchymal phenotype, in contrast with the heterogeneous epithelial and mesenchymal marker expression observed in tumors. Variations in ALK-rearranged circulating tumor cell levels were detected in the five patients being treated with crizotinib. The investigators wrote, “ALK rearrangement can be detected in [circulating tumor cells] of patients with ALK-positive NSCLC by using a filtration technique and [filter-adapted fluorescence in situ hybridization], enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that [circulating tumor cells] harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.” Pailler E, et al: J Clin Oncol. May 13, 2013 (early release online).

Elevated Serum miR-1290 May Distinguish Early Pancreatic Cancer In studies to identify circulating microRNA levels that could distinguish low-stage pancreatic cancer from healthy and disease controls, Li and colleagues, measured 735 microRNAs in pancreatic cancer case and control sera and selected 18 microRNA candidates for validation in an independent set of case and control samples. Of the significantly elevated circulating microRNAs in patients with pancreatic cancer compared to controls, miR-1290 had the best diagnostic performance. Receiver operating characteristic analysis of miR-1290 serum levels yielded area under the curve (AUC) values of 0.96 for subjects with pancreatic

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Lab Notes

cancer (n = 41) relative to healthy controls (n = 19), 0.81 for subjects with chronic pancreatitis (n = 35), and 0.80 for subjects with pancreatic neuroendocrine tumors (n = 18). Levels of miR-1290 were also significantly higher in subjects with intraductal papillary mucinous neoplasm (n = 20) than in healthy controls (AUC 0.76). Levels of miR-1290 distinguished patients with low-stage pancreatic cancer from controls better than CA19-9 levels; similar to CA19-9 values, higher miR-1290 levels also predicted poorer outcome among patients undergoing pancreaticoduodenectomy. Greater numbers of miR-1290 transcripts were detected by fluorescence in situ hybridization in primary pancreatic cancer and intraductal papillary mucinous neoplasm than in normal pancreatic duct cells, and miR-1290 was found to influence in vitro pancreatic cancer cell proliferation and invasive ability. The investigators concluded, “The detection of elevated circulating miR-1290 has the potential to improve the early detection of pancreatic cancer.” Li A, et al: Clin Cancer Res. May 29, 2013 (early release online).

Serum miR-21 as Diagnostic and Prognostic Biomarker in Colorectal Cancer The oncogenic microRNAs miR21 and miR-31 negatively regulate tumor-suppressor genes. Toiyama and colleagues conducted a series of studies to assess their potential as serum biomarkers in colorectal cancer. Screening in medium from two colorectal cancer cell lines and serum analysis in 12 patients with colorectal cancer and 12 controls showed that miR-21 was secreted from colorectal cancer cell lines and upregulated in serum of patients with colorectal cancer, but no significant difference was observed in serum miR-31 expression between patients with colorectal cancer and control subjects. In a validation cohort consisting of 186 patients with colorectal cancer, another 60 patients with colorectal cancer who had undergone curative surgery, 43 patients with advanced adenoma, and 53 control subjects, serum miR-21 levels were significantly elevated in preoperative serum from patients with colorectal cancer and those with

adenomas (both P < .001). Further, miR-21 expression was significantly decreased in postoperative serum from patients with colorectal cancer who had undergone curative surgery (P < .001). Serum miR-21 levels distinguished both adenoma patients (area under the curve [AUC] 0.81) and colorectal cancer patients (AUC 0.92) from control subjects. Analysis of matched sera and primary colorectal cancer tumor tissue from 166 patients showed that high miR-21 expression in serum and tissue was significantly associated with tumor size, distant metastasis, and poor survival, with serum miR-21 level being an independent prognostic marker (hazard ratio = 4.12, P = .03). The investigators concluded, “Serum miR-21 is a promising biomarker for the early detection and prognosis of [colorectal cancer].” Toiyama Y, et al: J Natl Cancer Inst. May 23, 2013 (early release online).

DRUG RESISTANCE Synergy of Metformin and Gefitinib in LKB1 Wild-type NSCLC Cell Lines Clinical resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment has been observed in lung cancer. The antidiabetic drug metformin has shown significant inhibitory and proapoptotic effects in several cancer models alone and in combination with chemotherapeutic drugs. Morgillo and colleagues assessed the effects of the selective EGFR tyrosine kinase inhibitor gefitinib (Iressa) and metformin in a panel of non– small cell lung cancer (NSCLC) cell lines. The combination of metformin with gefitinib induced a strong antiproliferative and proapoptotic effect in NSCLC cell lines with wild-type LKB1. Treatment with metformin alone induced activation and phosphorylation of MAPK through increased CRAF:BRAF heterodimerization. The inhibition of EGFR phosphorylation and downstream signaling with the addition of gefitinib prevented this effect and resulted in a strong apoptotic effect in vitro and in vivo. The investigators concluded, “Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells. However, further studies are

required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecular targeted agents.” Morgillo F, et al: Clin Cancer Res. May 21, 2013 (early release online).

