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Metastatic Renal Cell Carcinoma

36

| Lenalidomide Maintenance in Myeloma

1, 45, 93

| Adjuvant Gefitinib in NSCLC

96

VOLUME 5, ISSUE 1

JANUARY 15, 2014

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

ASH Annual Meeting

ASCO’s 50th Anniversary and the Road Ahead

Continuous Lenalidomide/Low-Dose Dexamethasone: A New Option for Older Patients With Newly Diagnosed Myeloma

A Conversation With Allen S. Lichter, MD, FASCO

By Alice Goodman

F

irst-line treatment of newly diagnosed multiple myeloma using the Rd regimen (continuous lenalidomide [Revlimid] plus low-dose dexamethasone) was superior to standard triplet treatment with MPT (melphalan, prednisone, and thalidomide [Thalomid]) for 72 weeks, according to initial results of the FIRST (Front-Line Investigation of Revlimid/Dexamethasone vs Standard Thalidomide) trial presented at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans.

Multiple Benefits Patients treated with Rd were 28% less likely to experience disease progression or death compared with those who received MPT, and Rd improved overall survival, response rates, and duration of response. Additionally, Rd appears to

What are your thoughts about ASCO’s origins and its 50th anniversary? A half-century ago, a group of seven physicians got together, unified by a singular mission: improving the care of people with cancer. That might sound simple, but back then it was bold and visionary. With more than 33,000 members today, ASCO has since grown into the world’s leading oncology medical professional organization. The

continued on page 50

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AACR International Conference

Risk-Based Breast Cancer Screening: Studies Suggest Alternatives to Age-Based Guidelines By Caroline McNeil

M

easuring certain hormone levels could help determine a woman’s risk for breast cancer and add a key factor to current risk-prediction models, according to investigators from Harvard Medical School. Their new study results were presented at the American Association for Cancer Research (AACR) Annual International Conference on Frontiers in Cancer Prevention Research, held in National Harbor, Maryland, in October.1

The findings come at a time when risk-based breast cancer screening is a major focus of research groups around the country and in Europe. Results like these could lead to more personalized risk profiles to help women and their physicians—and guideline developers—decide when and how often an individual should have a screening mammogram. Speaking at an AACR session on mammography,2 Karla Kerlikowske, MD, Professor in the Departments of Medicine and Epidemiology/ Recommendations for Biostatistics at the Unimammography have primarily been versity of California, San Francisco (UCSF), said based on age, but people in their 40s that risk-based screening can have the risk of a 50-year-old, and would allow those with a high-risk profile to have some people in their 50s are actually earlier and more frequent at a very low risk. screening and/or screen—Karla Kerlikowske, MD

Send your comments to editor@ASCOPost.com

A

s the American Society of Clinical Oncology celebrates its 50th anniversary, ASCO’s Chief Executive Officer Allen S. Lichter, MD, FASCO, recently talked with The ASCO Post about the Society’s past, present, and future.

have a safety advantage over MPT by causing fewer secondary hematologic malignancies. “Traditionally, newly diagnosed multiple myeloma patients have received short bursts of treatment, while continuous treatThierry Facon, MD ment was reserved for relapsed patients. However, we believe that these new results will help encourage more research on the efficacy and safety of continuous treatment for newly diagnosed patients to help maximize their chances for overall long-term survival,” stated lead author Thierry Facon, MD, Services des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille, France.

Important Milestone

Dr. Lichter is Chief Executive Officer of the American Society of Clinical Oncology.

MORE IN THIS ISSUE Oncology Meetings Coverage ASH Annual Meeting ...1, 4, 10, 45–49, 93 AACR International Conference on Frontiers in Cancer Prevention ............. 1 San Antonio Breast Cancer Symposium ................................... 3, 11, 16 International Society for Geriatric Oncology ...........................18–22 Inside the Black Box .................................52 Thomas A. Buchholz, MD, and Benjamin D. Smith, MD, on TARGIT-A....57 Direct From ASCO ........................... 71–74 Manfred Lehnert, MD, on Drug Development Challenges .............87 In Memoriam: Janet L. Rowley, MD.... 149

continued on page 24

A Harborside Press® Publication


The ASCO Post | JANUARY 15, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James  O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

Associate Editors

Alison Freifeld, MD University of Nebraska Medical Center

Joseph S. Bailes, MD Texas Oncology

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

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

Jimmie C. Holland, MD Memorial Sloan-Kettering 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 Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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 subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Mario E. Lacouture, MD Memorial Sloan-Kettering Cancer Center Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

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

Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

Lynn D. Wilson, MD Yale University School of Medicine

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center William T. McGivney, PhD Philadelphia, Pennsylvania

Jacek Jassem, MD Medical University of Gdansk, Poland

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Ctr Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System George W. Sledge, MD Indiana University

hibited. 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: $271;

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

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

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James L. Mulshine, MD Rush University Medical Center

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

David Khayat, MD Pitie-Salpetriere Hospital, Paris, France

Michael Buckley, Art Director Michael@harborsidepress.com Terri Caivano, Kristina O’Toole, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@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:

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


ASCOPost.com | JANUARY 15, 2014

PAGE 3

San Antonio Breast Cancer Symposium Breast Cancer

Adjuvant Bisphosphonates in Early Breast Cancer: Practice-Changing Findings? By Alice Goodman

A

djuvant use of bisphosphonates reduced the risk of bone recurrence by 34% and the risk of breast cancer death by 17% in postmenopausal women with early breast cancer in a large meta-analysis conducted by

Robert Coleman, MD

the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). The potentially practice-changing findings were presented at the 2013 San Antonio Breast Cancer Symposium by lead author Robert Coleman, MD, of University of Sheffield, United Kingdom.1 Adjuvant bisphosphonates achieved reductions in bone recurrence and breast cancer deaths in postmenopausal women regardless of estrogen receptor status, nodal status, and whether or not they received chemotherapy. However, no effects on disease outcome were observed in premenopausal women. “In addition to the 3.1% absolute reduction in breast cancer-related mortality, adjuvant bisphosphonates led to an absolute reduction of 2.3% in all-cause mortality at 10 years,” Dr. Coleman stated.

EBCTCG Meta-analysis The EBCTCG’s meta-analysis was prompted by evidence from previous trials suggesting that bisphosphonates

reduce distant metastases, predominantly in bone. This effect is largely confined to postmenopausal women. “Bisphosphonates interrupt the vicious cycle of bone destruction.” Dr. Coleman said. “They are thought to improve disease outcomes in women with low levels of reproductive hormones, such as those in naturally induced or treatment-induced menopause at start of treatment, and they have possible adverse effects on nonbone recurrence in premenopausal women.” The meta-analysis was based on individual patient data from 36 randomized controlled trials comparing adjuvant use of a bisphosphonate vs no bisphosphonate or placebo; a total of 22,982 women were enrolled in these trials. Seven of the trials compared clodronate vs no bisphosphonate or placebo (n = 5,174) and 29 looked at aminobisphosphonates (n = 17,808). Two-thirds of women on aminobisphosphonates were taking zoledronic acid, about one-quarter received ibandronate, and 11% were on other aminobisphosphonates.

Primary Endpoints Primary outcomes were time to any recurrence, time to first distant recurrence, and breast cancer mortality. Among all women, no significant difference was observed in the 10-year rate of all breast cancer recurrences or distant recurrences, including recurrence in bone. The recurrence rate was 25.4% in those who took bisphosphonates vs 26.5% in the nonbisphosphonate group; distant recurrence rates were 20.9% and 22.3%, respectively.

Large Meta-analysis of Adjuvant Bisphosphonates ■ A large meta-analysis evaluated adjuvant bisphosphonate therapy in over 22,000 women with early breast cancer. ■ In postmenopausal women, bisphosphonate therapy was associated with fewer bone recurrences and reduced breast cancer deaths; no effect was observed in premenopausal women. ■ These findings may change practice in the adjuvant treatment of postmenopausal women with early breast cancer.

Bone recurrence rate was 6.9% and 8.4%, respectively, and the nonbone recurrence rate was 15% in both study arms. The overall rates of local recurrence and contralateral breast cancer were quite similar in both arms at 10 years. However, among 11,036 postmenopausal women (including women aged more than 55 years if menopausal status was unknown), bisphosphonates achieved a highly significant difference in distant recurrence (18.4% in women on bisphosponates vs 21.9% on no bisphosphonates, P  =  .0003) and in bone recurrence (5.9% and 8.8%, respectively, P  <  .00001) vs no bisphosphonates. No significant effect of bisphosphonates was observed on nonbone recurrence.

Additional Data Among all participants, the 10year rates of breast cancer mortality

and non–breast cancer mortality did not differ significantly. In postmenopausal women, the 10year rate of breast cancer mortality was 15.2% for those treated with bisphosphonates vs 18.3% for no bisphosphonates (P = .004), and the 10-year rate of all-cause mortality was 21.5% vs 23.8%, respectively (P = .007). “Similar effects were seen on bone recurrence irrespective of type of bisphosphonate,” Dr. Coleman noted. n

Disclosure: Dr. Coleman has given expert testimony for Novartis, and has received honoraria from Amgen.

Reference 1. Coleman R, Gnant M, Paterson A, et al: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomized trials. 2013 San Antonio Breast Cancer Symposium. Abstract S4-07. Presented December 12, 2013.

EXPERT POINT OF VIEW

“T

hese results are striking in postmenopausal women. The survival advantage in postmenopausal women leaves no room for interpretation. If survival is improved, you have done something good,” stated Peter Ravdin, MD, commenting on the EBCTCG meta-analysis presented at the San Antonio Breast Cancer Symposium. Dr. Ravdin is Co-Director of the San Antonio meeting, as well as Director of Peter Ravdin, MD the Breast Health Clinic at the Cancer Therapy & Research Center of The University of Texas Health Science Center at San Antonio. When asked whether oncologists in the United States will offer adjuvant bisphosphonates to postmenopausal women based on this study, Dr. Ravdin said, “Guidelines will drive treatment, and I’m almost sure the [National Comprehensive Cancer Network] will incorporate them in the guidelines for adjuvant therapy.” Citing “fantastic” improvements in the treatment of breast cancer over the past few decades, he continued, “Hormonal agents improve survival by 30%, chemotherapy improves survival by 30%, trastuzumab [Herceptin] improves survival by 30% in HER2-positive breast cancer, and now this study shows a further 17% improvement in survival for postmenopausal women with bisphosphonates.” n Disclosure: Dr. Ravdin reported no potential conflicts of interest.

Visit The ASCO Post website at ASCOPost.com


The ASCO Post | JANUARY 15, 2014

PAGE 4

ASH Annual Meeting Hematology

Mounting Success in Trials of Genetically Engineered T Cells to Treat Leukemias and Lymphomas By Alice Goodman

R

eports have been trickling in from centers conducting research on the use of chimeric antigen receptor– modified T cells (CAR-T) in hematologic cancer, and the news is encouraging. When directed against CD19, such personalized therapeutic T cells

licensed to Novartis. In fact, Novartis is building a manufacturing facility to produce these cells near the University of Pennsylvania campus. Most recently, Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering Cancer Center, and Seattle Children’s

We’ve now seen remissions lasting for more than 3 years, and there are clues that the T cells continue to kill the leukemia cells in the body for months after treatment. —David L. Porter, MD

are known as CTL019, and small pilot trials of this treatment have shown dramatic improvement in some patients who had been gravely ill. Investigators from different institutions reported experience to date with CTL019 in patients with acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphoma at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans. The abstracts summarized here represent studies that are furthest along in the development of CTL019; at least seven other oral presentations at the ASH meeting focused on experience from other institutions.

‘Smart Bomb’ Approach The promise of the “smart bomb” approach with this immunologic therapy has attracted industry to partner with some investigators and their institutions. For example, CAR-T cells developed at the National Cancer Institute have been licensed to Kite Pharmaceuticals, and CAR-T cells developed at the University of Pennsylvania have been

Research Institute have joined forces to launch Juno Therapeutics, a new biotechnology company that will develop CAR-T cells. Experts predict that CTL019 therapies may become commercially available sometime between 2016 and 2020. The approach harnesses the power of the immune system by reprogramming a patient’s own T cells to recognize cancer cells for a precision immunologic attack. The patient’s cells are extracted, engineered ex vivo to include CAR, and programmed to target the CD19 antigen present on most leukemic cells. A viral vector is inserted, and then the cells are reinfused into the patient for a single treatment. The viral vector triggers the T cells to expand and proliferate once they are reinfused. The engineering process takes about 10 days. In several pilot studies, patients have experienced varying degrees of the cytokine release syndrome, which is characterized by high fevers, muscle pain, low blood pressure, and breathing difficulties. The University of Pennsylvania investigators initially showed that

Anti-CD19 Chimeric Antigen Receptor Therapy ■ Use of genetically engineered T cells to express the chimeric antigen receptor (CAR-T) directed against CD19 (CTL019) is a promising treatment option for patients with advanced leukemia and lymphoma. ■ Some very ill patients with no other treatment options have achieved durable complete remissions in early studies. ■ CTL019 treatment is still in its infancy, and its optimal use remains to be defined.

the interleukin-6 inhibitor tocilizumab (Actemra) tamps down this response,1 which typically is seen when the engineered T cells are expanding in the body, and several of the groups have reported rapid improvement in the cytokine release syndrome after treating with this drug.

Acute Lymphoblastic Leukemia Stephan A. Grupp, MD, PhD, Director of Translational Research in the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia and Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, reported on experience with relapsed/refractory ALL in adults and children.2 Twentytwo pediatric patients and five adult patients with relapsed, treatment-resistant ALL have been treated with CTL019 at the University of Pennsylavnia.

Stephan A. Grupp, MD, PhD

Among the children, 19 achieved a complete response, and remission is ongoing in 14, with 5 patients experiencing relapse. The first patient treated with the protocol remains in remission 20 months later. All five of the adults achieved complete remission, the longest of which has been 6 months. One patient subsequently underwent bone marrow transplant and remains in remission. One patient relapsed after 3 months in complete remission, and his disease tested negative for the engineered cell target. The overall complete response rate in this group was 89%. “Our results serve as another important milestone in demonstrating the potential of this treatment for patients who truly have no other therapeutic options,” Dr. Grupp said. A separate report from the University of Pennsylvania discussed the quantity, lifespan, and activity of the engineered T cells once they were reinfused into the pediatric and adult

Michael Kalos, PhD

patients with ALL (described above) and adults with advanced relapsed/ refractory CLL.3 Testing showed that patients with the greatest in vivo expansion of CTL019 cells (to more than 5% of all CD3-positive cells) were the most likely to achieve complete remission. Those with less robust but still detectable cell expansion were partial responders, while those with no or minimal detectable T-cell expansion were nonresponders. The CTL019 cells that were detected persisted for many months after infusion and continued to function as anticancer T cells. “These new and expanded data provide significant proof that T cells engineered to express cancer-targeting CARs not only work, but work dramatically and in a sustained manner in patients with relapsed/treatment resistant leukemia. [The results] further demonstrate the potential of this approach to help these patients achieve complete remission,” said study author Michael Kalos, PhD, Director, Translational and Correlative Studies Laboratory, Stellar-Chance Laboratories, and Adjunct Associate Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania. “Further, … we can potentially measure and track these engineered cells as a way to monitor treatment, an exciting finding considering that this treatment is often the last hope for these patients,” he added.

Chronic Lymphocytic Leukemia David L. Porter, MD, Director of Blood and Marrow Transplantation at the University of Pennsylvania’s Abramson Cancer Center, reported on experience in the treatment of 32 adults with CLL. Fifteen patients (47%) responded to therapy (7 complete responses and 15 partial responses). The continued on page 10


Announcing a

NEW INDICATION Neoadjuvant treatment of HER2+ breast cancer Indication PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated for: • Treatment of metastatic breast cancer in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease • Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival Limitations of Use: —The safety of PERJETA as a part of a doxorubicin-containing regimen has not been established —The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS and the following pages for additional Important Safety Information.


Significant improvement in pathologic complete response (pCR) with PERJETA-based neoadjuvant therapy NeoSphere trial overview1,2* • Randomized, multicenter trial in 417 patients with HER2+ breast cancer (T2-4d) • Randomization stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen-receptor (ER) or progesterone-receptor (PR) positivity • Primary endpoint: pathologic complete response (pCR) in the breast (ypT0/is) —FDA-preferred endpoint: pCR in breast and nodes (ypT0/is ypN0), (reported below) *The NeoSphere trial is referred to as “Study 2” in the PERJETA full Prescribing Information.

NeoSphere trial results1 PERJETA + Herceptin + docetaxel (n=107)

Herceptin + docetaxel (n=107)

PERJETA + Herceptin (n=107)

PERJETA + docetaxel (n=96)

pCR (ypT0/is ypN0), n (%)

42 (39.3%)

23 (21.5%)

12 (11.2%)

17 (17.7%)

[95% CI]

[30.0, 49.2]

[14.1, 30.5]

[5.9, 18.8]

[10.7, 26.8]

P=0.0223 (vs Herceptin + docetaxel)

P=0.0018 (vs PERJETA + Herceptin + docetaxel)

P=0.0063 (vs Herceptin + docetaxel)

Important Safety Information Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity • PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Additional Important Safety Information PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. Left Ventricular Dysfunction (LVD) • In Study 1, for patients with MBC, left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • In Study 2, for patients receiving neoadjuvant treatment, the incidence of LVSD was higher in PERJETA-treated groups than in the trastuzumab and docetaxel group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination

with trastuzumab and docetaxel. In the overall treatment period, LVEF decline >10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel • In Study 3, for patients receiving neoadjuvant treatment, in the overall treatment period, LVEF decline >10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, in 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and in 10.5% of patients treated with PERJETA in combination with TCH • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting and every 6 weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if LVEF has not improved or has declined further Infusion-Associated Reactions • PERJETA has been associated with infusion reactions • In Study 1, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting • In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE v3.0) Grades 1-2 • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions


TRYPHAENA trial overview1,3† • Phase II, randomized, multicenter trial in 225 patients with HER2+ breast cancer (T2-4d) • Patients were randomized to 1 of 3 neoadjuvant regimens —PERJETA + TCH —FEC followed by PERJETA + Herceptin + docetaxel —PERJETA + Herceptin + FEC followed by PERJETA + Herceptin + docetaxel • Randomization stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PR positivity • Primary endpoint: cardiac safety in the neoadjuvant treatment period —Incidence of left ventricular dysfunction (LVD) and symptomatic left ventricular dysfunction (LVSD) (congestive heart failure, CHF) • Secondary endpoints included pCR in breast and nodes (ypT0/is ypN0) †

The TRYPHAENA trial is referred to as “Study 3” in the PERJETA full Prescribing Information.

TRYPHAENA trial results1 • Incidence of LVD • Incidence of symptomatic LVSD (CHF) • pCR (breast and nodes) —PERJETA + TCH: 2.6% —PERJETA + TCH: 0.0% —PERJETA + TCH: 63.6% —FEC/PERJETA + Herceptin + —FEC/PERJETA + Herceptin + —FEC/PERJETA + Herceptin + docetaxel: 4.0% docetaxel: 2.7% docetaxel: 54.7% —PERJETA + Herceptin + FEC/PERJETA —PERJETA + Herceptin + FEC/PERJETA —PERJETA + Herceptin + FEC/PERJETA + Herceptin + docetaxel: 5.6% + Herceptin + docetaxel: 0.0% + Herceptin + docetaxel: 56.2% FEC = 5-fluorouracil, epirubicin, and cyclophosphamide; TCH = docetaxel + carboplatin + Herceptin.

Hypersensitivity Reactions/Anaphylaxis • In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 reactions was 2.0% and 2.5%, respectively, according to NCI-CTCAE (version 3) • In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1 • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions Metastatic Breast Cancer • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue Neoadjuvant Treatment of Breast Cancer • The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea

© 2013 Genentech USA, Inc.

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• The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting • The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. September 2013. 2. Gianni L, Pienkowski T, Im Y-H, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet. 2012;13:25-32. 3. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24:2278-2284.

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PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established. • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxel-treated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated

with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. 5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] 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. Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1

PERJETA Placebo + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 0.0 Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).

Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2. Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA Trastuzumab + trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % All Grades All Grades All Grades All Grades Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 10.3 0.0 2.8 0.0 0.9 0.0 Edema peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 Peripheral Sensory 12.1 0.9 8.4 0.9 1.9 0.0 Neuropathy Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 Metabolism and nutrition disorders Decreased appetite 6.5 0.0 14.0 0.0 1.9 0.0 Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0

25.5 1.1 16.0 2.1 5.3 0.0 25.5 0.0 8.5

0.0

67.0 0.0 28.7 1.1 54.3 36.2 16.0 9.6

4.3 1.1 2.1 0.0

64.9 57.4 13.8 8.5 12.8 0.0 7.4 0.0 10.6 0.0 21.3 0.0 9.6 0.0 14.9 0.0 8.5

0.0

The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3


Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal inflammation 23.6 0.0 20.0 0.0 17.1 1.3 Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile neutropenia 18.1 18.1 9.3 9.3 17.1 17.1 Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy peripheral 5.6 0.0 1.3 0.0 10.5 0.0 Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal pain 8.3 0.0 6.7 0.0 11.8 0.0 Metabolism and nutrition disorders Decreased appetite 20.8 0.0 10.7 0.0 21.1 0.0

Table 3 Summary of Adverse Reactions ≥ 10% in Study 3 (Cont) Body System/ Adverse Reactions

PTZ + T + D Ptz + T + FEC following FEC PERJETA + TCH followed by n=75 n=76 Ptz + T + D Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

Eye disorders Lacrimation increased 12.5 Psychiatric disorders Insomnia 11.1 Investigations ALT increased 6.9

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

0.0

5.3

0.0

7.9

0.0

0.0

13.3

0.0

21.1

0.0

0.0

2.7

0.0

10.5

3.9

FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/ Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/ Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm) Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the

observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision

should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

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

PERJETA is a registered trademark of Genentech, Inc. 09/13 PER0002094600 © 2013 Genentech, Inc. 10139000

Don’t Miss These Important Reports in This Issue of The ASCO Post

Jean-Yves Douillard, MD, PhD, on Metastatic Colorectal Cancer, see page 41

Gideon Blumenthal, MD, and Elizabeth Mansfield, PhD, on the FDA Drug Approval Process, see page 52

Manfred Lehnert, MD, on Drug Development Challenges, see page 87

Paul G. Richardson, MD, and Preet Paul Singh, MD, on Lenalidomide Maintenance in Multiple Myeloma, see page 45

Thomas A. Buchholz, MD, and Benjamin D. Smith, MD, on the TARGIT-A Trial, see page 57

Clifford A. Hudis, MD, FASCO, on ASCO’s Statement on the Status of Cancer see page 94

Visit The ASCO Post online at ASCOPost.com


The ASCO Post | JANUARY 15, 2014

PAGE 10

ASH Annual Meeting Genetically Engineered T Cells continued from page 4

complete remissions are ongoing, he noted. The 32 CLL patients included 14 who were in the pilot trial and the first 18 in a phase  II dose-optimization trial.4,5 “We are tremendously excited about these results. About half of our CLL patients responded to this therapy, with most of them having several pounds of tumors eradicated by the genetically modified T cells,” Dr. Porter said. “We’ve now seen remissions lasting for more than 3 years, and there are clues

were virtually untreatable and have a very poor prognosis. The novel finding is that anti-CD19 CAR-T cells can eradicate a solid tumor mass,” Dr. Kochenderfer said. Patients underwent a conditioning regimen with cyclophosphamide and fludarabine prior to receiving a single infusion of their own genetically modified T cells. This conditioning regimen was used because prior chemotherapy has been shown to enhance the activity of anti-CD19 CAR-T cells in patients. Seven patients achieved a complete response, five achieved a partial response, and one patient had stable

Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that—until this point— were virtually untreatable and have a very poor prognosis. —James N. Kochenderfer, MD

that the T cells continue to kill the leukemia cells in the body for months after treatment. Even in patients who had only a partial response, we often found that all cancer cells disappeared from their blood and bone marrow and their lymph nodes continued to shrink over time. In some cases, we have seen partial responses convert to complete remissions over several months.”