RISK ASSESSMENT Epigenome-wide Study of DNA Methylation in Breast Cancer Using Prospectively Collected Samples Available data suggest that DNA methylation in blood is a potential epigenetic marker of cancer risk, but this has not been evaluated on a genome-wide scale in prospective studies of breast cancer. Xu and colleagues measured DNA methylation at 27,578 CpG sites (ie, DNA regions where cytosine and guanine are separated by a single phosphate) in blood samples from 298 women who developed breast cancer 0 to 5 years after enrollment in the Sister Study cohort and in a random subgroup of 612 cohort women who remained cancer-free. Women were also genotyped for nine common polymorphisms associated with breast cancer. A total of 250 differentially methylated CpG sites between case subjects and noncase subjects were identified. Of these, 75% were undermethylated in case subjects compared with noncase subjects. Women diagnosed within 1 year of blood sampling had small but consistently greater divergence from noncase subjects compared with women diagnosed at more than 1 year after sampling. Receiver operating characteristic analysis estimated a prediction accuracy of 65.8% for methylation, compared with 56.0% for the Gail model and 58.8% for the common polymorphisms. The predictive accuracy of just five differentially methylated CpG sites (64.1%) was almost as high as that of the larger panel and was similar (63.1%) when replicated in a separate group of 81 women with diverse ethnic backgrounds. The investigators concluded, “Methylation profiling of blood holds promise for breast cancer detection and risk prediction.” Xu Z, et al: J Natl Cancer Inst 105:694-700, 2013.

GENE PROFILING New Susceptibility Variants for Childhood ALL in Ethnically Diverse Populations Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and the incidence of the disease varies by ethnicity. Available evidence indicates an inherited predisposition to ALL, but the genetic basis of ALL susceptibility in diverse ancestry has not been examined in detail. Xu and colleagues performed a multiethnic genome-wide association study in 1,605 children with ALL and 6,661 control subjects after adjusting for population structure, with validation performed in three replication series of 845 case subjects and 4,316 control subjects. A novel ALL susceptibility locus at 10p12.31-12.2 (BMI1-PIP4K2A, rs7088318, P = 1.1×10−11) was identified in the genome-wide association study, with independent replication in European Americans (P = .001), African Americans (P = .009), and Hispanic Americans (P = .04). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. The associations at ARID5B, IKZF1, and BMI1-PIP4K2A variants were consistent across ethnicity, with multiple independent signals at IKZF1 and BMI1-PIP4K2A loci. The frequency of ARID5B and BMI1-PIP4K2A variants differed by ethnicity, paralleling ethnic differences in ALL incidence. Evidence for a modifying effect of age on genetic predisposition to ALL was also observed. The ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at these single nucleotide polymorphisms being at a ninefold higher ALL risk compared with those carrying 0 to 1 risk alleles. The investigators concluded, “These findings indicate strong associations between inherited genetic variation and ALL susceptibility in children and shed new light on ALL molecular etiology in diverse ancestry.” n Xu H, et al: J Natl Cancer Inst 105:733-742, 2013. Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

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In the News Risk Reduction

Angelina Jolie’s Disclosure of Prophylactic Bilateral Mastectomy: A Positive Example for Women with BRCA Mutations? By Charlotte Bath

ngelina Jolie, in a New York Times article entitled “My Medical Choice,”1 disclosed that having a BRCA1 mutation and an estimated 87% risk of breast cancer, “I decided to be proactive and minimize the risk as much I could. I made a decision to have a preventive double mastectomy.” She was writing about it, she explained, “because I hope that other women can benefit from my experience.” The many media reports about Ms. Jolie’s choice mean that many women have undoubtedly learned about her experience, but the impact remains uncertain. Some commentators have applauded Ms. Jolie’s decision to speak out about the issue, while others have expressed concern that it could lead to an increase in women seeking unnecessary treatment.

Good Message and Model Ms. Jolie’s article presents “a good message,” Todd M. Tuttle, MD, MS, told The ASCO Post. He noted that the “red flags” in Ms. Jolie’s history—her mother died of cancer at age 56, and Ms. Jolie carries a BRCA1 mutation—were recognized and heeded. “She apparently went to a genetic counselor, had appropriate genetic tests, and acted on it. I think that is a good message, as opposed to someone who thinks she is at high risk and goes to a surgeon’s office requesting a double mastectomy without getting accurate information.” Dr. Tuttle is Chief of the Division of Surgical Oncology at the University of Minnesota in Minneapolis and Medical Director of the University of Minnesota Breast Center. Immediate Past ASCO President Sandra Swain, MD, FACP, expressed a similar opinion about Ms. Jolie’s medical decision and its disclosure, in comments for the PBS NewsHour blog, The Rundown.2 “I think the way she handled it is a great model for everyone because she’s really done it so carefully, so thoughtfully, and she’s speaking out which will really help other women,” Dr. Swain said. “She talked to the genetic counselor and took her time to make the decision. That was re-

ally important for everyone to see.” Dr. Swain is Medical Director of the Washington Cancer Institute at the MedStar Washington Hospital Center in Washington, DC.

some women who have breast cancer in one breast and have been diagnosed, it’s almost like they sense a ticking clock,” Dr. Tuttle said. Many Choose Surgery They think, “I’ve got Dr. Tuttle estimated that curto have surgery. I want rently, “probably more than 50% of to have surgery done in medically fit women with an identhe next few weeks, and tifiable gene mutation will undergo I am going to take care risk-reduction surgery,” and the figof both problems at the ure could be even higher. “I think same time.” women who decide to get the test, He noted, “the vast get the test to act on it. And I think majority of women who Angelina Jolie’s decision to undergo a prophylactic double mastecprobably the most definitive way to have breast cancer in tomy has been receiving much media attention. act upon it is to have a preventive one breast and choose she had an 87% risk of breast cancer mastectomy,” he stated. to have a double mastectomy do not and a 50% risk of ovarian cancer. “I Having researched and written have a gene mutation.” Women who made a decision to have a prevenabout the increasing use of contralatdo test positive for the gene mutative double mastectomy. I started eral prophylactic mastectomy among tion, but “who don’t have cancer, are with the breasts, as my risk of breast women with cancer diagnosed in healthy, have normal examinations cancer is higher than my risk of ovarone breast,3 Dr. Tuttle said that there and normal mammograms, and have also seems to be an increase in the ian cancer, and the surgery is more time to assess the situation, talk to complex,” Ms. Jolie wrote. (She did not provide any more specific infor[Ms. Jolie] apparently went to a mation about having or planning to have surgery to remove her ovaries.) genetic counselor, had appropriate She wrote that following her double genetic tests, and acted on it. I think mastectomy, “My chances of developing breast cancer have dropped that is a good message, as opposed to from 87% to under 5%.” someone who thinks she is at high risk It is not always possible to provide such a precise number for the and goes to a surgeon’s office requesting percentage of risk reduction, Dr. a double mastectomy without getting Tuttle said. “In general, we tell womaccurate information. en that their lifetime risk is about 70% to 80%, but it depends on the —Todd M. Tuttle, MD, MS age at which they were tested and a bit about their family history and number of women choosing bilatwhen their family members develtheir doctors and really understand eral prophylactic mastectomies. “We oped breast cancer,” he continued. the risks and complications of what don’t have as much data on women “Then the data are pretty solid that they may potentially get into,” he who do not have breast cancer as we the relative risk reduction is about stated. have for women who have unilateral 90% to 95%. So bilateral mastecWomen who test negative for a breast cancer, because those patients tomy doesn’t eliminate the risk of BRCA mutation may still decide to aren’t captured in cancer registries,” breast cancer, but it can certainly rehave prophylactic bilateral masteche explained. duce the risk.” tomy. “They may have other risk Women who test positive for a Women who have had prophyfactors for breast cancer,” Dr. Tuttle BRCA mutation and are planning lactic bilateral mastectomies should said. Conversely, testing negative for to have a prophylactic mastectomy continue to have routine physical a BRCA mutation may provide these may not necessarily choose to have examinations as well as follow-up of women with more accurate informathe surgery right away. “I think that any symptoms, Dr. Tuttle advised. “I tion to support their decision not to is one of the differences between don’t obtain mammograms or MRIs have prophylactic surgery. women who don’t have breast cancer on patients who’ve had prophylactic Percentage of Risk and who are deciding to have prosurgery,” he said. “In those rare cases Reduction phylactic surgery vs those who have in which women do develop breast In The New York Times piece, Ms. cancer in one breast and decide to cancer after prophylactic surgery, Jolie said her doctors estimated that have the other breast removed. For most of the tumors are found by the

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In the News

women themselves on physical examination underneath the skin.

Removal of the Ovaries According to the National Cancer Institute (NCI),4,5 there is “solid evidence” that prophylactic oophorectomies in women with BRCA gene mutations decrease breast cancer incidence by 50% and ovarian cancer by 90%. The National Comprehensive Cancer Network (NCCN) Guidelines for Breast Cancer Risk Reduction also include both bilat-

eral mastectomy and bilateral salpingo-oophorectomy for women who have known or strongly suspected BRCA1/2 mutations and desire riskreduction therapy.6 Some women chose to have both breasts and both ovaries removed at the same time, whereas others wait until after they are done having children to have their ovaries removed. “It is probably more important for the ovaries to come out, because we can screen very carefully for breast cancer, but ovarian cancer is much

Expect Questions about Preventive Double Mastectomies

or women who are considering prophylactic bilateral mastectomies, “I strongly encourage genetic testing, Todd M. Tuttle, MD, MS, said in an interview with The ASCO Post about the increased interest in preventive double mastectomy following Angelina Jolie’s disclosure that she had the procedure to reduce her risk of breast cancer. In a New York Times article entitled “My Medical Choice,”1 Ms. Jolie explained that she had an identified BRCA1 mutation and an estimated 87% risk of breast cancer, as well as a 50% risk of ovarian cancer. “The majority of the patients for whom I perform bilateral prophylactic mastectomy are those who have an identified gene mutation,” Dr. Tuttle added. “I do see people who think they are at increased risk and come in and talk about having bilateral mastectomies, and I usually will have them make sure we know their family history well and perform genetic testing when appropriate.” Dr. Tuttle is Chief of the Division of Surgical Oncology at the University of Minnesota in Minneapolis and Medical Director of the University of Minnesota Breast Center.

Recommendations According to the National Comprehensive Cancer Network (NCCN) Guidelines for Breast Cancer Risk Reduction:

Risk reduction mastectomy should generally be considered only in women with BRCA1/2, or other strongly predisposing gene mutation, compelling family history, or possibly with [lobular carcinoma in situ] or prior thoracic radiation therapy at < 30 y of age. Women considering risk reduction mastectomy should receive multidisciplinary counseling including consultation with genetics if not already done. Psychological consultation may also be of value.2 n Disclosure: Dr. Tuttle reported no potential conflicts of interest.