First Report in B-Cell Lymphoma James N. Kochenderfer, MD, an investigator in the Experimental Transplantation and Immunology Branch of the National Cancer Institute, Bethesda, Maryland, described successful treatment with anti-CD19 CAR-T cells in a total of 15 patients with chemorefractory B-cell lymphomas: 9 had aggressive large B-cell lymphomas, and 6 had a variety of indolent B-cell lymphomas. Patient ages ranged from 30 to 68 years.6 “Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that—until this point—

disease. One patient died of cardiac arrhythmias, and a second patient was lost to follow-up. Acute toxicities included fever, low blood pressure, focal neurologic deficits, and delirium. These toxicities resolved in less than 3 weeks. “We are particularly encouraged by the partial and complete responses that we observed in a number of patients with diffuse large B-cell lymphomas who had exhausted all other treatment options,” Dr. Kochenderfer said. “This approach offers an option for patients with chemotherapy-refractory large Bcell lymphomas who are generally not thought to be good candidates for hematopoietic stem cell transplantation.” In the protocol used by Dr. Kochenderfer and co-investigators, the CAR is encoded by a gamma retrovirus and incorporates regions of an antiCD19 antibody, part of CD28, and part of CD3-zeta. The anti-CD19 CAR-T cell protocols are evolving and still in early stages, he noted. “We will continue our research to further improve the protocol and evaluate its value in additional patients with treatment-resistant disease,” he said. n

EXPERT POINT OF VIEW

A

t the recent American Society of Hematology Annual Meeting, Prashant Kapoor, MD, Assistant Professor of Hematology at Mayo Clinic, Rochester, Minnesota, agreed that CTL019 is a promising, exciting, and novel approach to treating patients with advanced B-cell hematologic malignancies. “Although still in the preliminary stages of development, and offered only by very few centers, the ability of CTL019 cells to achieve sustained remissions makes them particularly attractive for patients with refractory diseases. The central nervous system (CNS) can occasionally serve as a sanctuary site for leukemia cells. CTL019 cells appear to efficiently migrate to the CNS and could prevent CNS relapse,” Dr. Kapoor said.

Cytokine Release Syndrome He noted that close monitoring is required after the single-infusion therapy because of the possibility of cytokine release syndrome reported in several of the small trials. In more recent trials, tocilizumab (an anti–interleukin-6 drug) has been effective. Despite this potential side effect, he continued, “Immune therapies typically have a favorable long-term toxicity profile. Unfortunately, relapses with subclones that do not express CD19 (‘CD19 escape cells’) have been shown to occur, but could theoretically be circumvented by simultaneously targeting antigens other than CD19.” Some of the current investigations are, in fact, targeting other antigens. n Disclosure: Dr. Kapoor reported no potential conflicts of interest.

Disclosure: The NCI trial was supported in part by Kite Pharma. Dr. Kochenderfer has no personal financial ties and has received no payments from Kite Pharma. Dr. Porter reported research funding and intellectual property/royalties in association with Novartis, as well as spouse employment with Genentech. Dr. Kalos reported patents and royalties in association with Novartis and is a member of the scientific advisory board for Adaptive Biotechnologies. Dr. Grupp receives research funding from Novartis.

References 1. Grupp SA, Kalos M, Barrett D, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509-1518, 2013. 2. Grupp S, Frey NV, Aplenc R, et al: T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) produce significant in vivo proliferation, complete responses, and long-term persistence without GVHD in children and adults with relapsed, refractory ALL. ASH Annual Meeting. Abstract 168. Presented December 8, 2013. 3. Kalos M, Nazimuddin F, Finklestein

JM, et al: Long-term functional persistence, B cell aplasia, and anti-leukemia efficacy in refractory B cell malignancies following T cell immunotherapy using CAR-redirected T cells targeting CD19. ASH Annual Meeting. Abstract 163. Presented December 8, 2013. 4. Porter D: Randomized phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. ASH Annual Meeting. Abstract 873. Presented December 10, 2013. 5. Porter D, Kalos M, Frey N, et al: Chimeric antigen receptor modified T cells directed against CD19 (CTL019 cells) have long-term persistence and induce durable responses in relapsed, refractory CLL. ASH Annual Meeting. Abstract 4162. Presented December 9, 2013. 6. Kochenderfer J, Dudley ME, Kassim SH, et al: Effective treatment of chemotherapy-refractory diffuse large B-cell lymphoma with autologous T cells genetically-engineered to express an anti-CD19 chimeric antigen receptor. ASH Annual Meeting. Abstract 168. Presented December 8, 2013.

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ASCOPost.com | JANUARY 15, 2014

PAGE 11

San Antonio Breast Cancer Symposium Breast Cancer

Anastrozole Halves Risk of First Breast Cancer in High-Risk Postmenopausal Women By Alice Goodman

F

ive years of treatment with anastrozole reduced the risk of breast cancer by 53% in postmenopausal women

Jack Cuzick, PhD

at high risk for developing the disease, according to an analysis of the International Breast Cancer Intervention Study (IBIS)-II trial. Anastrozole reduced the risk of estrogen receptor–positive invasive cancers by 58%. The study was published online in The Lancet1 to coincide with its presentation at the 2013 San Antonio Breast Cancer Symposium.2 “We believe these results provide strong support for prevention of breast cancer in high-risk [postmenopausal]

women. We think anastrozole should be the first choice for this indication,” said lead author Jack Cuzick, PhD, of Wolfson Institute of Cancer Prevention at Queen Mary University of London. “The effect of tamoxifen is sustained for at least 10 years. We need longer-term follow-up to determine if the preventive effect of anastrozole is sustained after treatment.” Session moderator Fabrice André, MD, PhD, Institut Gustave Roussy, Villejuif, France, said he felt that this was too strong a statement to make at this point and that additional evidence is needed before implementing this research finding. Dr. André noted that there are other good choices for prevention that are U.S. Food and Drug Administration–approved for this indication, including tamoxifen and raloxifene (Evista).

IBIS-II Details The international, double-blind, placebo-controlled IBIS-II randomly assigned 3,864 postmenopausal women at high risk of breast cancer (due to fam-

Role of Anastrozole in Breast Cancer Prevention ■ Five years of anastrozole therapy reduced the risk of primary breast cancer by more than 50% in postmenopausal women at high risk. ■ Anastrozole reduced the risk of estrogen receptor–positive invasive breast cancer by 58%.

ily history, atypia, or lobular carcinoma in situ, or breast density) to treatment with anastrozole or placebo for 5 years.

Fabrice André, MD, PhD

The study recruited women aged 40 to 70 years at 153 centers in 18 countries. Median age was 59.5 years, and 695 women (18%) were older than age 65;

one-third had body mass index >  29; and 47% previously used hormone replacement therapy. The vast majority of high-risk women had a family history of breast cancer; 50% had at least two family members with breast or ovarian cancer, 35% had one first-degree relative with breast cancer aged 50 years or younger, 9% had one first-degree relative with bilateral breast cancer, and 16% had lobular carcinoma in situ or estrogen receptor–positive ductal carcinoma in situ. At a median follow-up of 5 years, breast cancer occurred in 40 women in the anastrozole group (2%) and 85 (4%) in the placebo group. The predicted cumulative continued on page 16

Who Opts for Chemoprevention? By Caroline Helwick

B

ased on age and risk, an estimated 10 million women in the United States may be eligible for an agent aimed at preventing breast cancer, but chemoprevention is underutilized. Fewer than 5% of women at high risk who are offered tamoxifen for chemoprevention agree to take the drug, partly due to inadequate time for counseling, insufficient knowledge about risk-reduction strategies, and concerns about side effects, according to Parijathan S. Sivasubramanian, MD, of Columbia University College of Physicians and Surgeons, New York.1 Dr. Sivasubramanian led one of two studies examining the factors that influence the uptake of chemoprevention. The other was presented at the meeting by Erin W. Hofstatter, MD, of Yale University School of Medicine, New Haven, Connecticut.2

‘Richer and Wiser’ Women Dr. Hofstatter reported that be-

ing “richer and wiser” was a factor in the acceptance of chemoprevention, based on information from the National Health Interview Survey, a population-based survey conducted annually by the Centers for Disease Control. In 2010, the survey was conducted on 10,959 women ≥  35 years old, of whom 0.21% reported taking chemoprevention. Bivariate analysis revealed several factors associated with uptake: age, race/ethnicity, education, insurance status, income, and geographic region. “Interestingly, the use of breast MRI [magnetic resonance imaging], family history, and personal risk perception were not associated,” Dr. Hofstatter indicated. “On the multivariate analysis, education and income remained independent predictors of chemoprevention use. Risk perception and family history did not appear to correlate.” Compared to women with less

These findings highlight the potential disparities in access to appropriate chemoprevention options. Improved education and counseling of those women at increased risk of breast cancer is greatly needed. —Erin W. Hofstatter, MD

than a high school degree, the odds ratios for chemoprevention were 1.86 for high school education, 1.86 for some college, 3.23 for a Master’s degree and 25.2 for doctorate degrees (P < .0001). Compared to an income <  $35,000, income ≥  $100,000 carried an odds ratio of 3.78 (P = .03). “These findings highlight the potential disparities in access to appropriate chemoprevention options,” Dr. Hofstatter commented. “Improved education and counseling of those

women at increased risk of breast cancer is greatly needed.”

Breast Clinic Involvement The study reported by Dr. Sivasubramanian was a survey of consecutive women seen for initial consultation at the breast clinic of Columbia University Medical Center. Of 1,448 enrolled between 2007 and 2013, 416 were deemed at high risk or diagnosed with ductal carcinoma in situ (DCIS), continued on page 16


XOFIGO® IS INDICATED

for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Not an actual patient. Models used for illustrative purposes only.

Important Safety Information1 for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and • Contraindications: Xofigo is contraindicated in women who are or leukopenia—has been reported in patients treated with Xofigo. may become pregnant. Xofigo can cause fetal harm when administered Monitor patients with evidence of compromised bone marrow reserve to a pregnant woman closely and provide supportive care measures when clinically indicated. • Bone Marrow Suppression: In the randomized trial, 2% of patients Discontinue Xofigo in patients who experience life-threatening in the Xofigo arm experienced bone marrow failure or ongoing complications despite supportive care for bone marrow failure pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with • Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo bone marrow failure was ongoing at the time of death. Among Xofigo, the absolute neutrophil count (ANC) should be the 13 patients who experienced bone marrow failure, 54% required ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin blood transfusions. Four percent (4%) of patients in the Xofigo arm ≥10 g/dL. Prior to subsequent administrations, the ANC should and 2% in the placebo arm permanently discontinued therapy due to be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue bone marrow suppression. In the randomized trial, deaths related Xofigo if hematologic values do not recover within 6 to 8 weeks to vascular hemorrhage in association with myelosuppression were after the last administration despite receiving supportive care observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), • Concomitant Use With Chemotherapy: Safety and efficacy of serious infections (10%), and febrile neutropenia (<1%) was similar concomitant chemotherapy with Xofigo have not been established.

© 2013 Bayer HealthCare Pharmaceuticals and Algeta ASA. All rights reserved. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer AG. ALGETA is a trademark of Algeta ASA.

600-10-0009-13b

11/13

Printed in USA


Prolong life. Treat bone metastases.

30%

reduction in the risk of death vs placebo (hazard ratio [HR]=0.695)1

The first agent to extend overall survival by exerting an antitumor effect on bone metastases in CRPC1,2 • Exploratory updated analysisa: 3.6-month increase in median overall survival vs placebo (HR=0.695; 95% confidence interval [CI]: 0.581-0.832)1 —14.9 months for Xofigo (95% CI: 13.9-16.1) vs 11.3 months for placebo (95% CI: 10.4-12.8)1

• Prespecified interim analysis: 2.8-month increase in median overall survival vs placebo, P=0.00185 (HR=0.695; 95% CI: 0.552-0.875)1 —14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1

• Overall survival benefit supported by delay in time to first symptomatic skeletal event (SSE), favoring Xofigo.b The majority of events consisted of external beam radiation therapy to bone metastases1 • 1-minute intravenous injection every 4 weeks for 6 injections1

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis. b SSEs defined as external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention.

a

To learn more, visit www.xofigo-us.com

Outside of a clinical trial, concomitant use of Xofigo in patients on 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 • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients.

The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

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


Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. 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 efficacy of Xofigo in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo 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 Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo 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 Xofigo. 8.3 Nursing Mothers Xofigo 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 Xofigo, 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 efficacy of Xofigo in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-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 Xofigo 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 identified 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 CONDUCTEDÂŹ 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 Xofigo 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 Xofigo. Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies. There is no specific antidote. In the event of an inadvertent overdose of Xofigo, 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 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹÂŹK"QÂŹÂŹMICROCURIE 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. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGOÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGOÂŹ &OLLOWÂŹ good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed 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 fluids to avoid contamination. When handling bodily fluids, 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 Xofigo treatment.

Manufactured for:

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


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San Antonio Breast Cancer Symposium Chemoprevention continued from page 11

316 of whom were offered chemoprevention. Antiestrogen drugs (primarily tamoxifen) were adopted by 162 women, while 154 declined chemoprevention. She attributed the high rate of acceptance—about 50%—to the fact that the participants attended a breast clinic where they received accurate and comprehensive information about chemoprevention. Antiestrogen use was higher among women with DCIS (57.4%), compared to those with lobular carcinoma in situ or BRCA mutations (20.4%) and those with a 5-year Gail

Anastrozole and Breast Cancer Risk continued from page 11

incidence of primary breast cancers (including ductal carcinoma in situ) occurring at 7 years of follow-up was 5.6% of women in the placebo group vs 2.8% of the anastrozole group, representing a 53% decrease in risk (P < .0001). Estrogen receptor–positive invasive breast cancers developed in 3.3% of the placebo group vs 1.4% of the anastrozole group, representing a 58% decrease in risk (P = .001). No effect of anastrozole was seen in estrogen receptor–negative tumors, Dr. Cuzick said. Five years of treatment were completed by 72% of placebo patients and 68% of those taking anastozole, Dr. Cuzick noted. “An important finding was the high percentage of side effects that occurred in the placebo arm. In uncontrolled situations, they would likely be linked to the treatments,” Dr. Cuzick said.

Adverse Events Bone fractures were increased from 7.7% with placebo to 8.5% with anastrozole. Dr. Cuzick noted that all participants had a dual x-ray absorptiometry scan upfront and osteoporotic women were given bisphosphonate treatment, which could account for a smaller-thanexpected incidence of musculoskeletal/ fracture side effects. Musculoskeletal aches and pains were the most common adverse events in the anastrozole group and were reported in significantly more women given the aromatase inhibitor than in placebo recipients: (64% vs 58%, P = .0001). This difference between the two treatment arms was driven mostly by moderate ar-

risk ≥  1.67% (22.2%). In the multivariate analysis, only breast cancer risk category was an independent predictor of antiestrogen use. But a number of other things factored into a woman’s decision to either accept or decline chemoprevention, she said. Most important was knowledge about another woman’s experiences with tamoxifen, raloxifene (Evista), or aromatase inhibitors, cited by more than half the women as a factor. Results from clinical trials, conversations with friends and family, information from a health-care provider, and information from reputable websites were each cited by about 30% of the women as important in

decision-making. She noted that concerns about bone fractures with aromatase inhibitors were cited as a potential side effect five times more often (67%) than arthritis. With tamoxifen, women were most concerned about blood clots (44%) and uterine cancer (31%). The main concern with raloxifene was also blood clots (80%). Dr. Sivasubramanian suggested that a term other than “chemoprevention” be used in conversations with high-risk women, based on the perception among some participants that these agents would cause alopecia. “Most women don’t understand what chemoprevention is,” she said. n

thralgia, noted Dr. Cuzick. Other joint symptoms were also increased in the anastrozole group, including joint stiffness and carpal tunnel syndrome. Other side effects more frequently seen in the anastrozole group were dry eye and vasomotor symptoms. Thirty-five deaths were recorded by data cutoff (May 2013). Only two were breast cancer–related, and these occurred in the anastrozole group. Unexpectedly, the incidence of other cancers was reduced from 70 (4%)

in the placebo group to 40 (2%) in the anastrozole group. These were primarily skin cancers and colorectal cancers. “This was highly significant and merits further study,” Dr. Cuzick said. n

Disclosure: The study was funded by Cancer Research UK, the National Health and Medical Research Council of Australia, AstraZeneca, and Sanofi-Aventis. Dr. Cuzick is on the speaker’s bureau for AstraZeneca. Dr. André has received research grants from Novartis.

References 1. Cuzick J, Sestak I, Forbes JF, et al:

Disclosure: Dr. Sivasubramanian and Hofstatter reported no potential conflicts of interest.

References 1. Sivasubramanian PS, Reimbers LL, Greenlee H, et al: Uptake of breast cancer chemoprevention among high-risk women and those with ductal carcinoma in situ. 2013 San Antonio Breast Cancer Symposium. Abstract P5-13-01. Presented December 13, 2013. 2. Hofstatter EW, Lannin D, Horowitz N, et al: Richer and wiser: Factors correlated with chemoprevention use in the United States. 2013 San Antonio Breast Cancer Symposium. Abstract P5-13-15. Presented December 13, 2013.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBISII): An international, double-blind, randomized, placebo-controlled trial. Lancet. December 12, 2013 (early release online). 2. Cuzick J, Sestak I, Forbes JF, et al: First results of the International Breast Cancer Intervention Study II (IBIS-II): A multicentre prevention trial of anastrozole versus placebo in postmenopausal women at increased risk of developing cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S3-01. Presented December 12, 2013.

EXPERT POINT OF VIEW

A

fter the IBIS-II presentation at the San Antonio Breast Cancer Symposium, Carlos L. Arteaga, MD, of Vanderbilt Ingram Cancer Center, Nashville, noted that women at high risk are afraid of developing breast cancer and that pharmacologic intervention may allay their anxiety. “Dr. Cuzick’s study with more than 4,000 women shows that anastrozole has an impact on the development of breast cancer. His data showed that side effects are not terribly different in the anastrozole arm than in the placebo arm. He suggested that the bad rap of joint pain and arthralgias may not be due to the aromatase inhibitor itself.”

Toxicity Concerns In an accompanying editorial in The Lancet,1 David Cameron, MD, MRCP, Edinburgh Cancer Centre, Western General Hospital, Edinburgh, was less enthusiastic about the widespread use of anastrozole for preven-

tion of breast cancer. In his view, no study of pharmacoprevention of breast cancer, including IBIS-II, has demonstrated a reduction in mortality. “For any woman considering 5 years’ anti-oestrogen therapy to reduce her risk Carlos L. Arteaga, MD David Cameron, MD, MRCP of breast cancer without evidence to suggest that she will have a longer life, the perceived Dr. Cameron wrote that newer and actual toxicity of this intervention drugs are needed to reduce breast canbecomes important,” he wrote. “The cer mortality, with an improved safety financial costs of breast cancer preven- profile, and that better ways are needtion might have decreased, but the tox- ed to target the drugs to women who icity cost to women has not.” will derive the greatest benefit. n Disclosure: Dr. Arteaga and Cameron Dr. Cameron noted that compliance is an obstacle to chemopreven- reported no potential conflicts of interest. tion, and that about 100 to 200 additional women had musculoskeletal Reference 1. Cameron DA: Breast cancer cheand vasomotor events in the anastrozole group, “often to a moderate or se- moprevention: Little progress in practice. vere level—to prevent 15 symptom- Lancet. December 12, 2013 (early release online). atically diagnosed breast cancers.”


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SIOG 2013 Annual Conference International Society of Geriatric Oncology Meeting Explores Multidisciplinary, Tailored Treatment of Older Patients With Cancer By Stuart M. Lichtman, MD

T

he annual meeting of the International Society of Geriatric Oncology (SIOG, www.siog.org) was held in Copenhagen from October 24 to 26. The theme of the meeting was the “Multidisciplinary Approach Towards Personalized Treatments.”

cies; address issues of access to care, including the needs of the caregiver; and develop interdisciplinary geriatric oncology clinics. In the area of research, SIOG aims to develop, test, and disseminate easy screening tools; create a clear and operational definition of vulnerability/frailty applicable to

The information presented at the SIOG conference amply demonstrated that there is an accumulating database of information contributing to enhanced care of older patients. —Stuart M. Lichtman, MD

The Society, which was founded in 2000, is a multidisciplinary society, including physicians and allied health professionals in the fields of oncology and geriatrics, and has had over 1,000 members in more than 40 countries around the world. The goal of SIOG is to foster the development of health professionals in the field of geriatric oncology, in order to optimize treatment of older adults with cancer.

Three-Pronged Strategy SIOG promotes efforts in three strategic directions. Its goal in education is to disseminate knowledge in order to maintain a high common standard of health care in older cancer patients, integrate geriatric oncology in the curricula for medical and nursing education to ensure a high standard of qualification for health-care professionals, address the shortage of specialist oncologists/geriatricians and allied health staff in geriatric oncology, and increase public awareness of the worldwide epidemic of cancer in the elderly. The Society’s goal for clinical practice is to integrate geriatric evaluation (including comorbidities) into oncology decisionmaking and guidelines; improve the quality of prevention, diagnosis, treatment, and follow-up of older patients with malignanDr. Lichtman is Attending Physician, 65+ Clinical Geriatric Program, Memorial Sloan-Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, New York. He is also on the Board of Directors of the International Society of Geriatric Oncology.

oncology; increase the relevance of clinical trials for older patients; improve research in the field of geriatric oncology; and promote multidisciplinary, basic/translational research on the interface of aging and cancer. A major focus of the organization is the development of treatment guidelines by multidisciplinary task forces.1 These have included recommendations for Comprehensive Geriatric Assessment, and the incorporation of geriatric principles in the treatment of multiple solid tumors, surgery, radiotherapy, and supportive care.