References 1. Jolie A: My medical choice. New York Times, May 14, 2013. 2. National Comprehensive Cancer Network: NCCN Guidelines: Breast cancer risk reduction, version 1.2013. Available at www.nccn.org. Accessed June 5, 2013.

New from The ASCO Post

more difficult to screen for and often presents much later,” Dr. Tuttle said. For women with BRCA mutations, “you really can expect risk-reduction surgery that is a combination of mastectomies and oophorectomies to improve survival,” he stated.

Most Choose Reconstruction Most women who undergo double mastectomies do choose to have breast reconstruction, according to Dr. Tuttle. “In the United States now, the most common type of breast reconstruction is to have a temporary tissue expander followed by a permanent implant. A silicone implant is probably the most common type today,” Dr. Tuttle said. Autologous flap procedures, using tissue from another part of the patient’s body to create breasts, “were very popular in the 1990s but have lost a bit of their popularity in the past decade or so,” Dr. Tuttle added. Tissue expanders followed by a permanent implant is also the type of reconstruction chosen by Ms. Jolie. “You wake up with drain tubes and expanders in your breasts,” she wrote. “It does feel like a scene out of a science-fiction film. But days after surgery, you can be back to a normal life.”

Alternative Approaches Tamoxifen and raloxifene (Evista) have been shown to reduce the risk of estrogen receptor–positive, but not estrogen receptor–negative, breast cancers. Women with BRCA mutations, however, are more likely to develop estrogen receptor–negative, as well as progesterone receptor–negative and HER2-negative (triple-negative) breast cancers. Tamoxifen and raloxifene are “not consistently” recommended for women with BRCA mutations, according to Dr. Tuttle. “Sometimes these drugs are recommended for women with BRCA mutations who haven’t decided whether to have prophylactic surgery

or sometimes just until they have surgery,” Dr. Tuttle said. These may be women who choose “to be screened for a few years and maybe want to reduce their risk a little bit, and tamoxifen or raloxifene may reduce their risk of developing estrogen receptor–positive breast cancer over a short period of time.” For women who are identified with the BRCA mutation and choose not to have surgery—at least not in the near future—follow-up usually consists of alternating clinical breast examinations, mammography, and breast MRI. “Our practice here is clinical breast examinations a couple of times a year and then mammography and MRI sequenced every 6 months. That is a pretty common screening strategy for those women,” Dr. Tuttle said. n

Disclosure: Drs. Tuttle and Swain reported no potential conflicts of interest.

References 1. Jolie A: My medical choice. New York Times, May 14, 2013. Available at www.nytimes.com. Accessed June 5, 2013. 2. Bowser BA: Jolie’s decision sheds light on BRCA gene, importance of genetic counseling. PBS Newshour: The Rundown, May 14, 2013. Available at www.pbs.org. Accessed June 5, 2013. 3. Tuttle TM, Habermann EB, Grund EH, et al: Increasing use of contralateral prophylactic mastectomy for breast cancer patients: A trend toward more aggressive surgical treatment. J Clin Oncol 25:5203-5209, 2007. 4. National Cancer Institute: Breast cancer prevention (PDQ): Health professional version, last modified May 9, 2013. Available at www.cancer.gov. Accessed June 5, 2013. 5. National Cancer Institute: Ovarian cancer prevention (PDQ): Health professional version, last modified February 15, 2013. Available at www.cancer. gov. Accessed June 5, 2013. 6. National Comprehensive Cancer Network: NCCN Guidelines: Breast cancer risk reduction, version 1.2013. Available at www.nccn.org. Accessed June 5, 2013.

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The ASCO Post | JUNE 25, 2013

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In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER Liver-first Approach to Colorectal Cancer with Synchronous Hepatic Metastases “The liver-first approach for patients with colorectal cancer with synchronous liver metastases is possible but is associated with a wide range of survival outcomes, despite protocol similarities between studies,” according to a review of four cohort studies identified by a literature search. “All liver-first protocols administered neoadjuvant chemotherapy as the first intervention, using conventional oxaliplatin-based or irinotecan hydrochloride–based chemotherapy regimens augmented by biological agents, such as bevacizumab [Avastin], from the time of availability of these latter agents,” the researchers reported. “Liver resection was the first operative step (and the second intervention). Chemoradiotherapy was administered after liver resection in those patients with rectal primary tumors. Two protocols provided further adjuvant oxaliplatin- or irinotecan-based chemotherapy after resection of the primary tumor. Two protocols addressed the phenomenon of patients with a primary tumor that resolved after adjuvant chemotherapy by the adoption of a watch and wait policy.”