Meeting Topics The recent SIOG conference had 346 delegates participating from 42 countries. The meeting topics were divided into tracks: solid tumors, hematologic malignancy, new therapies and basic science, supportive care, and advocacy and socioeconomic issues. The 23 scientific sessions were held on multiple topics including targeted therapy, breast cancer, colorectal cancer, genitourinary malignancies, myelodysplasia, cancer cachexia, lung cancer, nursing and models of geriatric care. Industry-supported satellite sessions addressed chemotherapy-induced nausea and vomiting, prostate cancer, and hematologic malignancies. The plenary session topics included a review of the Institute of Medicine report, official presentation of Comprehensive Geriat-

Save the Date The 2014 SIOG conference will be held in Lisbon from October 23 to 25.

ric Assessment guidelines, and a special partnership session with ASCO and the European Society for Medical Oncology. Among the 162 posters, the highlighted topics included a questionnaire evaluating patients understanding of clinical trials in metastatic non–small cell lung cancer, a screening tool for geriatric impairments, sleep deprivation in elderly thoracic surgery patients, nutrition, hematologic malignancies, advocacy, and policy issues. The B.J. Kennedy Award for Best Poster went to Marije E. Hamaker, MD, PhD, of Diakonessenhuis Utrecht, the Netherlands, whose study addressed “Ongoing Clinical Trials in Elderly Patients With Hematologic Malignancy: Are We Addressing the Right Outcome Measures?” Also at the 2013 meeting, SIOG presented the Paul Calabresi Award to Supriya G. Mohile, MD, of the University of Rochester, New York, for her contributions to Geriatric Oncology. This was the first time that interviews were conducted during the conference by the UK-based ecancer—a nonprofit oncology channel committed to improving cancer communication and education with the goal of optimizing patient care and outcomes.2

Vulnerable Population The information presented at the SIOG conference amply demonstrated that there is an accumulating database of information contributing to enhanced care of older patients. Our ability to individualize treatment is improving, and this will lead not only to increased survival but also to better quality of life. The delegates were encouraged to develop trials and encourage participation of older patients with cancer. There is still much to be learned to be able to provide the best care for this vulnerable population. The 2014 meeting will be held in Lisbon from October 23 to 25. The SIOG Administrative office is in Geneva, Switzerland. n

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

References 1. International Society of Geriatric Oncology: SIOG clinical guidelines. Available at http://siog.org/index.php?option=com_con tent&view=article&id=246&Itemid=92. Accessed December 9, 2013. 2. ecancer conferences: Highlights from international oncology meetings. Available at http://ecancer.org/conference/519-siog2013--international-society-of-geriatric-oncology.php. Accessed December 9, 2013.

Evaluating and Screening Geriatric Patients for Treatment By Martine Extermann, MD, PhD

O

ne of the key questions in geriatric oncology is: How can we use all of the work geriatricians have done over the years in general geriatrics and apply that to the field of oncology? One-quarter to onethird of us are going to develop cancer throughout our lifetime, and half of the time it is going to be after the age of 70. So, many but not all of us will have other health problems by the time we have a cancer, and you can have some very healthy older persons. As Martine Extermann, MD, PhD cancer physicians, we give treatments that are pretty aggressive sometimes, so you have to know which person can have that treatment and get the full benefit of it and which person cannot have the treatment. To give full disclosure, I am a Past President of SIOG. We have been doing taskforce work in order to review the evidence and see what is the best way to evaluate these cancer patients with geriatric instruments. We advocate a twostep approach. Oncologists are very busy people. Not everybody over 70 needs a whole assessment by a geriatrician, it can take a bit of time to have that assesscontinued on page 19

Martine Extermann, MD, PhD, is Professor of Oncology and Medicine at the University of South Florida and Attending Physician in Senior Adult Oncology at the Moffitt Cancer Center in Tampa, Florida.


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SIOG 2013 Annual Conference ment by a geriatrician, so we advocate first using a short screening tool and then referring the patient who screened positive for a full geriatric assessment.

Assessment Guidelines for Older Patients When an oncologist is in a very busy private practice and sees a patient for the first time, it will often be a couple of weeks before actually starting the [patient’s] treatment, because you have to get the outside CT scan, and you have to get a port. So you have 2 weeks in which you can do further assessments, and a geriatrician can do a lot of things in 2 weeks. In 2005, we published our first set of guidelines1 for older cancer patients including the geriatric assessment, and this year we are presenting an update of those guidelines at the SIOG conference. [The update includes] which screening tool has published information and which one seems to be sensitive enough so we don’t miss too many problems and will be good enough to build a proper reference for a geriatrician or a multidisciplinary team that can see everybody. Then some other elements of this taskforce look at the geriatric assessment. [For example,] what do we detect in this cancer patient? How many problems [does the patient have], and do those problems change the cancer treatment? Many studies have shown that a geriatric consultation or a multidisciplinary interaction with a geriatrician does modify the cancer treatment about 25% to 50% of the time. So when physicians have new information from the geriatric side, they are going to change the treatment quite a few times. The data are still fairly scarce, [but] as we change the treatment, does it change the outcome? Does it change how the patient functions? Does it change how an older patient lives? Does it change the ability of cancer patients to finish their treatment? Adapted with permission from an interview conducted by eCancer Conferences at the 2013 International Society of Geriatric Oncology conference in October. To view the full interview and others, visit ecancer at http://www.ecancer.org. ecancer is an online oncology channel supported by the ECMS Foundation (ecancermedicalscience). The Foundation was established by Professor Umberto Veronesi and Professor Gordon McVie as an independent, not-for-profit organisation with charitable status to fund the speedy dissemination of cancer information. ecancer is Published by Cancer Intelligence Ltd, England and Wales.

Not Ready for Prime Time We know a geriatric assessment predicts all of that very well and differently from all of your classic prognostic cancer factors, but we don’t yet know if we can change that with a geriatric intervention. My thought is, are we ready for prime

time? And my answer would be, “Well maybe [we’re ready for] the mid-morning or the late evening, but we’re not quite ready for prime time.” Because screening is just good medicine—we know the authentic problems in a certain group of patients, and good medicine is being aware

of what problems the patient has. [So we know it is important to] take into account the assessment of the geriatrician, but in what form is open to discussion—we do not have studies showing which interventions change patient outcome. But there

continued on page 20

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SIOG 2013 Annual Conference Evaluating and Screening Geriatric Patients continued from page 19

is work in progress. Several studies of fairly large size are looking at the outcomes of treatment changes. A study in Belgium of 2,000

patients in 10 centers—both academic and private hospitals—showed that one-quarter have changes in treatment and they are now looking down the line at what is going to happen. The French also have a large trial [underway]. In the United States, I’m not aware of any mul-

ticenter trial on that particular aspect, but there are probably several geriatric oncology programs that are trying to [address these questions]. n Disclosure: Dr. Extermann is a past President of the International Society for Geriatric Oncology.

Reference 1. Extermann M, Aapro M, Bernabei R, et al: Use of comprehensive geriatric assessment in older patients: Recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 55:241-252, 2005.

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SIOG 2013 Annual Conference Addressing the Challenges of an Aging Population By Harvey J. Cohen, MD

W

e have an aging population, which is a good thing since people are living longer. [But] can-

cer is a disease that tends to occur most frequently in older people, so the combination of those two events

will lead to many more older people with cancer, a larger cancer population in general, and a larger number

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of cancer survivors. Both of those issues present a continued on page 22


The ASCO Post | JANUARY 15, 2014

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SIOG 2013 Annual Conference Challenges of an Aging Population continued from page 21

number of problems. It wouldn’t be a problem if older people were just the same as younger people, but we know from a number of studies that

the very elderly differ from younger people regarding the number of comorbidities, physiology, and social and financial situations. So many of these properties will lead to the need for different approaches to their cancer treatment.

What social problems are associated with these issues? For one, older people [often] live alone, and when they don’t live alone they often live with an older spouse. We often rely on caregivers for help in the care of patients, and Harvey J. Cohen, MD

in these situations you are dealing with an older caregiver as well as an older patient, which can result in substantial difficulties in management. There are also financial issues [to contend with]. In the United States, for example, we think of older people being covered by Medicare, and while that is true, there are substantial copays required [in association with the program] and for many of the new cancer treatments, which are very, very expensive, those copays can exceed people’s ability to pay. So I think there are many different issues that are going to have to be dealt with.

Are these problems being addressed in the United States?

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People are starting to be more and more aware of them. I think the dynamics of the population change is finally beginning to dawn on people. People in both the oncology and geriatric communities have been recognizing these problems and are starting to work together to approach these issues. This issue came to the attention of the Institute of Medicine (IOM), which recently issued a report 1 specifically dealing with the issues that Adapted with permission from an interview conducted by eCancer Conferences at the 2013 International Society of Geriatric Oncology conference in October. To view the full interview and others, visit ecancer at http://www.ecancer.org. ecancer is an online oncology channel supported by the ECMS Foundation (ecancermedicalscience). The Foundation was established by Professor Umberto Veronesi and Professor Gordon McVie as an independent, not-for-profit organisation with charitable status to fund the speedy dissemination of cancer information. ecancer is Published by Cancer Intelligence Ltd, England and Wales.

a


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SIOG 2013 Annual Conference are going to come about as a consequence of an aging population.

Do you work as part of a multidisciplinary team? Unfortunately, there aren’t as many of these types of clinical teams as are needed. But ideally (and in our program), we have geriatricians who work with oncologists who work with nurses and social workers and pharmacists, all of whom are geared to the care of the older patient. Everybody Harvey J. Cohen, MD, is Walter Kemper Professor of Medicine, Director of the Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina

can weigh in with their expertise and come up with the best plan for both the medical treatment and social treatment [needed] in the care of the patient.

Do nurses need to be specialized when working with older patients? It’s much like medicine in general. Certainly, in theory, all physicians should be able to deal with older patients as well, but many physicians haven’t been trained to be alert to specific characteristics. [For example,] older people may need specific attention to the disorders they get. And the same is true in nursing. So ideally we would like to have at least some people on these teams who

have geriatric nursing experience as well as oncology nursing experience. Unfortunately, the workforce in those areas is diminishing, so that’s another cause of substantial concern: having the appropriate workforce and the appropriately trained workforce.

Do you see a change in the number of older patients in clinical trials? Traditionally, older people have not been [enrolled] in [clinical trials] because of age exclusions. More recently, those exclusions have been removed, but there are still relatively few [older patients] represented, in part because they just aren’t referred for entry into these trials. Many older people don’t get to the

oncologist, who is usually the route for entry into these trials. This is something that is of substantial concern and one of the actions that the IOM called for— that is, increased attention to enrolling older people, roughly in proportion to their presence in the population in clinical trials. Hopefully, there will be some change on the horizon, but we will have to wait and see. n

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

Reference 1. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Institute of Medicine. September 10, 2013. Available at www.iom. edu.

Novel BRAF Fusions Identified in ‘Pan-Negative’ Melanomas Subset May Be Sensitive to MEK Inhibition

Journal Spotlight

By Jo Cavallo

A

study by Sosman et al has identified two novel BRAF fusions in melanomas previously considered to be negative for molecular targets. In addition, these “pan-negative” melanomas were found to be sensitive to MEK inhibitors. According to the study, BRAF fusions define a new molecular subset of melanoma, potentially comprising between 4% and 8% of pan-negative cases. The study was published recently in Clinical Cancer Research.1 The researchers used the FoundationOne platform to perform next-generation sequencing analysis on a melanoma sample from one of their patients and identified a fusion between two genes,  PAPSS1 and BRAF, which they called PAPSS1-BRAF, in a pan-negative melanoma. They then analyzed melanomas from an additional 51 patients, 24 of which were pan-negative. In one of the pan-negative samples, the research-

ers identified a second novel BRAF fusion, TRIM24-BRAF. “About 35% of melanomas are, as of today, considered pan-negative, which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ, and GNA11,” said study author Jeffrey A. Sosman, MD, Professor of Medicine at

Study Findings Additional studies in the laboratory revealed that both BRAF fusions activated the mitogen-activated protein kinase (MAPK) signaling pathway in the cancer cells. The investigators then treated these fusionbearing cells with either the BRAF inhibitor vemurafenib (Zelboraf ) or

Currently, there is immense value in identifying novel mutations in untreatable cancers because many of them are clinically relevant. —Jeffrey A. Sosman, MD

Vanderbilt-Ingram Cancer Center, in a statement. “We have been interested in looking at patients whose tumors have none of these driver mutations to see what their tumors do have that can be targeted therapeutically.”

Novel BRAF Fusions in Melanoma Subset ■ Researchers have identified two novel BRAF fusions in a subset of melanomas previously considered to be negative for molecular targets. ■ Melanomas with the novel BRAF fusions, PAPSS1-BRAF and TRIM24-BRAF, may be sensitive to MEK inhibition. ■ BRAF fusions define a new molecular subset of melanoma, potentially comprising between 4% and 8% of pan-negative cases.

trametinib (Mekinist), which inhibits MEK, a protein in the MAPK signaling pathway. They found that signaling induced by the BRAF fusions was not responsive to vemurafenib but could be inhibited by trametinib, leading them to conclude that the novel fusions they identified could make melanoma cells harboring them responsive to MEK inhibitor therapies or assist in selecting patients for MEK-directed therapy. “Currently, there is immense value in identifying novel mutations in untreatable cancers because many of them are clinically relevant, which means they may be sensitive to drugs

that are either being developed or are already FDA approved,” said Dr. Sosman in a statement. “Our data support the idea that ‘pan-negative’ cancers are not truly pan-negative.” The study authors concluded, “Collectively, these biochemical and genetic data define an additional molecular subset of melanoma that should be routinely screened for in the clinic, and knowledge about BRAF fusions in melanoma may provide insights into the mechanism of responses to treatment with an expanding list of available kinase inhibitors.” n Dr. Sosman and William Pao, MD, PhD, of Vanderbilt-Ingram Cancer Center, are the corresponding authors for the Clinical Cancer Research article.

Disclosure: Dr. Sosman is on the advisory board for GlaxoSmithKline PLC. The study was funded by the Stand Up To Cancer Melanoma Dream Team, the James C. Bradford Family Foundation, the American Cancer Society, the National Cancer Institute, a Stand Up To Cancer Innovative Research Grant, and the Joanna M. Nicolay Melanoma Foundation 2013 Research Scholar Award.

Reference 1. Hutchinson KE, Lipson D, Stephens PJ: BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition. Clin Cancer Res 19: 6696, 2013.


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AACR International Conference Breast Cancer Screening

Risk-Prediction Models

continued from page 1

Research on breast cancer risk models has been underway for years. The earliest and probably best known model, developed by Mitchell Gail at the NCI, is based on a woman’s medical and family history of breast cancer, previous biopsies, and reproductive history including age at menarche. Race was added to the Gail Model after research showed that African Americans were at increased risk. More recently developed models have added other factors such as breast density (BCSC model), and body mass index, alcohol use, and age at menopause (Rosner-Colditz model). Researchers continue to investigate these factors as well as a range of others, including genetic variants, sex hormone levels, types of breast density, biopsy findings, and combinations of various risk factors.

ing with more sensitive imaging modalities. Women with low risk could be screened less often and avoid the potential harms, such as the falsepositives that lead to unnecessary biopsies.

Current Guidelines Current mammography guidelines focus on age, with major national organizations issuing opposing recommendations; some say to begin at age 40, some say 50. But now many studies, like those presented at the AACR prevention meeting, suggest that the controversy may give way to an approach based less on age and more on an expanded list of risk factors that are emerging from research centers around the country.

Personalized Recommendations “The randomized trials [of mammography] were performed according to age at trial entry, and since randomized controlled trial results are considered the gold standard, recommendations for mammography have primarily been based on age,” said Dr. Kerlikowske. “But people in their 40s can have the risk of a 50-year-old, and some people in their 50s are actually at very low risk,” she said. The San Francisco Mammography Registry is one of seven centers in the Breast Cancer Surveillance Consortium (BCSC), a National Cancer Institute (NCI)-funded network of mammography registries linked to pathology and/or tumor outcomes. One BCSC focus is identifying and validating risk factors and risk models that could help personalize screening recommendations. “We’re now able to move the discussion about who should be screened to a more risk-specific context, trying to identify people who will really benefit from screening and those who would not benefit—for whom the harms would outweigh the benefits,” said Dr. Kerlikowske, who is also Principal Investigator of the San Francisco Mammography Registry.

Risk-Based Breast Cancer Screening ■ Risk-based breast cancer screening would tailor screening recommendations to a woman’s risk profile; those with higher-risk profiles could be screened earlier and more often. ■ Determining whether risk factors like breast density, sex hormone levels, and genetic variants should be added to current, standard risk-prediction models is an active area of research. ■ Part of this effort is learning which women would benefit from which imaging modalities, depending on their risk profiles.

that included mammographic density and genetic factors.”

Breast Density and Imaging Up to now, mammographic breast density has been one of the most studied risk factors. Hundreds of studies have shown that it’s a factor in both short-term and long-term risk, Dr. Kerlikowske said in an interview. In

The improvement in prediction when adding circulating hormone levels was better than the improvement observed by other studies that included mammographic density and genetic factors. —Shelley S. Tworoger, PhD

In the hormone study presented at the AACR meeting, Shelley S. Tworoger, PhD,1 Associate Professor in the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, and her colleagues looked at levels of half a dozen sex hormones in 437 postmenopausal women with invasive breast cancer and 770 matching controls in the Nurses’ Health Study. Using blood samples taken before diagnosis, they analyzed whether any of the hormones improved prediction of invasive breast cancer when added to either the Gail or the Rosner-Colditz risk model. They found that measuring estrone sulfate, testosterone, and prolactin levels offered the biggest improvement in risk prediction. Dr. Tworoger said in a statement that “the improvement in prediction when adding circulating hormone levels was better than the improvement observed by other studies

the short term, it plays a role because it makes it harder to see tumors with standard mammography. In the long term, it appears to heighten biologic risk, although why some women with dense breasts develop cancer and others don’t remains unknown. “Breast density is not all vanilla,” she said. “Most women with high breast density don’t develop breast cancer, and understanding what type of breast density contributes to cancer development could improve risk prediction.” The awareness that mammography is not equally sensitive in all women has raised new questions about the best imaging modalities to use with different risk profiles; MRI is the most sensitive modality, but other options, such as ultrasound, tomosynthesis, and computed tomography, are under study. One focus of the BCSC is how to add to or improve on its current risk model by showing which risk profiles would benefit from other imaging modalities.

Single Nucleotide Polymorphisms Other leading candidates to add to risk prediction models are the genetic variants known as single nucleotide polymorphisms or SNPs, some of which are known to contribute modestly to breast cancer risk. In one large NCI study, published in The New England Journal of Medicine in 2010,3 a panel of 10 SNPs, added to the Gail model, did a slightly better job of predicting which women would develop breast cancer than the standard model alone. The researchers, led by Sholom Wacholder, PhD, Senior Investigator in the Division of Cancer Epidemiology & Genetics at NCI, concluded that the improvement was too small to influence clinical decision-making. But research on SNPs continues. Dr. Kerlikowske said that the BCSC is looking at 76 SNPs in combination with breast density. Also under investigation by the consortium are sex hormone levels, SNPs, and breast density combined. Other candidates for further study are benign biopsy findings such as hyperplasia, she said. n

Disclosure: Drs. Kerlikowske, Tworoger, and Wacholder reported no potential conflicts of interest.

References 1. Tworoger SS: Inclusion of endogenous hormone levels in risk prediction models of postmenopausal breast cancer. 12th Annual AACR International Conference on Frontiers in Cancer Prevention Research. Presented October 29, 2013. 2. Kerlikowske KM: Risk-based breast cancer screening. 12th Annual AACR International Conference on Frontiers in Cancer Prevention Research. Presented October 29, 2013. 3. Wacholder S, Hartge P, Prentice R, et al: Performance of common genetic variants in breast-cancer risk models. N Engl J Med 362:986-993, 2010.


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FDA Update

Philips Receives FDA Clearance for Spectral Breast Density Measurement Application

R

oyal Philips has announced that that it has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for the Spectral Breast Density Management Ap-

plication for its MicroDose SI full-field digital mammography system. The application is the first spectral breast density measurement tool, meaning adipose and glandular tissue can be dif-

ferentiated to accurately measure volumetric breast density. The most frequently used methodology to determine breast density is a visual analysis of an image of the breast,

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FDA Update

but this is often highly subjective and several radiologists may allocate a different breast density score for the same image. Rather than estimating density, the spectral breast density measurement, obtained during a standard, low-dose MicroDose SI mammogram, allows breast density to be objectively measured.