Study Data The total number of patients in all four studies analyzed was 121, with 90 patients (74%) completing the full protocol and 23 patients (19%) experiencing disease progression during the protocol period. “Among the studies providing data on the hepatic burden of metastases, all report multiple lesions, with a majority of patients having bilobar disease,” the researchers noted. A total of 73 patients (60%) of the original 121 patients developed either progressive or recurrent disease. “A theoretical disadvantage of the liver-first approach is the delay to chemoradiotherapy for rectal tumors. Despite this, 91 of the 121 patients (75%) in the starting cohort underwent colorectal cancer resection,” the researchers stated. “A potential advantage of the liver-first approach,” they continued, “is that a small number of patients (4 of 121) had a complete response to treatment, with resolution of

the primary tumor, and thus did not require colorectal resection. This option for observation is clearly not available with the classic approach.” In an accompanying editorial, Andrew Klein, MD, MBA, of CedarsSinai Medical Center in Los Angeles stated that the investigators “correctly recognized that, among these 4 cohorts of patients, the heterogeneity of survival rates, which varied from 31% to 90%, precluded meaningful group analysis.” Dr. Klein also challenged the researchers’ conclusion that their analysis supports the need for a clinical trial comparing liver-first vs bowel-first approaches. “The pivotal factor limiting improvement in patient outcomes appears to be responsiveness to chemotherapy,” he stated. “Controlling progression of tumor growth during the protocol period …, as well as converting unresectable hepatic lesions to resectable, will be predicated on the development of increasingly effective chemotherapeutic agents, not the timing of surgical extirpation.” Jegatheeswaran S, et al: JAMA Surg 148:385-391, 2013. Klein A: JAMA Surg 148:392, 2013.

BREAST CANCER Chemotherapy-induced Peripheral Neuropathy Results in Dose Limiting and Less Chemotherapy Overall Chemotherapy-induced peripheral neuropathy events resulted in limiting the dosing of chemotherapy in a significant proportion of women with nonmetastatic breast cancer being treated with paclitaxel, and those who had their dose reduced or discontinued received significantly less cumulative drug, according to a retrospective cohort study. Reported in the Journal of Oncology Practice, the study reviewed electronic medical records for 488 women with nonmetastatic breast cancer who received docetaxel or paclitaxel at a single center. A total of 56 dose-limiting events (dose delay, dose reduction, or treatment discontinuation) attributed to chemotherapy-induced peripheral neuropathy occurred in 50 women (10.2%) and “accounted for more than one third (37.3%) of all the [dose-limiting] decisions oncologists made in this clinical practice population during nonmetastatic paclitaxel or docetaxel

chemotherapy,” the researchers stated. The incidence of dose-limiting chemotherapy-induced peripheral neuropathy “differed significantly by agent,” the investigators reported, occurring in 16.1% of patients receiving paclitaxel vs 2.4% of those receiving docetaxel (P < .001), “and occurred most frequently in the paclitaxel regimen of 80 mg/m2 weekly for 12 cycles (24.5%).” Dose-limiting neuropathy occurred in 14.4% of women receiving the paclitaxel regimen of 175 mg/m2 biweekly for four cycles.

Lower Cumulative Dose “On average, women who had their paclitaxel dose reduced because of [chemotherapy-induced peripheral neuropathy] (n = 9) received 9.4% less chemotherapy than what they would have received cumulatively according to their planned dose and regimen. The cumulative dose these individuals actually received differed significantly from the cumulative dose they would have received [1,065 mg/m2 vs 1,174.7 mg/ m2; P < .001],” the researchers reported. “Similarly, among women who had their treatment discontinued (n = 26), the cumulative dose actually received was significantly lower than their planned cumulative dose [968 mg/ m2 vs 1,355.5 mg/m2; P < .001]. On average these women received 28.4% less cumulative chemotherapy, and the percent difference did not differ by regimen,” the authors added. “Treatment modification events such as dose delays, dose reductions, and treatment discontinuation are clinically relevant and thus avoided in practice whenever possible. Therefore, it is somewhat surprising that of women who had a [dose-limiting chemotherapy-induced peripheral neuropathy] event, more than half (26 of 50) had their treatment discontinued,” the investigators noted. “Interestingly, only two of those 26 women had had a prior dose delay or dose reduction before the discontinuation. Factors leading to this decision by oncologists and patients are likely to be complex and multifactorial. Whether delaying or reducing the dose earlier in the course of treatment may have prevented the discontinuation of therapy … is unknown; this area would benefit from further study.” Speck RM, et al: J Oncol Pract. May 14, 2013 (early release online).

No Added Benefit from Radiotherapy after Lumpectomy/Tamoxifen in Older Women Long-term follow-up of Cancer and Leukemia Group B (CALGB) 9343 “confirms and extends the earlier report that in women age ≥ 70 years with clinical stage I, [estrogen receptor (ER)]-positive breast cancer treated with lumpectomy followed by tamoxifen, irradiation adds no significant benefit in terms of survival, time to distant metastasis, or ultimate breast preservation,” researchers reported in the Journal of Clinical Oncology. Radiation therapy did, however, provide a small decrease in ipsilateral breast cancer recurrence, the investigators added. CALGB 9343 randomly assigned women at least 70 years old with clinical stage I, ER-positive breast cancer treated with lumpectomy, to receive tamoxifen plus radiotherapy (n = 317) or tamoxifen alone (n = 319). All women received tamoxifen at 20 mg per day for 5 years. “Adjuvant hormonal treatment beyond 5 years was discretionary,” the investigators stated. At 10 years, “the incidence of locoregional recurrence is 8% lower, and the incidence of [ipsilateral breast recurrence] is 7% lower, with [tamoxifen plus radiotherapy] vs [tamoxifen] alone. This difference is statistically significant,” the authors wrote. Of the 32 women in the tamoxifen group who had locoregional recurrence, 20 had only ipsilateral breast recurrence; 6 had ipsilateral breast recurrence with distant metastasis; 5 had only axillary recurrence; and 1 had both ipsilateral breast recurrence and axillary recurrence. The six women in the tamoxifen-radiotherapy group who had locoregional recurrence all had ipsilateral breast recurrences. Among the 33 patients experiencing ipsilateral breast recurrence, 10 of 27 in the tamoxifen group, and 4 of 6 in the tamoxifen-radiotherapy group had mastectomies. The time to mastectomy did not differ significantly between the two groups and the 10-year probability of not undergoing mastectomy was 98% in the tamoxifen-radiotherapy group and 96% in the tamoxifen-only group. Time to distant metastases also did not differ significantly between the two groups, and the 10-year probability of freedom from distant metastases was 95% in both groups. A total of 334 deaths occurred, but

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In the Literature

only 21 as a result of breast cancer (13 of 166 deaths in the tamoxifen-radiotherapy group and 8 of 168 deaths in the tamoxifen-only group). Ten-year overall survival was 67% for tamoxifen-radiotherapy and 66% for tamoxifen only. “The toxicity of tamoxifen is not trivial, particularly in this elderly population. Well-known adverse effects include hot flashes, thrombotic events, and a small risk of endometrial cancer,” the authors noted. “However, despite the possibility that all patients were not able to complete the prescribed course of treatment, local control, distant disease-free survival, and cancer-specific survival remained excellent in this population with generally favorable disease characteristics.” Hughes KS, et al: J Clin Oncol. May 20, 2013 (early release online).

DCIS Score Quantifies Risk of Recurrence after Excision The ductal carcinoma in situ (DCIS) Score, a multigene expression assay, quantifies the risk of local recurrence and invasive local recurrence for women with DCIS treated with surgical excision, researchers reported in the Journal of the National Cancer Institute. “The DCIS Score can aid clinical decision making by identifying those patients with a lower DCIS Score for whom surgical excision alone may be adequate and those patients with a lower DCIS score for whom adding treating after surgical excision should be considered,” the researchers stated. The DCIS Score was developed and validated in a multistep strategy “based in part on evidence that quantitative expression of genes from the 21-gene Oncotype Recurrence Score (hereafter referred to as the Recurrence Score) may be useful for predicting local recurrence in DCIS,” investigators reported. The DCIS Score was calculated from seven cancer-related genes and five reference genes. To validate the DCIS Score, researchers looked at the association between the DCIS Score as a continuous variable and the risk of developing ipsilateral breast event—defined as local recurrence of DCIS or invasive carcinoma—among women who were treated with surgical excision but without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. Eligible patients had either low-grade or intermediategrade DCIS with tumor size ≤ 2.5 cm or high-grade DCIS with tumor size ≤ 1.0 cm. “Protocol specifications included a minimum negative margin width of at least 3 mm or no tumor on reexcision,” the researchers noted. An ipsilateral breast event developed

in 46 of the 327 patients with adequate tissue for analysis; 26 had DCIS only and 20 had invasive carcinoma. “The continuous DCIS Score was statistically significantly associated with the risk of developing an [ipsilateral breast event] (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.15 to 4.49; P = .02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive [ipsilateral breast event] (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P = .01),” the researchers reported. “For the prespecified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an [ipsilateral breast event] were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive [ipsilateral breast event], 3.7%, 12.3%, and 19.2%, respectively (both log rank P ≤ .006). In multivariable analyses, factors associated with [ipsilateral breast event] risk were DCIS Score, tumor size, and menopausal status (all P ≤ .02),” the authors added. “In contrast with the DCIS Score, the Recurrence Score was not statistically significantly associated with developing an [ipsilateral breast event],” the investigators stated. “No statistically significant association was seen for developing a contralateral breast cancer for either the DCIS Score or the Recurrence Score.”

A Controversial Issue Given that the management of DCIS is controversial, “a straightforward approach to selecting the optimum therapy—defined here as the minimum needed to avoid recurrence, particularly with an invasive component—is needed,” according to an accompanying editorial by Christine D. Berg, MD, of the School of Medicine, University of Queensland, Australia, and formerly of the National Cancer Institute. The DCIS assay “does appear to be a step forward,” Dr. Berg stated. “The clinical applicability of this assay for all women who present with DCIS remains to be determined,” she added. “Although the information provided by the DCIS Score may be useful in the correct setting and application, it is not a definitive guide,” and does not address the using or not using radiation therapy, Shivani Duggal, MD, and Thomas B. Julian, MD, of Allegheny General Hospital in Pittsburgh, commented in another editorial. “The DCIS Score should complement traditional clinical and pathologic factors used to guide decision-making in the treatment of DCIS.” Solin LJ, et al: J Natl Cancer Inst 105:701-710, 2013.

Berg CD: J Natl Cancer Inst 105:680681, 2013. Duggal S, Julian TB: J Natl Cancer Inst 105:681-683, 2013.

TREATMENT ADHERENCE Strength of Patient-Oncologist Alliance Linked to Willingness to Adhere to Treatment in Young Adults Among young adults with advanced cancer, developing a strong alliance with their oncologist was associated with greater perceived social support, a greater willingness to adhere to treatment, and greater adherence to oral medication, according to results of a study published in the Journal of Clinical Oncology. “These results indicate that the role of the oncologist extends beyond the prescription of medication and includes patients’ perception of social support, psychological well-being, and attitudes toward and actual behaviors regarding treatment adherence,” the authors concluded. The 95 patients participating in the study were between ages 20 and 40, with a mean age of 33.4 years. Most were white (86.3%) and female (68.4%). More than half the sample was married (56.8%), more than one-third had dependent children (40.0%). Onethird of the patients had breast cancer (33.7%), and other diagnoses included brain tumors, leukemia/lymphoma, soft-tissue cancers, and colon cancer.