How It Works The Spectral Breast Density Measurement Application works by independently measuring the glandularity and thickness in each pixel of the image to objectively calculate the total volume and volumetric percentage of glandular tissue in the breast. Once the calculations are completed the exami-

nation is automatically assigned a MicroDose density score that correlates to the breast imaging-reporting and data system (BI-RADS), the manual method for determining breast density. The measurement is displayed on the review workstation together in the DICOM tag of the acquired image and exported for display in a DICOM

structured report. At the recent annual meeting of the Radiological Society of North America (RSNA) in Chicago, Sabee Molloi, MD, Professor of Radiological Sciences, University of California-Irvine School of Medicine, presented data showing that spectral mammography may offer quantification of volumetric breast density with excellent precision and could eliminate inter-reader variability in the breast density scoring. Recent legislation passed in more than a dozen states has made it mandatory for clinicians to report breast density to their patients. The Spectral Breast Density Measurement Application will allow clinicians to comply with this legislation and deliver a more personalized examination to each woman. n

Contact

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

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Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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

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

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


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San Antonio Breast Cancer Symposium Breast Cancer

Seven Studies at SABCS Make Dr. Jame Abraham’s List of ‘Practice-Changing’ Talks By Caroline Helwick

F

rom December 10 to 14, the American Association for Cancer Research, the Cancer Therapy & Research Center at The University of Texas Health Sciences Center at San Antonio,

Jame Abraham, MD

and Baylor College of Medicine once again hosted the San Antonio Breast Cancer Symposium (SABCS), presenting state-of-the-art breast cancer research to an audience of more than 7,000 clinicians, investigators, and advocates. Jame Abraham, MD, Director of the Breast Oncology Program at the Taussig Cancer Institute of the Cleveland Clinic in Ohio, told The ASCO Post what he considers the biggest news to emerge from the meeting. He comments on each of these studies below. Be on the lookout for full coverage of these seven “practice-changing” studies in this and future issues of The ASCO Post. 1. Carboplatin as a neoadjuvant therapy for triple-negative breast cancer Patients with triple-negative breast cancer who received a regimen that included carboplatin had a 60% rate of pathologic complete response, vs 46% for those not receiving this drug—a highly significant increase (odds ratio = 1.76, P = .0018).1 “The role of carboplatin in triple-negative breast cancer has been debated for many years. Finally, we have a randomized study showing that carboplatin will definitely increase the pathologic complete response rate. This study will potentially change how we treat patients with triplenegative disease neoadjuvantly. Of course, we need to wait for long-term data, but at this point, pathologic complete response seems to be a good surrogate endpoint.” 2. Anastrozole for breast cancer prevention in postmenopausal highrisk patients In the IBIS-II trial, 5 years of anastrozole therapy reduced the risk of pri-

mary breast cancer by more than 50% in women at high risk of developing the disease.2 “With the results of IBIS-II, we can clearly say that aromatase inhibitors are as good as, or better than, SERMs [selective estrogen receptor modulators] in preventing breast cancer in postmenopausal women who are at high risk for the disease. Granted, it can be a tough sell. If you look at the penetration of tamoxifen within the population of high-risk patients who are eligible, it’s only about 5% to 10% for prevention at this time. But for the motivated patient at high risk, and after a discussion of the risks and benefits, anastrozole can be a good choice—especially compared to tamoxifen—because some of the major side effects (endometrial cancer and deep-vein thrombosis, for example) are less common. It was also interesting that patients on anastrozole in this trial had a lower incidence of any malignancy, not just breast cancer.” 3. The investigational PARP inhibitor veliparib for triple-negative breast cancer The I-SPY 2 trial uses an adaptive design to move promising drugs forward in clinical development. In a phase II study evaluating veliparib plus carboplatin for neoadjuvant therapy, the pathologic complete response rate was 52%, vs 26% with chemotherapy alone, in patients with triple-negative breast cancer.3 “The I-SPY trial is important from many different angles. One, the novel innovative trial design shows that we can initiate and conduct studies rapidly, and we can select patients based on their molecular profile and drugs based on their targets. Based on early findings, we can exclude drugs that don’t perform well, or advance the promising drugs in further studies. In this particular study, after disappointing results from other PARP inhibitors (eg, iniparib), we have some promising data, especially for triple-negative breast cancer, and this is exciting. Further phase III studies of veliparib will define its role.” 4. Role of bisphosphonates in postmenopausal women with early breast cancer The adjuvant use of bisphosphonates reduced the risk of bone recurrence by 34%, and the risk of breast cancer death by 17%.4 “After conflicting reports from large

randomized controlled trials, especially AZURE and the ABCSG-12 trial, we have an Oxford Overview analysis that clearly shows the benefit of adjuvant bisphosphonates—especially zoledronic acid—in postmenopausal women. Clearly, this is a practice-changing finding that can be immediately applied in the clinic. The finding that bisphosphonates are highly effective in low-estrogen states is consistent with previously published ABCSG-12 data.” 5. Role of exercise in managing arthralgias induced by aromatase inhibitors Women randomly assigned to a supervised moderate-intensity exercise program had a 20% reduction in pain scores at 12 months, vs 3% for the usual-care group.5 “The systematic incorporation of exercise as part of the care of patients receiving adjuvant aromatase inhibitors decreased musculoskeletal events and, therefore, should increase compliance with treatment and potentially improve survival. Comprehensive survivorship programs should include an exercise component. It’s extremely important, because we know that 30% of patients discontinue aromatase inhibitors due to side effects.” 6. Role of adjuvant radiation therapy in patients who are older than 65 years Older women with hormone receptor–positive breast cancer can omit whole-breast radiation therapy after breast-conserving surgery and adjuvant hormone therapy. An exploratory analysis by hormone receptor status showed recurrence rates in estrogen receptor–positive patients to be 3.2% without radiotherapy and 0.8% with radiotherapy, but there was no survival difference.6 “This study shows that radiation can be avoided in patients aged 65 and older. There was no added benefit to radiotherapy, over surgery alone, especially in women with estrogen receptor–positive tumors. There are benefits to avoiding radiation, and these findings are practice-changing.” 7. Affordability and adherence to treatment A high nonadherence rate (44%) was observed among patients whose copayment exceeded $20 a month.7 Adherence was higher (66%) with generic as compared with branded aromatase inhibitors.

“We could conduct many randomized trials and develop many new drugs, but if our patients cannot afford the medicines, none of these steps will help them. The patient’s copay and other out-of-pocket expenses are key factors in initiating cancer treatment. This study makes a case for greater access to medicine for all patients with cancer. The cost of drugs (and insurance coverage) do matter. Physicians should be sensitive to the ‘financial toxicity’ of their patient’s treatment.”

Disappointments as Well Most studies presented at the meeting were “winners,” according to Dr. Abraham, but not all. “Unfortunately, there were a few disappointments, and interestingly, two of these studies continued the theme of the failure of antiVEGF [vascular endothelial growth factor] therapy in breast cancer,” he noted. Not surprisingly, the phase III BETH trial, which evaluated the addition of bevacizumab (Avastin) to adjuvant chemotherapy and trastuzumab (Herceptin),8 was negative, as was the phase III ROSE/ TRIO-12 trial, which evaluated the addition of a new anti-VEGF antibody, ramucirumab, to first-line docetaxel chemotherapy in metastatic breast cancer.9 “We have been hoping that one of these agents would be effective, but so far they have not been,” Dr. Abraham said. “Hopefully, ongoing trials such as the MERiDiAN study will help us find biomarkers that can identify patients who will derive benefit from VEGFtargeted agents.” n

Disclosure: Dr. Abraham is an unpaid consultant for Pfizer.

References 1. Sikov WM, Berry DA, Perou CM, et al: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC on pathologic complete response rates in triple-negative breast cancer: CALGB 40603. 2013 San Antonio Breast Cancer Symposium. Abstract S5-01. Presented December 13, 2013. 2. Cuzick J, Sestak I, Forbes JF, et al: First results of the International Breast cancer Intervention Study II (IBIS-II): A multicentre prevention trial of anastrozole versus placebo in postmenopausal women at increased risk of developing breast cancer. 2013 San Antonio Breast Cancer Sympo-


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San Antonio Breast Cancer Symposium Breast Cancer

HER2-Positive Breast Cancer Patients With Small Tumors Benefit From Low-Toxicity Regimen By Caroline Helwick

T

here may be a benefit for treating small HER2-positive tumors—a breast cancer subset for whom treatment recommendations have not been established but for whom there is still risk of recurrence—and this can be done with little toxicity, according to a multicenter study presented at the 2013 San Antonio Breast Cancer Symposium.1

HER2 treatment for node-negative patients have included few subjects with tumors measuring < 2 cm and virtually none with tumors ≤ 1 cm, a group for whom treatment has been debated. The findings of the current study offer, for the first time, a set of standard treatment guidelines for recurrence prevention in this group of patients, according to Dr. Winer.

The development of effective targeted therapies provides the opportunity not only to improve outcomes, but to back off toxicity by limiting some of the chemotherapy. The challenge now is to determine in whom a completely chemotherapyfree regimen might be a possibility. —Eric P. Winer, MD

“Smaller, HER2-positive, nodenegative breast cancers are thought to have a sufficiently high chance of recurring that many doctors have offered patients a combination of chemotherapy and trastuzumab [Herceptin] to reduce that risk,” said senior author Eric P. Winer, MD, Chief of the Division of Women’s Cancers in the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute, Boston. “But, as this approach had not been tested in many women with smaller tumors, we have lacked a standard approach to preventing recurrence in this group.” That may be largely because previous studies of chemotherapy plus anti-

APT Trial

sium. Abstract S3-01. Presented December 12, 2013. 3. Rugo HS, Olopade O, DeMichele A, et al: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 trial. 2013 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 13, 2013. 4. Coleman R, Gnant M, Paterson A, et al: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A metaanalysis of individual patient data from

randomised trials. 2013 San Antonio Breast Cancer Symposium. Abstract S4-07. Presented December 12, 2013. 5. Irwin ML, Cartmel B, Gross C, et al: Randomized trial of exercise vs. usual care on aromatase inhibitor-associated arthralgias in women with breast cancer: The hormones and physical exercise (HOPE) study. 2013 San Antonio Breast Cancer Symposium. Abstract S3-03. Presented December 12, 2013. 6. Kunkler IH, Williams LW, Jack W, et al: The PRIME 2 trial: Wide local excision and adjuvant hormonal therapy ± postop-

The Adjuvant Paclitaxel and Trastuzumab (APT) study of 406 women with HER2-positive, node-negative tumors ≤ 3 cm was presented at the San Antonio Breast Cancer Symposium by Sara M. Tolaney, MD, MPH, a medical oncologist at Dana-Farber Cancer

Institute, who explained the need to balance risks and benefits in a group of patients who will likely derive a small absolute treatment benefit. “In balancing the risks and benefits of treatment, the development of regimens with lower degrees of toxicity is

particularly important for this patient population,” she said. The investigators, therefore, designed a more tolerable chemotherapy regimen than is often given. Patients received only paclitaxel at continued on page 33

EXPERT POINT OF VIEW

D

ebu Tripathy, MD, Professor of Medicine, Co-Leader of the Women’s Cancer Program, and the Priscilla and Art Ulene Chair in Women’s Cancer at the University of Southern California Norris Cancer Center, Los Angeles, commented on the APT study for The ASCO Post. “In treating early-stage HER2-positive breast cancer, we know that chemotherapy plus trastuzumab [Herceptin] lowers the risk of recurrence. Debu Tripathy, MD But when the risk itself is very low for small nodenegative tumors, the question is, at what point is it not worth it, because there are side effects,” he said. Dr. Tripathy noted that most trastuzumab trials included few tumors less than 1 or 2 cm, “so we don’t know much about the benefit of treatment in those situations.” Even studies attempting to estimate benefit are not felt to be very accurate, he said.

Absence of Doxorubicin Since this is a small population of patients who have a favorable outcome, and since accruing HER2-positive patients to a placebo arm would be impossible, a properly powered randomized trial was out of the question. Instead, Dr. Winer and his team designed a single-arm study to define outcomes in a uniformly treated patient cohort, without a comparator but with an appreciation of the expected rate of events in such a population. The weekly paclitaxel was standard treatment, but the omission of doxorubicin was not. “Did the absence of doxorubicin affect outcomes? We don’t know, but the number of events is low enough that it really doesn’t matter. The outcomes surpassed their expectations,” Dr. Tripathy pointed out, concluding that the research points to “a treatment option—a ‘niche regimen’—for these smaller tumors.” n

Disclosure: Dr. Tripathy’s institution (University of Southern California) receives payment under contract for clinical research studies from Genentech/Roche. Sara M. Tolaney, MD, MPH

erative whole breast irradiation in women ≥ 65 years with early breast cancer managed by breast conservation. 2013 San Antonio Breast Cancer Symposium. Abstract S2-01. Presented December 11, 2013. 7. Hershman DL, Tsui J, Meyer JW, et al: The change from brand-name to generic aromatase inhibitors and hormone therapy adherence for early stage breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S3-04. Presented December 12, 2013. 8. Slamon DJ, Swain SM, Buyse M, et al: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy

and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-03. Presented December 11, 2013. 9. Mackey JR, Ramos-Vazquez M, Lipatov O, et al: Primary results of ROSE/ TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 13, 2013.


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 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: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva (see Warnings and Precautions). Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva (see Warnings and Precautions and Adverse Reactions). WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently (see Contraindications and Adverse Reactions). 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 Contraindications, Adverse Reactions, and Patient Counseling Information in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. 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 (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. 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. EMBRyO-FETAL TOxICITy: 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). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time (see Use in Specific Populations). ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia (see Warnings and Precautions) • Osteonecrosis of the Jaw (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. 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 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 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. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

xgeva n = 2841 %

Zoledronic Acid n = 2836 %

GASTROINTESTINAL Nausea Diarrhea

31 20

32 19

GENERAL Fatigue/ Asthenia

45

46

INVESTIGATIONS Hypocalcemiab Hypophosphatemiab

18 32

9 20

NEUROLOGICAL Headache

13

14

RESPIRATORy Dyspnea Cough

21 15

18 15

Body System

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b 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 (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • 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% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in Specific Populations). • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53) (See Warnings and Precautions). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva (see Warnings and Precautions). Postmarketing Experience. Because postmarketing 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. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result 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 antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted 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 was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology in full Prescribing Information). USE IN SPECIFIC POPULATIONS: Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. 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. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. 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. a

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 growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and 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; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology in full Prescribing Information). 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 decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology in full Prescribing Information). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates 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) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Specific Populations). Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology in full Prescribing Information). Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva [see Use in Specific Populations and Patient Counseling Information]. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Contraindications, 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) • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy (see Contraindications and Warnings and Precautions) • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2013 Amgen Inc. All rights reserved. Printed in USA. 68257-R4-V1


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San Antonio Breast Cancer Symposium Breast Cancer

Can Postoperative Radiotherapy Be Avoided in Older Women With Early Breast Cancer and High Estrogen Receptor Expression? By Alice Goodman

A

more conservative approach that avoids radiation therapy seems to be a reasonable option for a subgroup of older women with hormone receptor– positive breast cancer at low risk of recurrence. Overall outcomes were similar with or without radiation in older women with hormone receptor–positive breast cancer in the PRIME II trial. Results suggest that radiation can be safely omitted in women whose tumors have high levels of estrogen receptor expression, accord-

ing to a presentation at the 2013 San Antonio Breast Cancer Symposium.1 “Postoperative radiation remains the standard of care for early breast cancer treated with breast-conserving surgery, irrespective of factors such as age. Older patients represent about 50% of all newly diagnosed early breast cancer, and these cancers are often relatively benign. Radiotherapy may represent overtreatment, and it is associated with risks. Also there is sparse level

Our results imply that quite a large group of women can benefit from the omission of radiotherapy. —Ian Kunkler, FRCR

Low-Toxicity Regimen continued from page 29

80 mg/m2 weekly plus trastuzumab weekly at 2  mg/kg for 12 weeks, followed by 9 months of trastuzumab every 3 weeks at 6 mg/ kg alone. The study was a nonrandomized prospective trial to define the outcomes in a uniformly treated cohort based on the fact that “a prospective randomized trial of trastuzumab-based therapy is likely not feasible,” Dr. Tolaney said.

Key Findings After a median follow-up of 3.6 years, only 10 of 406 patients experienced a recurrence or death, accounting for 2.5% of the population. There were only four local recurrences (0.9%). Study patients developed three new contralateral primary breast cancers (0.7%), all HER2-negative, and two distant recurrences (0.5%). Disease-free survival at 3 years was 98.7% (P  <  .0001). By hormone receptor status, disease-free survival rates were 98.5% in receptor-positive patients and 99.2% in receptor-negative ­patients. The recurrence-free survival rate (invasive locoregional recurrence, distant recurrence, death from breast can-

cer) was 99.2%, Dr. Tolaney reported. Few adverse events were noted. Only two patients (0.5%) developed symptomatic congestive heart failure, and both cases resolved after discon-

Postoperative Radiotherapy in Breast Cancer Reconsidered ■■ Postoperative radiation is the standard of care for all patients who undergo breast-conserving surgery and endocrine therapy. ■■ The PRIME II study has found that postoperative whole-breast radiation therapy may be avoided in some older women with high-estrogen receptor levels for whom adjuvant endocrine therapy is planned. ■■ For patients with low levels of estrogen receptor expression, radiation should remain standard of care.

I evidence for radiation in older women,” said lead author, Ian Kunkler, FRCR, Edinburgh Cancer Research Center, University of Edinburgh, Scotland, UK. “Our study shows that the proportion of women who will have a local recurrence without radiation is very small—under 5%.”

Study Details The multicenter PRIME II trial was conducted at 98 sites across six countries. The trial included 1,326 medically paclitaxel plus trastuzumab can be considered “a reasonable and appealing approach for the majority of patients with stage I HER2-positive breast cancer.”

Adjuvant Therapy in Stage I Breast Cancer ■■ Women with HER2-positive, node-negative breast cancer tumors ≤ 3 cm appeared to derive benefit from adjuvant treatment with weekly paclitaxel plus trastuzumab. ■■ Treatment of these small tumors has been debated; while very small (T1a) tumors probably would still not warrant treatment, the study confirms that treatment with a low-toxicity regimen (lacking doxorubicin) benefits many patients.

tinuation of trastuzumab. Asymptomatic declines in left-ventricular ejection fraction were observed in 13 patients (3.2%), and 11 patients were able to resume trastuzumab after a treatment interruption. Dr. Tolaney acknowledged that the study has limitations. It was a singlearm, nonrandomized trial, and about 20% of enrolled patients had T1a tumors that already have a very favorable prognosis. Also, two-thirds had hormone receptor–positive tumors, and this may be associated with late recurrence. Nevertheless, she suggested that

Practice-Changing Results Dr. Winer suggested that the results were practice-changing. For this population, the paclitaxel/trastuzumab doublet “should be considered one of the standard strategies for recurrence prevention,” he said. “This doesn’t mean that every single patient with node-negative HER2positive disease has to be treated with trastuzumab and chemotherapy, and there are patients with T1a tumors who almost certainly should not be treated systemically,” he said in an interview with The ASCO Post. The T1a population accounted for

fit patients aged 65 or older with hormone receptor–positive, node-negative, T1–2 breast cancer (up to 3 cm), clear surgical margins, and treated with adjuvant endocrine therapy. All patients had clear surgical margins of at least 1 mm. Either grade 3 tumors or lymphovascular invasion was allowed (but not both). Patients were randomly assigned to receive whole-breast irradiation (n = 658) at 40 to 50 Gy or no whole-breast irradiation (n = 668). continued on page 34

20% of subjects, while 9% had relatively large T2 tumors. “This was not just a population of patients with tumors less than 1 cm, and in spite of that, the outcome was very favorable,” he noted. “We think that for most women with stage I HER2-positive breast cancer, trastuzumab plus paclitaxel is an entirely reasonable, and certainly appealing, regimen because of its lowtoxicity profile,” he maintained. The APT study also “speaks to a larger point,” he said, “and that is the development of effective targeted therapies provides the opportunity not only to improve outcomes, but to back off toxicity by limiting some of the chemotherapy. The challenge now is to determine in whom a completely chemotherapy-free regimen might be a possibility.” n Disclosure: Dr. Winer receives research funding from Genentech/Roche. Dr. Tolaney reported no potential conflicts of interest.

Reference 1. Tolaney SM, Barry WT, Dang CT, et al: A phase II study of adjuvant paclitaxel and trastuzumab (APT) trial for nodenegative, HER2-positive breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 11, 2013.


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San Antonio Breast Cancer Symposium Postoperative Radiotherapy in Breast Cancer continued from page 33

The difference in 5-year ipsilateral breast cancer recurrence favored radiotherapy—6 recurrences (1.3%) with whole-breast irradiation vs 26 recurrences (4.1%) with no whole-breast irradiation (P = .002)—but Dr. Kunkler noted that the absolute difference of 2.8% was very small. Five-year overall survival was 94.2% for whole-breast irradiation vs 93.8% for no whole-breast irradiation, for an even smaller absolute difference of 0.4% (P = .24). An unplanned exploratory analysis of the effect of estrogen receptor status on local recurrence showed that high levels of estrogen receptor expression (Allred score 7/8) were associated with a very modest gain in local control (2.4%) in women treated with whole breast irradiation compared to those in whom it was omitted (0.8% vs 3.2%, respectively, P = .003). Among those with low levels of estrogen receptor expression (Allred score 2–6), the local recurrence rates

were 11.1% without radiotherapy vs 0 with radiotherapy (P = .025). In a multivariate analysis, both no radiotherapy and low estrogen receptor expression were significantly associated with recurrence. These results suggest that postoperative whole-breast irradiation can be safely omitted in some women aged 65 or older with node-negative, hormone receptor–positive breast cancer, tumors measuring up to 3 cm, and high estrogen receptor expression. “However, the data suggest that radiation can not be safely omitted in women whose tumors have low estrogen receptor expression,” Dr. Kunkler clarified.

‘Broadly Generalizable’ Findings “These results are broadly generalizable. This study is very likely to change practice within the United Kingdom. Older patients find radiotherapy burdensome. Radiotherapy has its own health risks, particularly in the elderly,

as well as the inconvenience of travel for daily treatment over 3 or 4 weeks. Our results imply that quite a large group of women can benefit from the omission of radiotherapy,” Dr. Kunkler stated.” All patients in PRIME II received hormonal therapy and breast-conserving surgery as part of management. During the question-and-answer session after the presentation, Steven Vogl, MD, a medical oncologist in the Bronx, New York, said that compliance with hormone therapy is important, and there was no way to know whether patients were actually taking their hormone therapy from the data presented. Dr. Kunkler said those data were not yet analyzed but would be included in the journal publication of the study. n

Disclosure: This study was funded by the Chief Scientist’s Office for Scotland. Dr. Kunkler declared no potential conflicts of interest.

Reference 1. Kunkler IH, Williams LW, Jack W, et al: The PRIME II trial: Wide local excision and adjuvant hormonal therapy ± postop-

EXPERT POINT OF VIEW

“O

ver time, we have been doing less radiation and less surgery to control local disease, mainly because our systemic therapies (endocrine therapy, aromatase inhibitors, and chemotherapy) are killing cancer cells and obviating the need for local therapy. This study is likely to be practice-changing,” said Kent Osborne, MD, Director of the Lester and Sue Smith Cancer Center at Baylor College of Medicine in Houston. Disclosure: Dr. Osborne reported no potential conflicts of interest.

erative whole breast irradiation in women ≥ 65 years with early breast cancer managed by breast conservation. 2013 San Antonio Breast Cancer Symposium. Abstract S2-01. Presented December 11, 2013.

Younger Women With Younger Children Less Likely to Receive Radiation Therapy After Breast-Conserving Surgery for Breast Cancer By Matthew Stenger

I

n a study reported in the Journal of the National Cancer Institute, Pan et al assessed factors associated with noncompliance with recommended radiation therapy following breastconserving surgery for breast cancer.1 A primary factor in underuse of radiation therapy was younger patients having children aged < 7 years.

Study Details The study involved use of the MarketScan Database to identify women aged 20 to 64 years with nonmetastatic breast cancer who had breast-conserving surgery between January 2004 and December 2009 and had continuous insurance enrollment 12 months before and Ya-Chen Tina Shih, PhD, of University of Chicago, is the corresponding author for the Journal of the National Cancer Institute article.

after the date of surgery. Patients who had radiation claims within 1 year after surgery were considered compliant.

Younger Children and Younger Women Overall, 18,120 (86%) of 21,008 patients received radiation therapy. Compared with women with ≥ 1 child aged < 7 years, those with children aged 7 to 12 years (odds ratio [OR] = 1.32, P = .02), those with children aged 13 to 17 years (OR = 1.41, P = .002), and those with no children or children aged ≥ 18 years (OR = 1.38, P = .001) were significantly more likely to be compliant with radiation therapy on logistic regression analysis. Compared with women aged ≤ 50 years, those aged 51 to 55 years (OR = 1.22, P = .001), 55 to 60 years (OR = 1.38, P < .001), and 61 to 64 years (OR = 1.28, P < .001) were significantly more likely to receive radiation therapy.

Among patients aged ≤ 50 years, those with ≤ 1 child aged < 7 years were significantly less likely to receive radiation therapy than those with children aged 7 to 12 years (OR = 1.40, 95% confidence interval [CI] =1.10–1.78), those with children aged 13 to 17 years (OR = 1.57, 95% CI = 1.23–2.01), and those with no children or children aged ≥ 18 years (OR = 1.40, 95% CI = 1.14–1.74). Although odds ratios were generally higher for family status of children aged ≥ 7 years vs < 7 years for women in older age groups, none were statistically significant.

Other Important Factors The investigators identified other important factors in radiation therapy compliance as including chemotherapy (OR   = 1.33, P < .001), imaging (OR = 1.57, P < .001), enrollment in health maintenance organizations or capitated preferred provider organizations (OR

= 0.70, P < .001), travel across census division to receive therapy (OR = 0.72, P < .001), and not being the primary holder of the insurance policy (OR = 1.20, P < .001). The investigators concluded, “Competing demands from child care can constitute a barrier to complete guideline-concordant breast cancer therapy. Younger patients may be confronted by unique challenges that warrant more attention in future research.” n

Disclosure: The study was supported by the Agency for Healthcare Research and Quality, University of Chicago Cancer Research Foundation Women’s Board, and Cancer Prevention & Research Institute of Texas.

Reference 1. Pan IW, Smith BD, Shih Y-CT: Factors contributing to underuse of radiation among younger women with breast cancer. J Natl Cancer Institute (early release online, December 7, 2013).


ASCOPost.com  |   JANUARY 15, 2014

PAGE 35

Journal Spotlight Gynecologic Oncology

Genetic Flaw That Drives Some Ovarian Cancers Identified

R

esearchers at Dana-Farber Cancer Institute, Boston, have identified an overactive gene that drives about one-third of high-grade serous ovarian tumors—the most common and malignant type of ovarian cancer.

The gene, GAB2, isn’t mutated or abnormal, but triggers cancerous cell growth because the gene has been amplified, the investigators report in the Proceedings of the National Academy of Sciences.1

When the amplified gene was inserted into normal ovarian and fallopian tube cells in the laboratory, it powerfully transformed them into cancer cells, said the researchers, led by William C. Hahn, MD, PhD, of

Dana-Farber and the Broad Institute of Harvard and MIT, who is the senior author of the report. The findings provide “strong evidence that GAB2 is a real oncogene—a driver of ovarian cancer,” Dr. Hahn said.

Innovative Screening Method Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and <1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and <2% thereafter [see Dosage and Administration (2)].

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be 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 GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3-4, and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of Pre-Existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic

8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those <75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) >30mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr<30mL/min. [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6, and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA™ [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

GAZYVA is a trademark of Genentech, Inc. 11/13 GAZ0002214500 © 2013 Genentech, Inc.

Dr. Hahn and his colleagues have devised a method for rapidly assessing the cancer-causing ability of large numbers of amplified genes. In the new study, they used data from The Cancer Genome Atlas to identify genes that were amplified in ovarian cancers. From these they selected 455 amplified genes for further ­testing. After inserting segments of the genes into cells in the laboratory and then injecting them into mice, the scientists found that 26 of the genes were able to form tumors. Of these, GAB2 had the greatest tumor-forming capability and in further experiments, the amplified GAB2 gene potently transformed normal ovarian and fallopian tube cells into cancer cells. Having successfully used the innovative screening method to identify the ovarian cancer oncogene, “This is a proof of principle that we can now systematically assess thousands of genes for their role in cancer on a large scale,” said Hahn.

Study Implications The researchers determined that amplification of the GAB2 gene in ovarian cancer cells triggers the PI3K signaling pathway. Moreover, their experiments showed that cells with abnormal PI3K signaling because of amplified GAB2 could be killed with experimental drugs that inhibit the PI3K pathway. Such inhibitors are currently being tested in a number of cancers. “This suggests that looking for GAB2 amplification in ovarian tumors could be helpful in identifying patients whose cancer may respond to PI3K inhibitors,” said Dr. Hahn. n Reference 1. Dunn GP, Cheung HW, Agarwalla PK, et al: In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene. Proc Natl Acad Sci USA. January 2, 2014 (early release online).


The ASCO Post  |   JANUARY 15, 2014

PAGE 36

JCO Spotlight Genitourinary Oncology

Tivozanib Improves Progression-Free but Not Overall Survival vs Sorafenib in Metastatic Renal Cell Carcinoma By Matthew Stenger

T

he investigational agent tivozanib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3. In a phase III trial reported in the Journal of Clinical Oncology by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC), and colleagues, tivozanib was found to improve progres-

62%). A greater proportion of sorafenib patients had better Eastern Cooperative Oncology Group (ECOG) performance status (0 in 54% vs 45%, P = .035). Seventy percent of patients in both groups had received no prior systemic treatment for metastatic disease, and 30% of both had received one prior treatment, with the predominant thera-

Further study of tivozanib is warranted to provide additional insights into the utility of tivozanib for the treatment of patients with metastatic renal cell carcinoma. —Robert J. Motzer, MD

sion-free survival but not overall survival and to exhibit a different toxicity profile when compared with sorafenib (Nexavar) as a first targeted therapy in patients with metastatic renal cell carcinoma.1

Study Details In this open-label trial, 517 patients with metastatic renal cell carcinoma with a clear cell component, prior nephrectomy, measurable disease, and no or only one prior therapy for metastatic renal cell carcinoma were randomly assigned to receive tivozanib at 1.5  mg/d for 3 weeks followed by 1 week off (n = 260) or sorafenib at 400  mg/d continuously. Prior VEGFtargeted therapy and mTOR inhibitors were not permitted. Hypertension for tivozanib and skin toxicity for sorafenib were managed according to specific guidelines. The primary endpoint was progression-free survival on independent review. Patients in the tivozanib and sorafenib groups were generally well matched for age (median, 59 years in both), sex (71% and 74% male), race/ethnicity (96% and 97% white), time from diagnosis to study entry (≥  1 year in 53% in both), most common sites of metastases (eg, lung in 82% and 79%, lymph nodes in 70% and 65%), number of involved organs (1 in 29% and 34%, > 2 in 33% and 25%), and MSKCC prognostic group (favorable in 27% and 34%, intermediate in 67% and

py (> 90% of patients) being interferon alfa. Prior adjuvant therapy had been given to 9% of patients in both groups. In total, 457 patients were from Central/Eastern Europe, 40 from North America/Western Europe, and 20 from South America/Asia.

Prolonged Progression-Free Survival Patients received tivozanib for a median duration of 12.0 months and sorafenib for 9.5 months at the data cutoff. Median progression-free survival was 11.9 months in the tivozanib group vs 9.1 months in the sorafenib group (hazard ratio [HR]  = 0.797, P = .042). Prespecified progression-free survival subgroup analyses based on baseline characteristics showed a consistent advantage with tivozanib treatment across subgroups. Significant advantages were observed among patients who were treatment-naive for metastatic disease (me-

dian, 12.7 vs 9.1 months, HR  = 0.756, P  =  .037), patients with ECOG performance status of 0 (14.8 vs 9.1 months, HR = 0.617, P = .004), and those in the MSKCC favorable prognostic group (16.7 vs 10.8, HR = 0.590, P = .018). Hazard ratios also significantly favored tivozanib among the 40 patients from North America/Western Europe and the 274 patients enrolled at ≥ 1 year from time of diagnosis. Overall response rates were 33.1% vs 23.3% (P = .014). A trend toward greater overall survival was observed for the sorafenib group (median, 28.8 vs 29.3 months, HR = 1.245, P = .105).

Subsequent Treatment A greater proportion of patients in the sorafenib group received subsequent therapy (65% vs 26%) including a nextline targeted therapy for renal cell carcinoma (63% vs 13%), with nearly all of the sorafenib patients receiving tivozanib (156 of 162, 61% of entire group) as part of a companion protocol that allowed crossover at progression. Subsequent therapies in the tivozanib group included VEGFR inhibitors (7%), mTOR inhibitors (6%), cytokines (5%), and radiotherapy (5%). Subsequent therapies apart from tivozanib in the sorafenib group included mTOR inhibitors (2%), cytokines (1%), and radiotherapy (1%). By region, next-line therapy was received by 23% of tivozanib patients and 64% of sorafenib patients from Central/ Eastern Europe, 59% and 78% of those from North America/Western Europe, and 33% and 82% of those from the rest of the world. In patients from North America/Western Europe, which had the greatest proportion of tivozanib patients receiving subsequent therapies, there was a trend toward increased over-

Tivozanib in Renal Cell Carcinoma ■■ Tivozanib was associated with improved progression-free survival, but not overall survival, and a different safety profile compared with sorafenib as initial targeted therapy for metastatic renal cell carcinoma. ■■ More patients in the sorafenib group received subsequent therapy, mostly tivozanib. ■■ Hypertension and dysphonia were more common with tivozanib, and hand-foot skin reaction and diarrhea were more common with sorafenib.

all survival in the tivozanib group (HR = 0.503, P = .195).

Safety Profiles Adverse events of any grade that were more common with tivozanib were hypertension (44% vs 34%) and dysphonia (21% vs 5%), and those more common with sorafenib were hand-foot skin reaction (54% vs 14%) and diarrhea (33% vs 23%). The most common grade 3 or 4 adverse events were hypertension (27%) and increased lipase (11%) in the tivozanib group and hypophosphatemia (26%), increased lipase (24%), hypertension (18%), and palmar-plantar erythrodysesthesia (17%) in the sorafenib group. Of deaths occurring within 30 days of the last dose of study drug, 13 in the tivozanib group and 12 in the sorafenib group were considered related to causes other than progressive disease. Dose reduction due to adverse events occurred in 14% of tivozanib patients and 43% of sorafenib patients (P  <  .001), treatment interruptions occurred in 19% and 36% (P  <  .001), and discontinuation due to treatmentrelated adverse events occurred in 4% and 5%. Dose reductions were most commonly due to hand-foot syndrome (2% vs 18%), diarrhea (1% vs 5%), and hypertension (2% vs 4%). Mean relative dose intensities of tivozanib and sorafenib were 94% and 80%. Assessment of health-related quality of life showed no clinically meaningful changes from baseline in either group over the first 12 months of treatment. Dr. Motzer told The ASCO Post, “Tivozanib improved progression-free survival but not overall survival in patients with metastatic renal cell carcinoma. Further study of tivozanib is warranted to provide additional insights into the utility of tivozanib for the treatment of patients with metastatic renal cell carcinoma.” n

Disclosure: The study was supported by AVEO Oncology and Astellas. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Motzer RJ, Nosov D, Eisen T, et al: Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial. J Clin Oncol. September 9, 2013.


FOR OVERALL SURVIVAL LOOK TO ZELBORAF Significant improvement in overall survival (OS) demonstrated in a Phase III trial vs dacarbazine in BRAF V600E(+) patients with unresectable or metastatic melanoma*

Indication and Usage: ZELBORAF速 (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information on New Primary Malignancies Cutaneous Malignancies Cutaneous squamous cell carcinoma (cuSCC), keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF. The incidence of cuSCC and keratoacanthomas in the ZELBORAF arm was 24%. New primary malignant melanoma occurred in 2.1% of patients receiving ZELBORAF. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF. Please see Brief Summary of Prescribing Information and next page for additional Important Safety Information.

* Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and progression-free survival (PFS) were coprimary endpoints. Best overall response rate (BORR) and time to response (TTR) were secondary endpoints. There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.1,2


EXTEND SURVIVAL

WITH ZELBORAF

Significant improvement in OS in a randomized, open-label Phase III trial* OS at FDA approval (August 2011)†‡ 100

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

Percentage surviving

80 60 Not reached

7.9

40 20 0

0

2

4

ZELBORAF (n=337)

6 8 OS (months)

10

12

14

Dacarbazine (n=338)

HR=hazard ratio CI=confidence interval *Trial design (N=675): patients with BRAF V600E mutation-positive unresectable stage IIIC or IV melanoma received either ZELBORAF 960 mg twice daily by mouth (n=337) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=338) for first-line treatment. Patients were allowed to cross over from dacarbazine to ZELBORAF per recommendation from the Data and Safety Monitoring Board. Results were censored at crossover. OS and PFS were coprimary endpoints. BORR and TTR were secondary endpoints.1,2 † At the time of FDA approval, median follow-up was 6.2 months (range, 0.4-13.9 months) for ZELBORAF patients vs 4.5 months (range, <0.1-11.7 months) for those taking dacarbazine. ‡ There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of FDA approval.

56% reduction in risk of death from any cause in patients treated with ZELBORAF® (vemurafenib) tablets vs dacarbazine (HR=0.44; 95% CI, 0.33-0.59; P<0.0001) Indication and Usage ZELBORAF® (vemurafenib) tablets are indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. ZELBORAF is not indicated for use in patients with wild-type BRAF melanoma. Important Safety Information New Primary Malignancies (cont’d) Non-Cutaneous Squamous Cell Carcinoma Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF. Monitor patients receiving ZELBORAF closely for signs or symptoms of new non-cutaneous SCC. Other Malignancies ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies. Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.

© 2013 Genentech USA, Inc. All rights reserved. BRF0000653205

Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF. Hypersensitivity and Dermatologic Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. In patients who experience a severe hypersensitivity or dermatologic reaction, ZELBORAF treatment should be permanently discontinued. QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc >500 ms, or long QT syndrome, or in patients who are taking medicines known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc >500 ms (grade 3). Upon recovery to QTc ≤500 ms (grade ≤2), restart at a reduced dose.


Significant improvement in PFS ~4-month improvement in median PFS vs dacarbazine (5.3 months vs 1.6 months; 95% CI, 4.9-6.6 months vs 1.6-1.7 months) (HR=0.26; 95% CI, 0.20-0.33; P<0.0001)

Superior response demonstrated vs dacarbazine first line2 48.4% of treatment naive patients had confirmed response (partial response + complete response) with ZELBORAF vs 5.5% with dacarbazine (95% CI, 41.6%-55.2% vs 2.8%-9.3%; P<0.001) —There were 2 complete responses (1%) and 104 partial responses (47.4%) with ZELBORAF

Rapid response achieved in treatment naive patients3

Baseline assessment

1 month

First postbaseline assessment

Permanently discontinue ZELBORAF treatment if the QTc interval remains >500 ms and increased >60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) Hepatotoxicity Liver laboratory abnormalities can occur. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage lab abnormalities with dose reduction, treatment interruption, or treatment discontinuation. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established. In a dose-finding trial, grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg bid or 720 mg bid). Photosensitivity Mild to severe photosensitivity can occur. Advise patients to avoid sun exposure and use adequate sun protection. Institute dose modifications for intolerable grade 2 or greater photosensitivity. Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for uveitis.

75%

of responses to ZELBORAF occurred by 1.6 months, approximately the time of the first postbaseline assessment

Embryo-Fetal Toxicity Apprise patients who are pregnant or who may become pregnant that ZELBORAF can cause fetal harm. Most Common Adverse Reactions The most common (≥30%) adverse reactions of any grade reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was required to be reported as grade 3 per protocol. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying Brief Summary of Prescribing Information for additional Important Safety Information. References: 1. Center for Drug Evaluation and Research. Clinical review—NDA 202429: Zelboraf™ (vemurafenib) for the treatment of BRAF V600E mutation-positive unresectable or metastatic melanoma. Accessdata.fda.gov Web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000MedR.pdf. Published July 28, 2011. Accessed August 26, 2013. 2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 3. Data on file. Genentech, Inc.

Learn more at Zelboraf.com/EXPERIENCE


The ASCO Post  |   JANUARY 15, 2014

PAGE 40

Journal Spotlight Gastrointestinal Oncology

Study Explores Protective Effect of Aspirin Against Colorectal Cancer By Matthew Stenger

I

t has been posited that aspirin treatment may reduce risk for colorectal cancer through inhibition of WNT/cadherinassociated protein β1 (CTNNB1, or β-catenin) signaling. In a study reported recently in the Journal of the National Cancer

Institute, Nan et al investigated the potential role of the single nucleotide polymorphism rs6983267 (chromosome 8q24) in the protective effect of aspirin.1 This colorectal cancer susceptibility locus afSafety:7" fects binding activity of transcription factor

ZELBORAF ® (vemurafenib) tablet, oral 6 ADVERSE REACTIONS Initial U.S. Approval: 2011 6.1 Clinical Trials Experience This is a brief summary of information about ZELBORAF. Before Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot prescribing, please refer to the full Prescribing Information. be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable clinical practice. or metastatic melanoma with BRAF V600E mutation as detected by an This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 FDA-approved test. randomized (1:1) 675 treatment-naive patients with unresectable or Limitation of Use: ZELBORAF is not indicated for treatment of patients metastatic melanoma to receive ZELBORAF 960 mg orally twice daily with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior 5 WARNINGS AND PRECAUTIONS systemic therapy received treatment with ZELBORAF 960 mg orally 5.1 New Primary Malignancies twice daily. Cutaneous Malignancies Table 1 presents adverse reactions reported in at least 10% of patients Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma treated with ZELBORAF. The most common adverse reactions of any occurred at a higher incidence in patients receiving ZELBORAF compared grade (≥ 30% in either study) in ZELBORAF-treated patients were to those in the control arm in Trial 1. The incidence of cutaneous squamous arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse 24% compared to <1% in the dacarbazine arm [see Adverse Reactions reactions were cuSCC and rash. The incidence of Grade 4 adverse (6.1)]. The median time to the first appearance of cuSCC was 7 to 8 weeks; reactions was ≤ 4% in both studies. approximately 33% of patients who developed a cuSCC while receiving The incidence of adverse events resulting in permanent discontinuation ZELBORAF experienced at least one additional occurrence with median of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% time between occurrences of 6 weeks. Potential risk factors associated for the dacarbazine arm. In Trial 2, the incidence of adverse events with cuSCC observed in clinical studies using ZELBORAF included age resulting in permanent discontinuation of study medication was 3% in (≥ 65 years), prior skin cancer, and chronic sun exposure. ZELBORAF-treated patients. The median duration of study treatment In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial patients receiving ZELBORAF compared to none of the patients receiving 1, and 5.7 months for ZELBORAF in Trial 2. dacarbazine. Reactions Reported in  ≥  10% of Patients Treated Perform dermatologic evaluations prior to initiation of therapy and every Table 1 Adverse with ZELBORAF* 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for Trial 2: Patients Trial 1: Treatment Naïve Patients 6 months following discontinuation of ZELBORAF. with Failure of at Non-Cutaneous Squamous Cell Carcinoma Least One Prior Systemic Therapy Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving ZELBORAF [see Adverse Reactions (6.1)]. ZELBORAF Dacarbazine ZELBORAF ADRs Monitor patients receiving ZELBORAF closely for signs or symptoms of n= 336 n= 287 n= 132 new non-cutaneous SCC. Grade Grade All Grade All All a Other Malignancies Grades 3a Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) Based on mechanism of action, ZELBORAF may promote malignancies associated with activation of RAS through mutation or other mechanisms Skin and subcutaneous [see Warnings and Precautions (5.2)]. Monitor patients receiving ZELBORAF tissue disorders closely for signs or symptoms of other malignancies. Rash 37 8 2 0 52 7 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation of ZELBORAF [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.4 Dermatologic Reactions Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving ZELBORAF. Permanently discontinue ZELBORAF in patients who experience a severe dermatologic reaction [see Adverse Reactions (6.1)]. 5.5 QT Prolongation Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.6)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Evaluate ECGs before treatment with ZELBORAF, 15 days after treatment initiation, monthly during the first 3 months of treatment, and every 3 months thereafter or more often as clinically indicated. Monitor ECG and electrolytes, including potassium, magnesium, and calcium, after dose modification of ZELBORAF for QTc prolongation. Withhold ZELBORAF in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue ZELBORAF treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) [see Dosage and Administration (2.3)]. 5.6 Hepatotoxicity Liver laboratory abnormalities can occur with ZELBORAF (Table 2) [see Adverse Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.3)]. Concurrent Administration with Ipilimumab The safety and effectiveness of ZELBORAF in combination with ipilimumab have not been established [see Indications and Usage (1)]. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)]. 5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. Institute dose modifications for intolerable Grade 2 or greater photosensitivity [see Dosage and Administration (2.2)]. 5.8 Ophthalmologic Reactions Uveitis, blurry vision, and photophobia can occur in patients treated with ZELBORAF. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis. 5.9 Embryo-Fetal Toxicity ZELBORAF 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. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

33 45 23 24 9 8 19 5 14

3 <1 1 1 2 0 0 <1 0

4 2 1 <1 <1 3 1 0 2

0 0 0 0 0 0 0 0 0

49 36 30 28 21 17 16 13 8

3 0 2 0 6 0 0 0 0

53 13 18 8 8

4 <1 <1 0 <1

3 1 6 4 5

<1 0 2 <1 <1

67 24 9 11 11

8 <1 0 0 <1

Table 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 2 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

0

* For ALT, alkaline phosphatase, and bilirubin, there were no patients with a change to Grade 4 in either treatment arm. 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible. 7.2 Effect of Vemurafenib on CYP1A2 Substrates Concomitant use of ZELBORAF with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as ZELBORAF may increase concentrations of CYP1A2 substrates [see Clinical Pharmacology (12.3)]. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates. 7.3 Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF [see Warnings and Precautions Section 5.6]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. ZELBORAF can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vemurafenib revealed no evidence of teratogenicity in rat embryo/ fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3-5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during ZELBORAF therapy and for at least 2 months after discontinuation of ZELBORAF. 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. 8.3 Nursing Mothers It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ZELBORAF in nursing infants, 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.

38 17 19 11

2 <1 <1 <1

33 5 9 9

2 0 <1 <1

54 23 17 2

4 0 2 0

35 28 18 12

2 <1 1 <1

43 13 26 24

2 <1 1 0

37 29 26 16

2 <1 2 0

23 14

<1 0

10 3

0 0

27 11

0 0

8.5 Geriatric Use Clinical studies of ZELBORAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe hepatic impairment.

21 24 10

<1 22 <1

0 <1 1

0 <1 0

30 24 14

0 24 0

5

3

1

0

15

6

18

0

8

<1

21

0

8

0

7

0

12

0

10

0

0

0

14

0

8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 18 have not been established.

8.7 Renal Impairment No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of ZELBORAF has not been established in patients with severe renal impairment. 10 OVERDOSAGE There is no information on overdosage of ZELBORAF.

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. a Grade 4 adverse reactions limited to gamma-glutamyltransferase increased (<1% in Trial 1 and 4% in Trial 2). † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol. Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: neuropathy peripheral, VIIth nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma Infections and infestations: folliculitis Eye disorders: retinal vein occlusion Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation

The study involved investigation of regular aspirin use and colorectal cancer risk according to genotypes of rs6983267 and CTNNB1 expression in two prospective case-control studies within the Nurses’ Health Study (women) and the Health Professionals Follow-up Study (men). In total, 840 patients with colorectal cancer and 1,686 age- and race-matched control subjects were included. On multivariate analysis, a lower risk of colorectal cancer was observed among men (adjusted odds ratio [OR] = 0.80, P = .03), women (OR = 0.85, P = .05), and all patients (OR = 0.83, P = .004) with the T allele. Among subjects of any genotype, regular aspirin use was associated with a significantly reduced risk of colorectal cancer on multivariate analysis (OR = 0.71, P = .0001 for trend).