Therapeutic Alliance All patients had advanced disease at the time they were interviewed for

the study. The interviews included measures of psychosocial well-being, willingness to adhere to treatment, and treatment adherence. The Human Connection scale was used to measure the extent to which patients feel a sense of mutual understanding, caring, and trust with their oncologists. The scale has been validated in older patients with advanced cancer, although the therapeutic alliance between young adults and their oncologists “may have unique characteristics not captured in a measure developed in older samples,” the authors acknowledged. “Alliance was significantly (P ≤ .01) and positively associated with greater perceived social support and less severe illness-related grief,” the researchers reported. “After controlling for significant confounding influences (ie, metastases, appraised support, and grief), alliance remained significantly (P ≤ .01) associated with greater willingness to adhere to treatment and greater adherence to oral medication.” Several factors may complicate the development of strong alliances, the authors pointed out. For example, medical professionals may not be familiar with issues unique to young adults, and young adults are generally unfamiliar with the health-care system. “Oncologists who want to foster a therapeutic alliance with their patients should strive to listen attentively to their concerns, convey respect, offer empathic support, and promote trust in working together toward shared goals of care,” the authors advised.” n Trevino KM, et al: J Clin Oncol 31:1683-1689, 2013.

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Essential Reading. Influential Information.

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Pioneers in Oncology ‘Matriarch of Modern Cancer Genetics,’ Janet D. Rowley, MD, Helped Propel the Field of Molecular Oncology By Jo Cavallo

Janet D. Rowley, MD

ven as a child, Janet D. Rowley, MD, found the intellectual order and logic of science appealing. Born on April 5, 1925, in New York, Dr. Rowley’s parents, Hurford and Ethel Ballantyne Davison, moved the family to Chicago 2 years later. Both educators, the Davisons encouraged their only child in her academic pursuits, especially her interest in science.

Advanced Placement Program When Dr. Rowley’s mother learned about an advanced placement program at the University of Chicago’s Hutchins College that combined the last 2 years of high school with the first 2 years of college, she helped her daughter apply for a scholarship. That event would prove to be the catalyst for a 7-decades-long association with the University of Chicago and alter the course of Dr. Rowley’s professional and personal life. In 1940, at just 15, Dr. Rowley was awarded the scholarship, and earned a Bachelor of Philosophy degree in 1944. Two years later, she completed a Bachelor of Science degree and graduated from medical school in 1948. The following day, she married fellow medical student Donald Adams Rowley and, after completing an internship in 1951, she began raising a family that would eventually include four sons. Wanting to practice medicine only part-time while her children were young, Dr. Rowley spent three afternoons each week working in a variety of well-baby clinics. Later she worked in a Chicago clinic for children with mental disabilities, including Down syndrome, a genetic disorder caused by an extra chromosome. That experience would lead to a change in her professional fo-

cus from medicine to research and a lifelong study of the genetics of cancer. “In 1959, the French pediatrician and geneticist Jérôme Lejeune reported that Down syndrome resulted from trisomy 21,” said Dr. Rowley. “My husband was going to England on sabbatical, and I couldn’t practice medicine there, so I decided I would learn cytogenetics at Oxford University. I got involved in a research project studying the pattern of deoxyribonucleic acid (DNA) replication in normal and abnormal human chromosomes. The field was so interesting, I decided I didn’t want to go back to work in the clinic and instead wanted to keep on doing research in chromosomes.”

Chromosomal Translocations When Dr. Rowley returned to the University of Chicago in 1962, with the support of hematologist Leon Jacobson, MD, she continued work on her research project while obliging Dr. Jacobson, who

techniques such as fluorescence in situ hybridization [FISH] are often used to detect genetic abnormalities associated with cancer.) Dr. Rowley learned the banding technique during her return trip to England while her husband was completing his second sabbatical at Oxford University. When she moved back to Chicago in 1972, Dr. Rowley used that knowledge to reexamine the slides of Dr. Jacobson’s patients with acute myeloid leukemia (AML) and found that chromosomes 8 and 21 were broken and had switched ends. It was the first discovery of a recurring chromosomal translocation in cancer. Soon after, Dr. Rowley found a different translocation in the cells of patients with chronic myelogenous leukemia (CML). This time, one end of chromosome 22 was exchanged for a piece of chromosome 9, a translocation that results in the Philadelphia chromosome seen in CML. “Prior to this discovery, the Phil-

Prior to this discovery, the Philadelphia chromosome had been thought to be a deletion. Showing that it wasn’t a deletion but was instead a translocation was a pretty major event. —Janet D. Rowley, MD

asked Dr. Rowley to look at the chromosomes of his leukemia patients. “The problem in the 1960s was that the method of staining chromosomes resulted in a uniform stain and you couldn’t tell one from the other except for a few that had distinctive sizes and shapes. All you could do was count and see whether there were 46 chromosomes, more than 46, or less than 46,” said Dr. Rowley. By the early 1970s, a new chromosomal staining technique called banding came into use. With this method, metaphase chromosomes are treated with trypsin and stained with Giemsa, or stained with quinacrine mustard, and then examined under a fluorescent microscope to analyze chromosomes for alternating light and dark stripes that appear along their length. The banding pattern allows the identification of chromosomal aberrations. (Today, molecular cytogenetic

adelphia chromosome had been thought to be a deletion, and the biology was thought to involve a loss of DNA from the cell, with the missing genes on that DNA involved in regulating normal cell growth. Showing that it wasn’t a deletion but was instead a translocation was a pretty major event,” said Dr. Rowley. Understanding the genetic abnormalities of CML eventually led to the development by Nicholas Lydon, PhD, and Brian Druker, MD, in the 1990s, of the tyrosine kinase inhibitor imatinib (Gleevec), which was approved by the Food and Drug Administration in 2001 for the treatment of CML. In the late 1970s, Dr. Rowley identified a third translocation, the 15;17 translocation found in the rare disease acute promyelocytic leukemia (APL). This discovery convinced Dr. Rowley of the importance of translocations and helped her to solidify the consensus among sci-

entists that cancer is a genetic disease. Dr. Rowley has been the recipient of numerous awards, including the Albert Lasker Clinical Research Award and the National Medal of Science. In 2009, she received the Presidential Medal of Freedom, the nation’s highest civilian honor. In May, she was awarded the Albany Medical Center Prize in Medicine and Biomedical Research along with Peter Nowell, MD, for his work showing that a genetic defect could be responsible for cancer, and Dr. Druker for the development of imatinib. The three scientists will share the $500,000 award. Dr. Rowley’s portion will go to fund her five grandchildren’s college educations.

Early Fascination with Patterns While Ethel Davison’s encouragement of her daughter’s academic pursuits and her doggedness in tracking down the scholarship that led to Dr. Rowley’s enrollment in Hutchin’s College at age 15 were instrumental in Dr. Rowley’s professional success, it was her father’s hobby of stamp collecting that developed the skills contributing to Dr. Rowley’s later interest in deciphering the patterns in chromosomal aberrations in cancer. “My father introduced me to stamp collecting when I was about 10 or 12 and while the stamps looked similar on the surface, there were subtle variations in the engraving or the watermarks, which make the stamps different. Studying those patterns taught me to pay close attention to patterns early on,” said Dr. Rowley. Named the Blum-Riese Distinguished Service Professor of Medicine, Molecular Genetics and Cell Biology at the University of Chicago in 1984, the university further recognized Dr. Rowley’s scientific accomplishments with the establishment of the Janet Davison Rowley, MD, Professorship in Cancer Research in 2012. Now, 88, Dr. Rowley interacts actively with colleagues in a laboratory in the Department of Medicine/Section of Hematology/Oncology at the University of Chicago, investigating the expression patterns of microRNA in leukemia cells. n

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The ASCO Post | JUNE 25, 2013

FDA Update Supportive Care

FDA Clears Multicenter Trial of Treatment for Hair Loss Related to Chemotherapy

he FDA has approved initiation of a multicenter trial of the DigniCap System, a scalp-cooling device for chemotherapy-related hair loss. The trial is the second and final phase of study for the DigniCap System. A pilot study previously conducted by researchers at the University of California San Francisco and Wake Forest Baptist Medical Center found that the treatment was successful and well tolerated in the majority of women.

Multicenter Trial Clinical trials will be conducted with 110 patients at major medical centers in the United States, including UCSF and Wake Forest. Two additional sites in New York and one in California are expected to open during the summer. To participate in the trial, patients must be 18 years of age and have a documented diagnosis of stage I or II breast cancer. Eligible patients must plan to complete chemotherapy within 6 months using standard chemotherapy regimens stipulated in the trial protocol. “Hair loss is an inevitable side effect caused by [chemotherapy], and for many women this is the most emotionally distressing and disturbing impact from their diagnosis. A short course of chemotherapy results in total hair loss taking many months to grow back,” said Hope S. Rugo, MD, Principal Investigator for the study at UCSF and Director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center. “Devices that can reduce hair loss have the potential to have a significant impact on patients’ quality of life, and this study is the first of its kind in the United States,” Dr. Rugo added.

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Cap Reduces Risk of Hair Loss The DigniCap System features a tight-fitting silicone cap that is placed directly on the head, and an outer neoprene cap that insulates and secures the inner one. A coolant circulates throughout the inner silicone layer, delivering consistent cooling to all areas of the scalp. The system contains built-in temperature sensors and a precision cooling mechanism that allows for gradual scalp temperature fluctuations. When a cap is applied to the head, the temperature of the scalp is lowered and blood vessels surrounding the hair roots contract, resulting in a

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

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).]

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. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 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 (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

significant reduction of cytotoxins to the follicle. Reduced blood flow leaves a smaller amount of chemotherapy available for uptake in the cells, and the decreased temperature results in less absorption of and reduced effects from chemotherapy. These factors together reduce the risk of hair loss. Historically, cooling systems and cold caps have not been used in the United States because of concerns that the scalp cooling could allow cancer cells to hide in the scalp. However, based on a large review of published data, the use of scalp-cooling systems did not increase the already very low incidence of scalp metastases, Dr. Rugo reported. “We are carefully following patients using these systems in several clinical trials,” she said. n

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

4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 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

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age 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).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) 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 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 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)