Effects of T Allele On multivariate analysis, the protective effect of aspirin was confined to individuals with at least one T allele (P  = .01 for interaction). Compared with nonregular use, regular aspirin use was associated with odds ratios for colorectal cancer of 0.61 (P = .0001) among those with GT genotype, 0.52 (P = .002) among those with TT genotype, and 0.99 (P = .94) among those with GG genotype.   On multivariate analysis stratified by rs6983267 genotype, regular aspirin use was associated with significantly lower risk of having colorectal cancer positive for nuclear CTNNB1 expression among patients with the GT or TT genotype (OR = 0.44, P = .003; P = .04 for interaction) but not among those with GG genotype (OR = 0.95, P = .88). In contrast, regular aspirin use was not associated with risk of having tumors negative for nuclear CTNNB1 among either patients with GG genotype (OR = 1.28, P = .49) or those with GT or TT genotype (OR = 0.86, P = .49; P = .33 for interaction). The investigators concluded, “Our results support an influence of aspirin on WNT/CTNNB1 signaling and suggest that aspirin chemoprevention may be tailored according to rs6983267 genotype.” n

Safety:10"

5.3 Hypersensitivity Reactions Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with ZELBORAF. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. Permanently discontinue ZELBORAF in patients who experience a severe hypersensitivity reaction.

Photosensitivity reaction Alopecia Pruritus Hyperkeratosis Rash maculo-papular Actinic keratosis Dry skin Rash papular Erythema Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in extremity Musculoskeletal pain Back pain General disorders and administration site conditions Fatigue Edema peripheral Pyrexia Asthenia Gastrointestinal disorders Nausea Diarrhea Vomiting Constipation Nervous system disorders Headache Dysgeusia Neoplasms benign, malignant and unspecified (includes cysts and polyps) Skin papilloma Cutaneous SCC†# Seborrheic keratosis Investigations Gammaglutamyltransferase increased Metabolism and nutrition disorders Decreased appetite Respiratory, thoracic and mediastinal disorders Cough Injury, poisoning and procedural complications Sunburn

7 like-2 (TCF7L2) to CTNNB1 and alters expression of target oncogenes, including MYC. The study showed that the T allele of rs6983267 was associated with a protective effect in regular aspirin users and was associated with reduced MYC expression.

Disclosure: The study was supported by grants from the National Institutes of Health.

Reference 1. Nan H, et al: J Natl Cancer Institute 105:1852-1861, 2013. Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

BRF0000422003 Initial U.S. Approval: August 2011 © 2013 Genentech, Inc


ASCOPost.com  |   JANUARY 15, 2014

PAGE 41

Journal Spotlight Gastrointestinal Oncology

Overall Survival Improved by Adding Panitumumab to FOLFOX4 but Only in Metastatic Colorectal Cancer Without RAS Mutation By Matthew Stenger

P

atients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 and patients with other activating RAS mutations do not benefit from anti–epidermal growth factor receptor (EGFR) therapy and may in fact be harmed by it. In an analysis reported in The New England Journal of Medicine by Jean-Yves Douillard, MD, PhD, of Institut de Cancérologie de l’Ouest René Gauducheau, Nantes, France, and colleagues, it was found that the addition of panitumumab (Vectibix) to FOLFOX4 (oxaliplatin, fluorouracil, and leucovorin) in the PRIME trial was associated with improved progressionfree and overall survival among patients with metastatic colorectal cancer who had no RAS mutations, and worse progressionfree survival and overall survival in patients with any RAS mutations.1

ing to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.

Effect of RAS Mutation A total of 512 patients had no RAS mutations. Among these patients, median progression-free survival was 10.1 months with panitumumab/ FOLFOX4 (n  =  259) vs 7.9 months

FOLFOX4 patients (n = 57) in progression-free survival (7.3 vs 8.0 months, HR = 1.28, P = .33), overall survival at the time of the primary analysis (17.1 vs 18.3 months, HR = 1.29, P = .31), or overall survival at the time of updated analysis (17.1 vs 17.8 months, HR = 1.39, P = .12). Among 221 panitumumab/ FOLFOX4 patients and 219 FOLFOX4 patients with KRAS mutations in exon 2, progression-free survival was 7.3 vs 8.8 months (HR = 1.29, P = .02), overall survival at primary analysis

The benefit-risk profile of panitumumab/FOLFOX4 was improved by excluding patients with mutated RAS metastatic [colorectal cancer] tumors. —Jean-Yves Douillard, MD, PhD, and colleagues

Study Details The PRIME trial compared panitumumab/FOLFOX4 vs FOLFOX4 as first-line therapy in patients with metastatic colorectal cancer according to KRAS exon 2 status. At the time of the primary analysis (when 54% of patients had died), panitumumab/FOLFOX4 was associated with a significant improvement in median progression-free survival (9.6 vs 8.0 months, P  =  .02) and a nonsignificant improvement in median overall survival (23.9 vs 19.7 months, P = .07) among patients without KRAS mutations in exon 2. In an exploratory updated analysis (when 82% of patients had died), panitumumab/FOLFOX4 was associated with a significant improvement in overall survival (23.8 vs 19.4 months, P = .03) among these patients. In a prospectively planned retrospective analysis, the effects of panitumumab/FOLFOX4 vs FOLFOX4 were assessed among patients accord-

with FOLFOX4 alone (n = 253; hazard ratio [HR]  = 0.72, P = .004). Median overall survival was 26.0 vs 20.2 months (HR = 0.78, P = .04) at the time of primary analysis and 25.8 vs 20.2 months (HR = 0.77, P = .009) at the time of updated analysis among these patients. Among 548 patients with any RAS mutations, panitumumab/FOLFOX4 (n  =  272) was associated with significantly shorter progression-free survival (7.3 vs 8.7 months, HR = 1.31, P = .008) and overall survival at the time of primary analysis (15.6 vs 19.2 months, HR = 1.25, P = .03) and updated analysis (15.5 vs 18.7 months, HR = 1.21, P = .04) compared with FOLFOX4 alone (n = 276). Among 108 patients with nonmutated KRAS exon 2 but other RAS mutations, there were no significant differences between panitumumab/ FOLFOX4 patients (n  =  51) and

PRIME Trial Results ■■ RAS mutations in addition to KRAS exon 2 mutations predicted a lack of response in patients who received panitumumab/FOLFOX4. ■■ In patients without RAS mutations, a significant improvement in overall survival was observed with panitumumab/FOLFOX4. ■■ BRAF mutation was a negative prognostic factor.

was 15.5 vs 19.3 months (HR = 1.24, P = .07), and overall survival at updated analysis was 15.5 vs 19.2 months (HR = 1.16, P = .16).

Effect of BRAF Mutation BRAF mutation was an overall negative prognostic factor. Among 228 patients in the panitumumab/FOLFOX4 group and 218 in the FOLFOX4 group with no RAS or BRAF mutations, progression-free survival was 10.8 vs 9.2 months (HR = 0.68, P = .002) and overall survival was 28.3 vs 20.9 months (HR = 0.74, P = .02). However, there was no difference between groups in progression-free survival (6.1 vs 5.4 months, HR = 0.58, P  =  .12) or overall survival (10.5 vs 9.2 months, HR = 0.90, P = .76) among 24 panitumumab/ FOLFOX4 patients and 29 FOLFOX4 patients with BRAF mutation but no RAS mutation. Among 296 panitumumab/ FOLFOX4 patients and 305 FOLFOX4 patients with BRAF or RAS mutations, progression-free survival was 7.3 vs 8.0 months (HR = 1.24, P = .03) and overall survival was 15.3 vs 18.0 months (HR = 1.21, P = .06). Among 75 panitumumab/FOLFOX4 patients and 86 FOLFOX4 patients with no KRAS mu-

tation in exon 2 but other RAS or BRAF mutations, progression-free survival was 6.7 vs 7.3 months (HR = 1.05, P = .80) and overall survival was 14.5 vs 15.8 months (HR = 1.14, P = .51).

Adverse Events Adverse event rates in the two treatment groups according to presence or absence of RAS mutations were similar to those reported in the two treatment groups overall. Among panitumumab/FOLFOX4 patients and FOLFOX4 patients with no RAS mutations, rates of adverse events with a worst grade of 3, 4, and 5 were 57%, 28%, and 5% vs 50%, 20%, and 6%. Moreover, serious adverse events occurred in 43% of the panitumumab/FOLFOX4 group vs 37% of the FOLFOX4 alone group, and adverse events led to discontinuation of study treatment in 25% vs 16%. Among panitumumab/FOLFOX4 patients and FOLFOX4 patients with any RAS mutations, rates of adverse events with a worst grade of 3, 4, and 5 were 57%, 24%, and 7% vs 53%, 20%, and 4%. Serious adverse events occurred in 45% vs 31% of the two groups, respectively, and adverse events led to discontinuation of study treatment in 22% vs 13%. No new safety signals were identified. The investigators concluded: …RAS mutations, in addition to KRAS exon 2 mutations, predict a lack of response to anti-EGFR therapy in patients with metastatic [colorectal cancer]. Panitumumab plus oxaliplatincontaining regimens have no value in patients with metastatic [colorectal cancer] and mutated RAS. The benefit-risk profile of panitumumab/ FOLFOX4 was improved by excluding patients with mutated RAS metastatic [colorectal cancer] tumors. Pooled trials or metaanalyses of anti-EGFR therapy are needed to confirm these findings. n

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

Reference 1. Douillard J-Y, Oliner KS, Siena S, et al: Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013.


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

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

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

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


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

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

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

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© 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013E-076-7984-3 12/13 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.


XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARYOF 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 castration-resistant 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 [see Use in Specific Populations]. 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 to rates in the clinical trials of another drug and may not reflect the rates observed 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. 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 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of 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 randomized clinical trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 (%) Grade 3-4 (%)

General Disorders Asthenic Conditionsa 50.6 Peripheral Edema 15.4 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 Arthralgia 20.5 Musculoskeletal Pain 15.0 Muscular Weakness 9.8 Musculoskeletal Stiffness 2.6 Gastrointestinal Disorders Diarrhea 21.8 Vascular Disorders Hot Flush 20.3 Hypertension 6.4 Nervous System Disorders Headache 12.1 Dizzinessb 9.5 Spinal Cord Compression and 7.4 Cauda Equina Syndrome Paresthesia 6.6 Mental Impairment Disordersc 4.3 Hypoesthesia 4.0 Infections And Infestations Upper Respiratory Tract 10.9 Infectiond Lower Respiratory Tract And 8.5 Lung Infectione Psychiatric Disorders Insomnia 8.8 Anxiety 6.5 Renal And Urinary Disorders Hematuria 6.9 Pollakiuria 4.8 Injury, Poisoning And Procedural Complications Fall 4.6 Non-pathologic Fractures 4.0 Skin And Subcutaneous Tissue Disorders Pruritus 3.8 Dry Skin 3.5 Respiratory Disorders Epistaxis 3.3 a b c d e

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

9.0 1.0

44.4 13.3

9.3 0.8

5.3 2.5 1.3 1.5 0.3

24.3 17.3 11.5 6.8 0.3

4.0 1.8 0.3 1.8 0.0

1.1

17.5

0.3

0.0 2.1

10.3 2.8

0.0 1.3

0.9 0.5 6.6

5.5 7.5 4.5

0.0 0.5 3.8

0.0 0.3 0.3

4.5 1.8 1.8

0.0 0.0 0.0

0.0

6.5

0.3

2.4

4.8

1.3

0.0 0.3

6.0 4.0

0.5 0.0

1.8 0.0

4.5 2.5

1.0 0.0

0.3 1.4

1.3 0.8

0.0 0.3

0.0 0.0

1.3 1.3

0.0 0.0

0.1

1.3

0.3

Includes asthenia and fatigue. Includes dizziness and vertigo. Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of 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 arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). 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. Fallrelated 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 opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased 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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. 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 [see Clinical Pharmacology]. 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 [see Clinical Pharmacology (12.3)]. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. 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., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology ]. 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 [see Clinical Pharmacology ]. USE IN SPECIFIC POPULATIONS Pregnancy- Pregnancy Category X [see Contraindications]. 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 were 65 and over, while 25 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with 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 volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage 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 [see Clinical Pharmacology]. 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 [see Clinical Pharmacology]. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose 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 in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal 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 at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC). PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). • Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. • Inform patients receiving a GnRH analog that they need to maintain this treatment during the course of treatment with XTANDI. • Inform patients that XTANDI has been associated with an increased 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. • Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, hypoesthesia, and falls. • Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their physician. Inform patients that 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. • Apprise patients of the common side effects associated with XTANDI: 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. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Inform patients that XTANDI may be harmful to a developing fetus. 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: Manufactured for and Distributed by: Catalent Pharma Solutions, LLC, Astellas Pharma US, Inc., St. Petersburg, FL 33716 Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Issued: August 2012 12A005-ENZ-BRS Rx Only © 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc. 0131-076-8930


ASCOPost.com  |   JANUARY 15, 2014

PAGE 45

ASH Annual Meeting Hematology

Surprising Findings for Lenalidomide Maintenance in Updated IFM 2005-02 Analysis By Caroline Helwick

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new analysis of the multiple myeloma Intergroupe Francophone du Myelome (IFM) 2005-02 trial showed that lenalidomide (Revlimid) maintenance prolongs progression-free survival after stem cell transplantation, but does not improve overall survival.1 This is possibly attributed to the shorter survival time after first disease progression than is observed in patients receiving placebo, the investigators suggested. The study, presented by Michel Attal, MD, of the Centre Hospitalier Regional Universitaire Hôpital Purpan in Toulouse, France, was met with some surprise by attendees at a session during the 2013 American Society of Hematology (ASH) Annual Meeting (see sidebar). The meaning of these findings, according to Dr. Attal, is that “the benefit of lenalidomide maintenance is an early benefit, occurring in the first 2 years.” He suggested that a “late effect” occurs with continued lenalidomide treatment, which induces the emergence of drug resistance. “We must be cautious, but I think something is happening that looks like

Michel Attal, MD

what we, in the old times, called multidrug resistance,” he said.

Study Details IFM 2005-02 was a randomized, placebo-controlled phase  III trial that investigated the efficacy of lenalidomide maintenance after transplantation in 614 myeloma patients younger than age 65 who had not shown disease progression after first-line autologous stem cell transplantation. Patients were randomly assigned to continuous lenalidomide maintenance (10–15 mg/d) or placebo until disease progression. The initial findings were reported after a median follow-up of 45 months.2 The initial analysis found a 50% improvement in progression-free survival

but no advantage for overall survival. The investigators had two hypotheses for this discrepancy: insufficient followup and therefore a low number of reported deaths, or worse outcomes after progression in the lenalidomide arm, possibly due to clonal selection and/or induced resistance with lenalidomide therapy. “We felt that a follow-up analysis was required to answer this,” he said. The data cutoff for this subsequent analysis was November 2013, which was at 67 months postrandomization and 77 months postdiagnosis. No patient in the placebo arm received lenalidomide before progression, but about half of the patients underwent a second transplant sometime in their disease course, he indicated.

New Analysis Looked Closely at Progression In the new analysis, median progression-free survival from randomization was 46 months with lenalidomide and 24 months with placebo (P < .001) but median overall survival was still not significantly improved with maintenance,

despite the longer 77 months of followup. Median overall survival was 81 and 82 months, respectively (P = .80), Dr. Attal reported. “The discrepancy between progression-free and overall survival was still present,” he said. “We believe the poor outcome after progression for patients in the lenalidomide maintenance group is the most reliable hypothesis.” Describing the “poor outcome after progression” in the lenalidomide maintenance arm, Dr. Attal called attention to the median second progression-free survival point, which was the time from the first progression to the second progression. In this scenario, the placebo arm was superior, with median second progression-free survival of 24 months vs 13 months with lenalidomide (P = .001). About 50% of patients received an immunomodulatory drug–based regimen upon first progression, and in this group, median second progression-free survival was 19 months with placebo and 8 months with lenalidomide (P = .003). For the 25% of patients receiving continued on page 46

IFM 2005-02 Update Differs From CALGB 100104: Why? By Caroline Helwick

T

he updated analysis of the Intergroupe Francophone du Myelome (IFM) 2005-02 trial in newly diagnosed multiple myeloma patients showed that lenalidomide (Revlimid) maintenance prolongs progression-free survival after stem cell transplantation, but does not improve overall survival, according to Michel Attal, MD, of the Centre Hospitalier Regional Universitaire Hôpital Purpan in Toulouse, France.1 The fact that the new analysis does not support the findings of an overall survival benefit demonstrated in the Cancer and Leukemia Group (CALGB) 100104 trial2 spurred a lively debate among myeloma researchers at the 2013 American Society of Hematology (ASH) Annual Meeting. Also presented at the session, a meta-analysis of four key randomized controlled trials showed only a “modest improvement” in overall survival for maintenance, according to the abstract,

though the benefit in progression-free survival was clear.3

More Data Needed “Where this leads us in my view is that we need more data—further studies and more maturity of current studies will be vital, and in the United States, the answer will hopefully be provided by the currently open randomized trial IFM/DFCI 2009, which is now endorsed by both the CTN [Blood and Marrow Transplant Clinical Trials Network] and the Alliance [for Clinical Trials in Oncology],” said Paul G. Richardson, MD, of DanaFarber Cancer Institute, Boston. “The obvious difference between IFM 200502 and the other trials discussed was that lenalidomide was continued until disease progression in all of these except the IFM study (where patients got lenalidomide for a median of 24 months and were then stopped),” he told The ASCO Post. “Whilst possible resistance is al-

ways a worry, the opposite appears to be the case with continuous therapy utilizing our best novel agents in multiple other phase III trials reported to date. I am also struck that different salvage strategies are a key factor here, as a high proportion of Paul G. Richardson, MD Preet Paul Singh, MD the patients in the IFM study on prior lenalidomide (and who then pleted.” Dr. Richardson commented. had disease progression) got immunoThe Mayo Clinic meta-analysis [see modulatory drug–based therapy and page 93] showed a significant survival did worse, perhaps not surprisingly. benefit for lenalidomide maintenance Importantly, those who got bortezo- until the newest analysis from IFM was mib [Velcade] did just as well in both added just prior to the meeting. Once arms,” added Dr. Richardson. this was done, there was still an overall “All in all, I was left with the impres- survival benefit, but its significance was sion that the results of the IFM study more marginal, as reported by Preet were the real outlier in the debate, Paul Singh, MD, at the ASH meeting. although obviously some provoca- The methodology used to assess sective questions were raised, which I ond progression-free survival for the do think will be answered as the field IFM findings was then called into quescontinued on page 47 evolves and ongoing studies are com-


The ASCO Post  |   JANUARY 15, 2014

PAGE 46

ASH Annual Meeting Lenalidomide Maintenance continued from page 45

a bortezomib (Velcade)-based regimen, median progression-free survival was 8 and 9 months, respectively (P = .28). For the 25% of patients who received no new agents, median progression-free survival was 30 months vs 18 months, respectively (P = .06). Dr. Attal suggested that the reduced second progression-free survival with maintenance may be due to clonal selection or secondary resistance, suggested by the [median progression-free survival] in the [immunomodulatory drug] group and the “no new agent group.” Second primary malignancies totaled 21 (7%) in the placebo arm and 37 (13%) in the lenalidomide arm, for a cumulative incidence of 20.6 per 1,000 patient-years with placebo and 33.7 with lenalidomide—a statistically significant difference (P = .025). The lenalidomide cohort also had more severe neutropenia (51% vs 18%).

Plenary Session (see page 1), he noted. “Elderly patients spend about 70% of their myeloma life during their firstline treatment. If you can prolong this [remission] in the first line, you can probably improve overall survival,” he predicted. n

Disclosure: Drs. Attal and Jagannath reported no potential conflicts of interest.

References 1. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance afS:6.75” ter stem-cell transplantation for multiple

myeloma: Follow-up analysis of the IFM 2005-02 trial. 2013 ASH Annual Meeting. Abstract 406. Presented December 9, 2013. 2. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782-1791, 2012.

COMETRIQ™ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

No Treatment Recommendation While Dr. Attal declined to make a treatment recommendation based on the data, he did agree with Sundar Jagannath, MD, Director of the Multiple Myeloma Program at Mount Sinai Hospital, New York, that it helps to view the findings for their relevance in elderly as compared to younger newly diagnosed patients. An overall survival benefit has been shown for lenalidomide maintenance in older patients, including the FIRST trial presented at an ASH

IFM 2005-02 Trial Update ■■ In a new analysis of the IFM 2005-02 trial, lenalidomide maintenance prolonged progression-free survival in patients with multiple myeloma post-transplant, but median overall survival was still not significantly improved, despite the longer 77 months of follow‑up. ■■ The median second progressionfree survival (the time from first progression to second progression) was longer for patients in the placebo arm compared with lenalidomide. ■■ Investigators suggested that the reduced second progressionfree survival time with lenalidomide maintenance may be due to clonal selection or secondary resistance.

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. IMPORTANT SAFETY INFORMATION WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE • Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo

(3% vs 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs 3% and arterial thromboembolism: 2% vs 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

© 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 05/13 [03-13-00091-A]

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ASH Annual Meeting validity of such a last minute change to the results presented.

continued from page 45

tion by Shaji K. Kumar, MD, from the Mayo Clinic at the session, which in itself raised some concern regarding the

Other Theories S:6.75” Shaji K. Kumar, MD

Philip McCarthy, MD, of Roswell Park Cancer Institute, Buffalo, New

York, who was principal investigator of CALGB 100104, proposed some theories for the different findings. He noted that there are several differences between IFM 2005-02 and continued on page 48

PROD

IFM 2005-02 Study vs CALGB 100104

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

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> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

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Adverse Reactions: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, PPES, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

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Please see brief summary of full Prescribing Information on next page.

COMETRIQ.com

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit fda.gov/medwatch or call 1-800-FDA-1088.

Disk release

Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

T:10.25”

*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

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ASH Annual Meeting IFM 2005-02 Study vs CALGB 100104 continued from page 47

CALGB 100104, including the duration of continuous lenalidomide, different induction regimens, the use of consolidation or not, the use of DCEP

(dexamethasone, cyclophosphamide, etoposide, cisplatin) or not, and the use of double transplants or not. “There’s enough heterogeneity between the trials that we are comparing apples and oranges,” he suggested. He noted that the most important differ-

COMETRIQ™ (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) 1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; reversible posterior leukoencephalopathy syndrome. In Patients with Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop

ence is a median of 2 years of maintenance on the IFM trial and maintenance until progression in the CALGB study. This strongly suggests that continued maintenance is the preferred approach, especially in light of the RV-MM-PI209 study, which shows both a progression-

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia hypocalcemia, fatigue hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving

free and overall survival benefit for lenalidomide maintenance. In addition, half the patients in the IFM study received VAD (vincristine, doxorubicin, dexamethasone), which is no longer a standard regimen, whereas the majority of the CALGB study pa-

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0


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ASH Annual Meeting tients received an immunomodulatory drug (thalidomide [Thalomid] or lenalidomide) or bortezomib, Dr. McCarthy pointed out. Dr. Attal responded, “This is an important debate and these are good questions,” but he maintained that in-

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade All Grade Grades 3-4 Grades 3-4 CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 5 Palmar-plantar erythrodysesthesia syndrome 1

2

tertrial heterogeneity is not the cause. His study failed to show that differences in induction regimens, DCEP, or double transplant were independently associated with overall survival, he said. “I do agree with your observation regarding consolidation,” he continued,

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose 1

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased singledose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be

though he further suggested that “2 months of consolidation would not abrogate an overall survival benefit of 3 years of maintenance.” Dr. Attal also speculated that the lack of crossover in the IFM study, and the make-up of the placebo arm, could well influence the outcomes.

apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

“The major difference is not between our lenalidomide arms, but in our placebo arms,” he said. “The IFM placebo arm is probably better than the CALGB trial’s.”

‘A Complex Problem’ The trial investigators and others who commented agreed with Gareth Morgan, MD, who called this “a complex problem” and indicated that the ongoing Medical Research Council (MRC) lenalidomide maintenance study, which is randomizing 2,500 patients to maintenance or no maintenance, will help “resolve this argument.”

Gareth Morgan, MD

Dr. Morgan also emphasized the point about lenalidomide being stopped at 2 years in the IFM trial vs being given until disease progression in other studies, calling this a key difference in the maintenance strategies that could explain the divergent findings. Dr. McCarthy said there will continue to be analysis of the landmark CALGB 100104 trial. Even though the 100104 study has met the primary endpoint of progression-free survival, there is also an overall survival benefit, and this study is quite valuable in allowing us to continue analyzing the outcome, he commented. He emphasized, “In our last analysis, we were still seeing an overall survival benefit on an intent-to-treat basis, despite crossovers in the study.” n

Disclosure: Drs. Kumar, McCarthy, Attal, and Morgan reported no potential conflicts of interest.

References 1. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stemcell transplantation for multiple myeloma: Follow-up analysis of the IFM 2005-02 trial. 2013 ASH Annual Meeting. Abstract 406. Presented December 9, 2013. 2. McCarthy PL, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012. 3. Singh PP, Kumar S, LaPlant B, et al: Lenalidomide maintenance therapy in multiple myeloma: A meta-analysis of randomized trials. 2013 ASH Annual Meeting. Abstract 407. Presented December 9, 2013.


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ASH Annual Meeting Continuous Lenalidomide continued from page 1

“Continuous Rd represents a new standard of care for older transplant-ineligible patients. For some patients with low-risk multiple myeloma, this continuous regimen could make this disease a manageable, chronic condition,” Dr. Facon stated.

Study Details The multicenter, open-label, phase III trial, conducted at 246 centers in 18 countries, enrolled 1,623 newly diagnosed multiple myeloma patients who were ineligible for stem cell transplant due to older age or

onstrating a highly significant 28% reduction in risk of disease progression or death (P  =  .00006). Median progression-free survival was 25.5 months for continuous Rd vs 21.2 months for MPT. Median progression-free survival was also significantly better for continuous Rd vs Rd for 18 cycles: 25.5 months vs 20.7 months (P = .00001). Even more important, continuous Rd led to improvement in overall survival (59% at 4 years) vs MPT (51.4% at 4 years). The 4-year median survival rate in patients receiving Rd for 18 cycles was 55.7%.

Continuous Rd represents a new standard of care for older transplant-ineligible patients. For some patients with low-risk multiple myeloma, this continuous regimen could make this disease a manageable, chronic condition. —Thierry Facon, MD

other reasons. Median age was 73 (range, 40–92 years), and 35% of patients were aged 75 or older; 41% had stage III disease. Participants were randomly assigned to one of three arms: continuous Rd in 28day cycles until disease progression. Rd for 18 cycles (72 weeks), or MPT for 12 cycles (72 weeks). Responses were assessed after each cycle of chemotherapy. Dose adjustments were permitted for adverse events. All patients received antithrombotic prophylaxis as part of the protocol. At a median follow-up of 37 months, the study met its primary endpoint of progression-free survival comparing continuous Rd vs MPT for 72 weeks, dem-

Continuous Rd achieved consistent improvement over MPT for all secondary endpoints: Overall response rate (partial response or better) was 75% vs 62% (P < .0001), respectively.

Adverse Events The safety profiles for the two treatment arms (continuous Rd vs MPT) were similar, with numerically fewer hematologic side effects in the doublet arm, as well as fewer hematologic malignancies. In this study, the incidence of secondary solid cancers was identical in both arms (2%), and the incidence of secondary hematologic malignancies

Continuous Lenalidomide in Multiple Myeloma ■■ Continuous lenalidomide plus low-dose dexamethasone extended progression-free survival and overall survival compared with standard melphalan, prednisone, and thalidomide in older multiple myeloma patients who were ineligible for transplant. ■■ Results suggest that older patients can be spared the toxicities of oral melphalan as first-line treatment.

EXPERT POINT OF VIEW

“T

hese are exciting data from the headto-head phase  III comparison of MPT [melphalan, prednisone, and thalidomide (Thalomid)], a globally accepted standard of care, to the novel combination of lenalidomide/lowdose dexamethasone in newly diagnosed multiple myeloma patients ineligible for transplant,” said Joseph R. Mikhael, MD, Mayo Clinic, Scottsdale, Arizona. Dr. Mikhael moderated a Joseph R. Mikhael, MD press conference at the American Society of Hematology (ASH) meeting where these data were presented. “The study has implications for our colleagues in Europe, where MPT is widely used as first-line therapy. It is also important for hematologists in the United States, where lenalidomide [Revlimid]/dexamethasone is used, but it is used less often in older patients who are not candidates for transplant. The study shows that continuous Rd [lenalidomide (Revlimid) plus low-dose dexamethasone] can be used to convert multiple myeloma to a more chronic stable condition, especially in older adults,” Dr. Mikhael said.

European Perspective MPT and MVP (melphalan, bortezomib [Velcade], prednisone) are both standard of care in Europe, said Jesus F. San Miguel, MD, PhD, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain, who introduced the talk by Thierry Facon, MD, at the ASH Plenary Session. “This study compared one of those standards [MPT] to continuous lenalidomide/low-dose dexamethasone, and patients were treated until progression. This is the largest registration trial ever conducted in multiple myeloma,” he continued. About 20% of the patients had high-risk genetics. The study included the sickest patients and those with renal insufficiency, who are not usually enrolled in clinical trials, Dr. San Miguel continued. “This is close to a real-life population,” he said. “The trial establishes continuous Rd as a convenient, effective, and tolerable standard of care for the older patient with myeloma,” Dr. San Miguel stated. n

Disclosure: Dr. Facon is a member of the Board of Directors or advisory committee and the speakers bureau for Celgene. Drs. Mikhael and San Miguel reported no potential conflicts of interest.

was 0.4% with continuous Rd vs 2.2% with MPT. Relevant grade 3 or 4 adverse events in the continuous Rd arm vs MPT, respectively, were neutropenia (28% vs 45%), thrombocytopenia (8% vs 11%), febrile neutropenia (1% vs 3%), infection (29% vs 17%), neuropathy (5% vs 15%), and deep-vein thrombosis (5% vs 3%). n Disclosure: The study was supported by Celgene and the French Francophone Myeloma

Intergroup. Dr. Facon is a member of the Board of Directors or advisory committee and the speakers bureau for Celgene.

Reference 1. Facon T, Dimopoulos M, Dispenzieri A, et al: Initial phase 3 results of the FIRST trial in newly diagnosed multiple myeloma patients ineligible for stem cell transplant. 2013 ASH Annual Meeting. Abstract 2. Presented December 8, 2013.

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Inside the Black Box Molecularly Targeted Therapy for Lung Cancer

A Conversation With FDA’s Office of Hematology and Oncology Products

INSIDE THE BLACK BOX is an occasional column offering insight into the FDA and its policies and procedures. This installment addresses a changing paradigm in the treatment of lung cancer, exemplified by concurrent approval of a companion diagnostic with each of several new targeted agents or new drug indications. Gideon Blumenthal, MD, FDA Clinical Team Leader of Thoracic Oncology in the Center for Drug Evaluation and Research, and Elizabeth Mansfield, PhD, Director of the Personalized Medicine Staff in the Center for Devices and Radiological Health, discuss this new approval paradigm and future directions for targeted drug-diagnostic codevelopment.

R

ecent U.S. Food and Drug Administration (FDA) coapprovals of companion diagnostic tests for erlotinib (Tarceva) and afatinib (Gilotrif) in EGFR mutation–positive non–small cell lung cancer (NSCLC) and crizotinib (Xalkori) in ALK-positive NSCLC highlight a changing paradigm in lung cancer treatment. Drs. Blumenthal and Mansfield discuss the new therapeutic trend and the corresponding evolution of the FDA approval process.

New Therapeutic Model How has the treatment paradigm in lung cancer changed? Dr. Blumenthal: In the past decade, with technologic improvements in molecular testing and a better understanding of molecular pathways driving oncogenesis, the field has shifted from treatment based solely on histologic classifications (such as adenocarcinoma, squamous cell) to treatment based on a tumor’s underlying molecular alterations. What is a specific example of this change? Dr. Blumenthal: One of the first examples was crizotinib, a tyrosine kinase inhibitor that targets ALK. ALK gene rearrangements were first described as an oncogenic driver in NSCLC in 2007. Patients with ALK-rearranged NSCLC were entered into early clinical trials with crizotinib that same year. Crizotinib subsequently received accelerated approval based on high overall response rates, which were durable in single-arm trials in 2011. Accelerated

approval is an approval pathway based on a surrogate endpoint (such as overall response rate) that is reasonably likely to predict clinical benefit. As a condition of accelerated approval, the sponsor is required to conduct postmarketing trials to confirm clinical benefit for regular approval. In November 2013, crizotinib was given regular approval based on a postmarketing randomized trial demonstrating a large magnitude of progression-free survival benefit and improved overall response rate compared to standard second-line chemotherapy (pemetrexed [Alimta] or docetaxel) in ALKpositive NSCLC. The trial showed that the median progression-free survival for the crizotinib-treated patients was 7.7 months, while the median progression-free survival for patients on the chemotherapy arm was 3.0 months. This randomized trial also corroborated the high response rate observed in the single-arm trial. The overall response rate was significantly higher in the crizotinib arm—65% vs 20%— with median response durations of 7.4 and 5.6 months in the crizotinib and chemotherapy arms, respectively. No difference in overall survival was noted between the two arms in a planned interim analysis. Approximately 64% of patients on the chemotherapy arm subsequently received crizotinib— a fact that may confound the analysis of overall survival. Are there other examples of this new paradigm in drug development?

Dr. Blumenthal: Another example of the new treatment paradigm in lung cancer is the exon 19 and 21 mutations in EGFR conferring sensitivity to EGFR tyrosine kinase inhibitors. In 2013, the FDA expanded the approved use of erlotinib and approved afatinib for the first-line treatment of metastatic NSCLC in patients whose tumors have these EGFR mutations, based on improved progression-free survival and overall response rate compared to platinum doublet chemotherapy.

Other Targets Besides EGFR and ALK, what other potential targets have been identified in lung cancer? Dr. Blumenthal: In addition to identifying EGFR and ALK, novel sequencing techniques have identified other oncogenes (such as BRAF, RET, HER2, and ROS1) that can be targeted. Drugs are in development, both approved for other indications and unapproved, that can potentially target these genetic changes in small subsets of patients with lung cancer. Another interesting phenomenon in lung cancer is that we are rapidly learning mechanisms of primary and acquired drug resistance to these targeted therapies, and new agents are being developed to target these resistance pathways, such as second-generation ALK inhibitors and EGFR inhibitors targeting the T790M gatekeeper mutation.

Single-Arm Trials Given that smaller subsets of lung cancer are being identified and targeted, are you evaluating more data based on singlearm trials? Dr. Blumenthal: Yes, we are seeing more drugs in selected populations demonstrating impressive activity in expansion cohorts of early clinical trials. The endpoint we evaluate in singlearm trials is magnitude and durability of overall response rate. The downside of single-arm trials, compared to randomized trials, is that no comparative safety data can be directly obtained. Endpoints such as progression-free survival and overall survival cannot be accurately evaluated in single-arm trials. Are there other downsides to singlearm trials?

FDA Clinical Reviewers

Gideon Blumenthal, MD

Elizabeth Mansfield, PhD

Dr. Blumenthal: Without a randomized comparison, it may be unclear whether a biomarker is either prognostic or predictive in the biomarker-positive subset. We do not know whether a drug actually delayed progression or prolonged survival (a predictive claim), or whether the selected biomarkerpositive population has a more indolent natural history compared to the general lung cancer population (a prognostic claim). In some cases, a randomized trial may not be feasible, such as if the magnitude and durability of overall response rate is very large in a rare subset with high unmet medical need. Randomized trials should be performed only if equipoise exists between treatment arms.

Coapproval Process Can you discuss the process of coapproval of a drug with a companion diagnostic? Dr. Mansfield: An in vitro companion diagnostic device provides information that is essential for the safe and effective use of a corresponding therapeutic product. Companion diagnostics help health-care professionals determine whether a patient with a


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Inside the Black Box particular disease should receive a particular drug or how much of the drug to give. In July 2011, the FDA released draft guidance to explain its policy requiring review and regulatory approval of companion diagnostics as essential tools to guide use of the corresponding therapies.1 The guidance, aimed at stimulating early collaborations between drug and device makers, clarified the FDA’s definition of a companion diagnostic, recommended early interaction between drug and device manufacturers and the FDA, and identified instances

tive treatments exist and the benefits of the use of the drug with an unapproved or uncleared in vitro companion diagnostic are so pronounced as to outweigh the risks from the lack of an approved in vitro companion diagnostic device. The second is where the FDA determines that the labeling for an already approved drug must be revised to address a serious safety issue, and the change made to address this issue would require the use of a diagnostic test that is not yet cleared or approved. In both cases, there is an expectation that there will be a subsequent regula-

[A 2011 draft guidance] clarified the FDA’s definition of a companion diagnostic, recommended early interaction between drug and device manufacturers and the FDA, and identified instances where the FDA may approve a targeted medicine in the absence of a cleared or approved companion diagnostic. —Elizabeth Mansfield, PhD

the FDA, nonprofit organizations such as Friends of Cancer Research, academia, patient advocacy groups, and the pharmaceutical and device industries, worked jointly to design a master protocol for refractory squamous cell cancer of the lung. The protocol will use next-generation sequencing, and based on a patient’s molecular profile, will randomly assign patients to one of several targeted treatments or to a control regimen of standard chemotherapy. The protocol is designed to be a seamless phase  II/III design, and data from the trial may be used as the basis for a new drug application (NDA) or biologic license application (BLA). We are very encouraged that this protocol will serve as a model for enhancing the efficiency of the clinical trials enterprise in the United States and help deliver safe and effective therapies to a patient population where few such therapies exist. If successful, this type of master protocol could serve as a model for similar trials in other malignancies.

Single-Platform Testing where the FDA may approve a targeted medicine in the absence of a cleared or approved companion diagnostic. We are currently in the last steps of writing draft guidance on principles that are useful when sponsors need to codevelop a companion diagnostic for a therapy.

tory submission for the in vitro companion diagnostic. The circumstances described above ensure that lifesaving therapies are not delayed when the riskbenefit assessment suggests approval without contemporaneous approval of a companion diagnostic would be appropriate.

Approval Flexibility

Master Protocols

Does the guidance provide flexibility in allowing targeted agents to be approved without an in vitro companion diagnostic device? Dr. Mansfield: Yes. As stated in the guidance, the FDA may decide it is appropriate to approve a drug even though the in vitro companion diagnostic device with which it is labeled for use is not being FDA-approved or FDA-cleared contemporaneously. The guidance highlights two areas where this may be encountered. The first is for drugs intended to treat serious or life-threatening disease, such as cancer, where no satisfactory alterna-

What is the FDA view on master protocols for lung cancer? Dr. Blumenthal: National and international endeavors for sequencing the cancer genome, such as The Cancer Genome Atlas, have found potential underlying molecular alterations that can be targeted not only for lung adenocarcinoma but also for squamous cell carcinoma of the lung, among many other cancers. Unlike adenocarcinoma of the lung, there are no approved targeted therapies in squamous cell lung cancer. A number of key stakeholders, including the National Cancer Institute,

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It sounds like there are many potentially important molecular aberrations that can be targeted in lung cancer. What is the FDA’s view on developing a single platform to test for a number of these aberrations? Dr. Mansfield: In general, we think a single platform may have many advantages. For example, in metastatic lung cancer, it is often challenging to get sufficient tumor tissue to test for the increasing number of molecular abnormalities that may be important to making treatment decisions. Nextgeneration sequencing and other tests that can measure many molecular aberrations—such as substitutions, deletions, insertions, amplifications, copy number variants, and overexpression—at one time and provide all the information in one test may completely change the treatment paradigm for lung cancer. The FDA encourages and is actively working with device manufacturers on the development of these platforms.

Guest Editor

Richard Pazdur, MD

Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology ­Products.

Immune Checkpoint Inhibitors There is a great deal of progress in moving away from conventional chemotherapy toward more targeted therapies in lung cancer. Are there any other exciting approaches on the horizon? Dr. Blumenthal: Another emerging field for the treatment of lung cancer is immunotherapy. Although lung cancer has not been traditionally thought of as an immune-sensitive tumor type like renal cell cancer and melanoma, early clinical trials have suggested that immune checkpoint inhibitors such as anti–PD-1 and anti–PD-L1 antibodies have activity in lung cancer. Perhaps the high mutational load in many lung tumors presents the opportunity for increased antigen presentation to immune cells and thus a therapeutic window for these checkpoint inhibitors. Regardless, there is a great deal of activity in developing these immune checkpoint inhibitors in lung cancer. n Disclosure: Drs. Blumenthal and Mansfield reported no potential conflicts of interest.

Reference 1. U.S. Food and Drug Administration: Guidance for Industry and Food and Drug Administration Staff—In Vitro Companion Diagnostic Devices. Issued July 14, 2011. Available at http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ ucm262292.htm. Accessed December 11, 2013.

■■ Continued coverage from: American Society of Hematology Annual Meeting ■■ Plus, reports from: 2014 Gastrointestinal Cancers Symposium, January 16-18, 2014, San Francisco 2014 Genitourinary Cancers Symposium, January 29-February 1, 2014, San Francisco

Visit ASCOPost.com for ongoing coverage of oncology meetings.


MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1282b 09/13

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment


The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

50

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

40

Patients (%)

50

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

0

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus kinase.

• Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.


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Announcements Thoracic Oncology

American Lung Association Applauds U.S. Preventive Services Task Force Recommendation of Screening for Those at High Risk of Lung Cancer

T

he American Lung Association issued the following statement on December 31, 2013, in response to the recommendation of the U.S. Preventive Services Task Force (USP-

STF) to screen individuals at high risk of lung cancer. “The [USPSTF] made a recommendation that will save lives. The Task Force released its final recommendation, grad-

ing annual low-dose CT screening for individuals at high risk for lung cancer with a B grade. Under the Affordable Care Act, effective prevention measures, graded A

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions]. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] 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. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All a Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Grades (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Jakafi is a registered trademark of Incyte Corporation. All rights reserved. U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved. Issued: June 2013 RUX-1216

or B, are included in the Essential Health Benefit. Patients who meet the screening criteria will have insurance coverage for screening without copayments or other barriers starting January 1, 2015 or the beginning of their next plan year. The USPSTF high-risk populations include current and former smokers, ages 55-80 years, who have significant cumulative tobacco smoke exposure and have smoked within the last 15 years. The American Lung Association urges all insurers to cover the screening for high-risk patients immediately. Lung cancer is the leading cause of cancer death for both men and women in the United States. The 5-year survival rate for lung cancer patients is only 16%. This new screening test has the potential to dramatically improve lung cancer survival rates by finding the disease at an earlier, more treatable stage.  The USPSTF estimates that if everyone who is at high risk is screened, there will be an approximately 14% reduction in lung cancer deaths in the United States. The American Lung Association applauds the USPSTF for their final recommendations on lung cancer screening. We hope that over time, this screening will have a similar, positive impact by increasing lung cancer early detection, treatment and survival rates as have other USPSTF screening recommendations.” In April 2012, the American Lung Association released guidelines to assist physicians and their patients in discussions about lung cancer screening. The Lung Association’s guidelines, based on the National Cancer Institute’s National Lung Cancer Screening Trial, mirror that of the USPSTF’s recommendations. The full American Lung Association Report on Lung Cancer Screening and related educational materials at www.lung.org. n

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Journal Spotlight Breast Cancer

Targeted Intraoperative Radiotherapy Plus Lumpectomy Noninferior to External-Beam Radiotherapy in Preventing Breast Cancer Recurrence By Matthew Stenger

I

n the randomized noninferiority TARGIT-A trial reported in The Lancet, Jayant S. Vaidya, PhD, FRCS, and Michael Baum, MD, FRCS, of University College London, and colleagues compared risk-adapted radiotherapy

when delayed until after lumpectomy (postpathology). Breast cancer mortality did not differ significantly between the two groups, but intraoperative radiotherapy was associated with reduced non–breast cancer mortality.

[Targeted intraoperative radiotherapy] concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative [externalbeam radiotherapy]. —Jayant S. Vaidya, PhD, and colleagues

using single-dose targeted intraoperative radiotherapy vs fractionated external-beam radiotherapy in women with breast cancer.1 Targeted intraoperative radiotherapy met the noninferiority margin for 5-year local recurrence among all patients and when given concurrently with lumpectomy but not

Study Details In this open-label randomized trial, 3,451 women aged ≥ 45 years with invasive ductal carcinoma were randomly assigned to receive risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (n = 1,721) or whole-breast external-beam radiothera-

py according to standard schedules over several weeks (n = 1,730) at 33 centers in 11 countries between March 2000 and June 2012. Patients were stratified by center and by timing of intraoperative radiotherapy; randomization occurred either before lumpectomy (prepathology stratum, intraoperative radiotherapy given concurrent with lumpectomy, total n  =  2,298) or after lumpectomy (postpathology stratum, intraoperative radiotherapy given subsequently by reopening the wound, total n = 1,153). The risk-adapted strategy meant that as per protocol, patients in the targeted intraoperative radiotherapy group were to receive supplemental external-beam radiotherapy (excluding a boost) if deemed necessary based on final pathology; overall, 15.2% of the intraoperative radiotherapy group received external-beam radiotherapy, including 21.6% in the prepathology stratum and 3.6% in the postpathology stratum and there was no significant difference between strata in terms of timing of delivery of external-beam radiotherapy. Overall, most cancers were small and had good prognosis; 87% were ≤ 2 cm, 85% were grade 1 or 2, 84% were nodenegative, 93% were estrogen receptor–

positive, and 82% were progesterone receptor–positive. Cancers were detected by screening in 69% of women. Nevertheless, there were a significant number of patients who had adverse prognostic factors such as positive nodes (n = 502) or grade 3 tumors (n – 459). The primary outcome was the absolute difference in local recurrence in the conserved breast, with a prespecified noninferiority margin of 2.5% at 5 years. The current report consisted of 5-year results for local recurrence and the first analysis of overall survival.

Recurrence Rates Overall, median follow-up was 2 years and 5 months in 3,451 patients, 4 years in 2,020, and 5 years in 1,222. The 5-year risk for local recurrence in the conserved breast was 3.3% in the intraoperative radiotherapy group vs 1.3% in the external-beam radiotherapy group (absolute difference = 2%, P = .042) among all patients, 2.1% vs 1.1% (absolute difference  =  1.0%, P  =  .31) among patents in the prepathology stratum, and 5.4% vs 1.7% (absolute difference > 2.5%; P = .069) in the postpathology stratum. The rate continued on page 58

Cautious Comments on the TARGIT-A Trial By Thomas A. Buchholz, MD, and Benjamin D. Smith, MD

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umerous randomized trials have demonstrated that wholebreast irradiation plays an important role after breast-conserving surgery for invasive breast cancer. A recent meta-analysis of these trials indicated that whole-breast irradiation decreased the risk of total breast cancer relapse events and improved overall survival.1 However, whole-breast irradiation requires 3 to 6 weeks of daily treatments, which can be a source of inconvenience and cost. Accordingly, new strategies to mitigate the prolonged treatment schedules are being

Dr. Buchholz is Division Head and Dr. Smith is Associate Professor, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

investigated, including attempts to accelerate treatments by targeting only the tumor-bed region of the breast. The most convenient of all such approaches is intraoperative radiation delivered as a single radiation fraction at the time of lumpectomy. This strategy has been studied with an intraoperative electron therapy approach by investigators in Milan, who conducted a phase III randomized trial and unfortunately reported a hazard ratio for the development of in-breast recurrence of 9.3 (95% confidence interval  = 3.3–26.3) for treatment with intraoperative radiotherapy vs whole-breast irradiation.2

Early TARGIT-A Data In the United Kingdom, investigators developed a similar intraoperative strategy, termed targeted intraopera-

tive radiation therapy (TARGIT). In contrast with the Milan approach, targeted intraoperative radiation therapy uses an orthovoltage technique rather than electrons and prescribes a lower radiation dose. This approach served as a basis of the TARGIT-A trial, a randomized trial comparing singlefraction intraoperative radiation with or without whole-breast irradiation vs whole-breast irradiation. The original results of the trial were published in 2010 after a median follow-up of only 2 years.3 Many felt that the publication of such early results was not particularly informative with respect to the primary outcome of in-breast recurrence, especially considering that cumulative incidence of in-breast recurrence rises slowly over a period of 10 or more years after diag-

nosis in patients with favorable breast cancer, such as those included in the TARGIT-A trial.

Updated Report After the original study was analyzed in 2010, the investigators continued accrual for an additional 2 years. The new 2013 report from this trial by Vaidya and colleagues in The Lancet, reviewed in this issue of The ASCO Post, therefore includes a larger number of total patients but again has a very short median follow-up of 2.5 years.4 This time, however, even with this short follow-up, the authors found a statistically significantly higher inbreast recurrence risk in patients randomly assigned to targeted intraoperative radiation therapy, compared to the continued on page 59


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Journal Spotlight

Targeted Intraoperative Radiotherapy continued from page 57

of local recurrence in patients receiving intraoperative radiotherapy plus external-beam radiotherapy was 0.9% but did not differ significantly from that in patients receiving intraoperative radiotherapy alone.

Post hoc exploratory analyses showed no significant differences in 5-year rates of regional recurrence (1.1% vs 0.9%), distant recurrence (3.9% vs 3.2%), any other recurrence (4.9% vs 4.4%), or all recurrence (8.2% vs 5.7%). The difference in all recurrence was smaller in the prepathology stratum (6.9% vs 5.8%) than in the postpathol-

ogy stratum (10.4% vs 5.4%), as was the difference in any recurrence other than local recurrence (4.8% vs 4.7% in prepathology stratum, 5.2% vs 3.7% in postpathology stratum). The difference in locoregional recurrence (4.2% vs 2.0%) was also smaller in the prepathology stratum (3.1% vs 2.0%) than in the postpathology stratum (6.2% vs 2.0%).

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Mortality Five-year mortality was 3.9% in the targeted intraoperative radiotherapy group vs 5.3% in the external-beam radiotherapy group (P  =  .099), with no significant difference in breast cancer mortality (2.6% vs 1.9%) but a significant advantage for intraoperative radiotherapy in non–breast cancer mortality (1.4% vs 3.5%, P =.0086), reflecting fewer deaths from cardiovascular causes and other cancers. In the prepathology stratum, 5-year mortality was 4.6% vs 6.9% (P  =  .123), with no significant difference in breast cancer mortality (3.3% vs 2.7%, P = .72) and an advantage for intraoperative radiotherapy in non– breast cancer mortality (1.3% vs 4.4%, P  =  .016). In the postpathology stratum, 5-year mortality was 2.8% vs 2.3% (P  =.674), with no significant difference in breast cancer mortality (1.2% vs 0.5%, P =.35) or non–breast cancer mortality (1.6% vs 1.8%, P =.32). Mortality in patients receiving intraoperative radiotherapy plus external-beam radiotherapy was high (8.0%), reflecting the poor prognostic features in this group. Overall, there were 17 deaths in the intraoperative radiotherapy group and 35 in the external-beam radiotherapy group due to causes other than breast cancer (P = .0086). These causes included other cancers in 8 intraoperative radiotherapy patients vs 16 external-beam radiotherapy patients and cardiovascular causes in 2 vs 11, including cardiac causes in 2 vs 8, stroke in 0 vs 2, and ischemic bowel disease in 0 vs 1. Apart from deaths due to other can-

Radiotherapy Strategies for Breast Cancer ■■ Targeted intraoperative radiotherapy was noninferior to external-beam radiotherapy in preventing local recurrence among all patients and among patients receiving intraoperative radiotherapy concurrently with lumpectomy but not among those receiving intraoperative radiotherapy postpathology as a delayed second procedure. ■■ Five-year breast cancer mortality did not differ between groups, but intraoperative radiotherapy was associated with reduced non–breast cancer mortality. continued on page 59


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TARGIT-A Trial continued from page 57

whole-breast irradiation arm. The absolute difference was small, although it is likely that this difference will continue to grow with additional follow up as the cumulative incidence of in-breast recurrence continues to rise. It is also interesting that the authors present 5-year in-breast recurrence outcomes when the median follow-up is only half this period, but they choose not to show the tail end of the local recurrence curves, which are truncated at 5 years posttreatment. If patients have appropriately complied with follow-up, then we would expect that 10-year data already exist for those patients enrolled and treated in the years 2000 to 2002. Such data would be helpful to illuminate any long-term differences in risk of in-breast recurrence between targeted intraoperative radiotherapy and whole-breast irradiation. A major theme of the current publication is the assertion that patients treated with intraoperative radiotherapy “prepathology” (at the time of lumpectomy) experienced rates of in-breast recurrence that were comparable to whole-breast irradiation. In contrast, patients treated with intraoperative radiotherapy performed as a second procedure “postpathology” experienced a higher risk of in-breast recurrence than patients treated with whole-breast irradiation.4

Study Limitations It is important to note that there was no randomized component of

Targeted Intraoperative Radiotherapy continued from page 58

cers or cardiovascular causes, there were 7 additional deaths in the intraoperative radiotherapy group (2 due to diabetes, 1 to renal failure, 1 to liver failure, 1 to sepsis, 1 to Alzheimer’s disease, and 1 to unknown cause) and 8 additional deaths in the external-beam radiotherapy group (1 due to myelopathy, 1 to perforated bowel, 1 to pneumonia, 1 to

timing of targeted intraoperative radiotherapy and that a number of potential biases may have contributed to these results. For example, one likely contributor to these outcomes was the much greater use of adjuvant whole-breast irradiation in the “prepathology” patients randomly assigned to targeted intraoperative

treated with whole-breast irradiation. A final important note concerning targeted intraoperative radiotherapy is the relatively low radiation dose, a concern raised by our group in a letter to The Lancet following the 2010 publication.5 With targeted intraoperative radiotherapy, only 5 Gy is delivered to the tissue that extends 1 cm beyond

Due to the much smaller volume treated, and the much lower dose delivered, we fear that the modest increase in risk of inbreast recurrence noted in patients randomized to intraoperative radiotherapy compared to wholebreast irradiation will become more pronounced as the median followup of the study matures. —Thomas A. Buchholz, MD, and Benjamin D. Smith, MD

radiotherapy, compared to the “postpathology” patients randomized to targeted intraoperative radiotherapy. One could thus interpret this study finding as illustrating that to achieve results similar to whole-breast irradiation, it is better to have 21.6% of intraoperative radiotherapy recipients also treated with whole-breast irradiation than to have only 3.6% of intraoperative radiotherapy recipients also

the tumor bed, and the dose rapidly drops off beyond 1  cm. This dose is markedly lower than the dose delivered with other partial-breast radiation techniques or with conventional whole-breast irradiation. Due to the much smaller volume treated and the much lower dose delivered, we fear that the modest increase in risk of in-breast recurrence noted in patients randomized to intraoperative

old age, and 4 to unknown cause). There were no significant differences between groups in wound-related complications, but external-beam radiotherapy was associated with a significantly greater frequency of grade 3 or 4 radiotherapy-related skin complications (0.8% vs 0.2%, P = .029). The investigators concluded, “[Targeted intraoperative radiotherapy] concurrent with lumpectomy within a risk-adapted approach should be con-

sidered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative [externalbeam radiotherapy].” n Disclosure: The study was supported by University College London Hospitals (UCLH)/ UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council,

radiotherapy as compared to wholebreast irradiation will become more pronounced as the median follow-up of the study matures. Accordingly, we are hesitant to agree with the authors’ conclusion that targeted intraoperative radiotherapy should currently be considered as a standard of care. n

Disclosure: Dr. Smith receives research funding from Varian Medical Systems and ASCO’s Conquer Cancer Foundation.

References 1. Early Breast Cancer Trialists’ Collaborative Group: Effect of radiotherapy after breast-conserving surgery on 10year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011. 2. Veronesi U, Orecchia R, Maisonneuve P, et al: Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol 14:1269-1277, 2013. 3. Vaidya JS, Joseph DJ, Tobias JS, et al: Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, prospective, randomised, non-inferiority phase 3 trial. Lancet 376:91-102, 2010. 4. Vaidya JS, Wenz F, Bulsara M, et al: Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet November 8, 2013. 5. Smith BD, Buchholz TA, Kuerer HM: Intraoperative radiotherapy for early breast cancer (correspondence). Lancet 376:1141, 2010.

and German Federal Ministry of Education and Research. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Vaidya JS, Wenz F, Bulsara M, et al: Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. November 11, 2013.

Visit The ASCO Post website 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.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (N=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (N=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A Phase II, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy


For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program. VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. 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. 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.


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.

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

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

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-POM120033a


The ASCO Post  |   JANUARY 15, 2014

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Announcements

ESMO Releases Position Paper on Med-Oncs’ Role in Cancer Care

A

new position statement from the European Society for Medical Oncology (ESMO) reports that medical oncologists have a vital role to play in cancer care.1 According to the position statement, medical oncologists are specialist cancer physi-

cians trained to provide treatment with drugs, spanning from chemotherapy to newer targeted agents and immunotherapies. ESMO’s aim with the statement is to guarantee to Europe’s growing number of cancer patients access to optimal 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)]. 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

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

treatment, said Razvan A. Popescu, MD, ESMO National Representatives and Membership Committee Chair. “There are many complex decisions to be made around cancer treatment, and recent scientific advances are making the provision of optimal care even more Toxicity

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

challenging,” said Dr. Popescu. “Only medical oncology training prepares physicians to deal with this complexity.” The new ESMO position paper outlines formally for the first time the role of medical oncologists. Developed in consultation with medical oncologists (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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Announcements

Razvan A. Popescu, MD

Martine Piccart, MD

• 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

and professional organizations across Europe, endorsed by all medical oncology societies in Europe, it represents a consensus view of the medical oncologist’s place in the treatment of cancer. The ESMO statement establishes, among others, what

(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)]

the internationally recognized standard of education and training should be for a medical oncologist. “By bringing attention to the role of medical oncology, ESMO hopes to improve the treatment of patients across Europe,” said ESMO President Martine Piccart, MD. n

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.

Reference 1. Popescu RA, Schafer R, Califano R, et al: The current and future role of the medical oncologist in the professional care for cancer patients: A position paper by the European Society for Medical Oncology (ESMO). Ann Intern Med 25:915, 2014.


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Clinical Trials Resource Guide

Ongoing NCI-Funded Clinical Trials Actively Recruiting Patients With Advanced Cancer Compiled by Jo Cavallo

T

his issue of The ASCO Post launches a Clinical Trials Resource Guide to increase awareness of NCI-funded phase I, II, and III clinical

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.

studies for your patients with advanced cancer. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

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

The clinical trials included here are currently recruiting patients with breast cancer, colorectal cancer, non-small cell lung cancer, and prostate cancer.

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

BREAST CANCER Study Type: Randomized Phase III/Interventional Study Title: A Randomized Phase III Trial of the Value of Early Local Therapy for the Intact Primary Tumor in Patients With Metastatic Breast Cancer Study Sponsor and Collaborators: Eastern Cooperative Oncology Group; National Cancer Institute Purpose: To study early surgery to see how well it works compared to standard palliative therapy in treating patients with stage IV breast cancer.

Eligibility Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Overall survival Principal Investigator: Seema A. Khan, MD, Robert H. Lurie Cancer Center For More Information: Visit ClinicalTrials.gov and refer to this study by its ClinicalTrials.gov identifier: NCT01242800 Study Type: Randomized Phase II/Interventional Study Title: A Randomized, OpenLabel Comparative Study of Combination Therapy With Cyclophosphamide and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine With or Without Trastuzumab for the Treatment of Metastatic Breast Cancer That Does Not Over-express HER-2/Neu Study Sponsor and Collaborators: Sidney Kimmel Comprehensive Cancer Center; National Cancer Institute Purpose: To study the side effects of giving cyclophosphamide together with vaccine therapy and to see how well it works compared with giving cyclophosphamide and vaccine therapy together with trastuzumab in treating patients with metastatic breast cancer.

Eligibility Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Toxicity as assessed by NCI CTCAE v3.0; Time Frame: 3 years; Progression-free survival at 6 months; Time


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Frame: 3 years; HER-2/neu-specific immune responses; Time Frame: 3 years; Pharmacodynamics of peripheral CD4+CD25+ regulatory T cells; Time Frame: 3 years. Principal Investigator: Leisha A. Emens, MD, PhD, Sidney Kimmel Comprehensive Cancer Center For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00971737

COLORECTAL CANCER Study Type: Non-Randomized Phase 1/II/Interventional Study Title: A Phase 1/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer Study Sponsor and Collaborators: National Cancer Institute Purpose: Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the DNA of growing cancer cells and is most often used with other chemotherapy drugs. Researchers want to test irinotecan with an experimental drug, ISIS 183750, to see if the drugs are a safe and effective treatment for advanced solid tumors or colorectal cancer that has not responded to other treatments.

Eligibility Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Maximum tolerate dose Principal Investigator: Tim F. Greten, MD, National Cancer Institute Contacts: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01675128

and refer to this study by its identifier: NCT01866410

NON-SMALL CELL LUNG CANCER Study Type: Non-Randomized Phase II/Interventional Study Title: Phase II Trial of XL184 (Cabozantinib), Plus Erlotinib in Patients With Advanced EGVRMutant Non-Small-Cell Lung Cancer Who Have Progressed on Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy Study Sponsor and Collaborators: National Cancer Institute Purpose: This phase II trial investigates how well cabozantinib-s-malate and erlotinib hydrochloride works in treating patients with previously treated metastatic non-small cell lung cancer. Cabozantinib-s-malate and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Giving cabozantinib-s-malate together with erlotinib hydrochloride may be an effective treatment for non-small cell lung cancer.

Study Type: Randomized Phase II/Interventional Study Title: A Randomized Phase II Trial of Cytotoxic Chemotherapy With or Without Epigenetic Priming in Patients With Advanced Non-Small Cell Lung Cancer Study Sponsor and Collaborators: National Cancer Institute Purpose: This randomized phase II trial is studying how effective azacitidine and entinostat given before chemotherapy is in treating patients with advanced non-small cell lung cancer. Drugs used in chemotherapy, such as azacitidine, irinotecan hydrochloride, gemcitabine hydrochloride, docetaxel, and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving azacitidine and entinostat before chemotherapy may be an effective treatment for non-small cell lung cancer.

Eligibility

Eligibility

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Objective response defined by Response Evaluation Criteria in Solid Tumors (RECIST) V1.1; Time Frame: Up to 2 years Principal Investigator: Karen Reckamp, MD, MS, Beckman Research Institute Contacts: Visit ClinicalTrials.gov

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Percentage of patients progression-free at 6 months from the time of randomization; Time Frame: at 6 months Principal Investigator: Julie Brahmer, MD, Johns Hopkins University Contacts: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01935947

PROSTATE CANCER Study Type: Non-Randomized Phase I/Interventional Study Title: Evaluation of Ferumoxytol Enhanced MRI for the Detection of Lymph Node Involvement in Prostate Cancer Study Sponsor and Collaborators: National Cancer Institute Purpose: Ferumoxytol is an approved iron replacement therapy agent that has some potential for use as a contrast agent in imaging studies of the lymph system, especially involving lymph nodes that have been affected by cancer. Because ferumoxytol has not yet been approved for use as an imaging agent, researchers are interested in testing its effectiveness as a contrast agent for studies of normal lymph tissue and cancer tissue in lymph nodes of individuals with prostate cancer. The objective of this study is to evaluate the safety and effectiveness of ferumoxytol as a contrast agent in individuals who are scheduled to have prostate removal surgery to treat prostate cancer.

Eligibility Ages Eligible for Study: 18 years and older Genders Eligible for Study: Male Accepts Healthy Volunteers: No Primary Outcome Measures: To determine the optima dose of ferumoxytol for enhancing lymph nodes in patients with prostate cancer Principal Investigator: Peter L. Choyke, MD, National Cancer Institute Contacts: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01296139 n

Contact The ASCO Post Editorial Correspondence

Rates, reprints, or supplements

James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

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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IN A L K+ N SC LC

reCognize progression

iDentify symptoms

• Prior to 2011, there were no targeted therapies available to treat patients with ALK+ NSCLC1-3

• Symptoms, including cough, dyspnea, fatigue, pain, hemoptysis, and anorexia, can serve as signals of progression7,8

• Inevitably, patients develop resistance to currently available ALK inhibitor therapy and typically progress after 10 months4-6 • Common sites of disease progression include the CNS, lung, and liver6

• Up to half of patients with NSCLC may develop CNS metastases, and symptoms include headaches, seizures, cognitive impairment, and neurological deficits9,10

ALK, anaplastic lymphoma kinase; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; NSCLC, non-small cell lung cancer. References: 1. XALKORI® (crizotinib) Prescribing Information. New York, NY: Pfizer Labs; October 2013. 2. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46(10):1773-1780. 3. US Food and Drug Administration. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Released August 26, 2011. Accessed November 5, 2013. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.2.2014. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed November 4, 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. 5. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4(120):1-12. doi:10.1126/scitranslmed.3003316. 6. Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011-1019. 7. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Cancer. 1994;73(8):2087-2098. 8. de Marinis F, Pereira JR, Fossella F, et al. Lung cancer symptom scale outcomes in relation to standard efficacy measures. J Thorac Oncol. 2008;3(1):30-36. 9. Hu C, Chang EL, Hassenbusch SJ III, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer. 2006;106(9):1998-2004. 10. Fokas E, Steinbach JP, Rödel C. Biology of brain metastases and novel targeted therapies: time to translate the research. Biochim Biophys Acta. 2013;1835(1):61-75. 11. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 12. Sánchez de Cos J, Sojo González MA, Montero MV, et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009;63(1):140-145.


A LOT CAN HAPPEN IN A MONTH Can CheCking monthly for symptoms help yoU DeteCt progression earlier? intervene noW • By assessing patient symptoms monthly during routine physical exams, progression may be detected earlier8 • According to guidelines, a CT scan is the best method for monitoring response to therapy11 • Early detection of CNS metastases by cranial CT or MRI—even before symptoms develop—may improve prognosis12

visit www.progressioninALK.com to register for updates.

novartis oncology is committed to advancing research into the alk pathway to help find new options for patients with lung cancer.

Novartis Pharmaceuticals Corporation east hanover, new Jersey 07936-1080

© 2013 novartis

11/13

lCD-1074669


The ASCO Post  |   JANUARY 15, 2014

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Perspective

Allen S. Lichter, MD, FASCO continued from page 1

Society’s dedication to furthering the field of oncology has placed it at the epicenter of cancer research, cutting-edge technology, health-care policy, advocacy, and a vast number of educational platforms. ASCO’s scope is best measured not in size and numbers but by its efforts to enhance every facet of cancer care— and in its unyielding dedication to the founders’ original charter of improving the lives of people with cancer. Celebrating a 50th anniversary is an important milestone for any organization, especially for one in the challenging and constantly evolving environment of health care. In many respects, however, ASCO is a young organization. In fact, most of our sister societies are much older—some well over 100 years old. The specialty of oncology is less than 50 years old, so ASCO’s maturation has spanned the entire formal history of American oncology itself. When the seven original founders began laying out the organization’s mission, surgery and radiation therapy were not oncologic specialties. Moreover, there were a mere handful of cancer drugs that were largely ineffective and hard for patients to handle; we now have about 160 agents in our armamentarium. Progress in oncologic surgery, radiation oncology, and oncologic imaging has been equally impressive. And when one looks at the progress we’ve made in cancer survival and overall care, it is apparent that ASCO never veered from its original mission.

On ASCO Leadership What are your thoughts on ASCO’s leadership, and how has your own leadership role within the Society changed over the years? Part of ASCO’s success has been the result of its leadership structure and our leaders’ guiding principles. It is es-

sential for our leaders to have a grasp of three key questions: Where have we been? Where are we going? And how are we going to get there? In all the positions I’ve held—prior to becoming the Society’s CEO, I also served as Chair of several committees as well as being on the Board of Directors and ASCO President—I have tried to fully appreciate the importance of asking and answering those three simple questions. Now that the Society has reached

is all part of a very well organized leadership structure that gets the job done.

Working With ASCO Presidents How would you describe the relationship between ASCO’s CEO and its President? Could you share some of your experiences in working with different ASCO Presidents and adapting to their individual styles and goals? As CEO, I work for the ASCO Board of Directors. The President of the Society

It is ultimately up to the physicians to hold each other accountable for finding solutions to measuring outcomes and delivering quality care. ASCO has been at the forefront of this movement with its CancerLinQ project, and I am confident that in time, we will not only change the way oncology is practiced, but all of medicine. —Allen S. Lichter, MD, FASCO

this 50-year milestone, it is a good place to pause and refresh our memory about where we have been and how much we’ve accomplished. But it is also a time to look forward with great anticipation of future accomplishments. Positions that I’ve held in academic medicine, such as department chairman and dean, are directly involved in developing the careers of others and adding to the knowledge that underscores the oncology discipline. In ASCO we do that as well, although as CEO, my participation in that process is more indirect. We support our members, who in turn help support the development of students, trainees, and the next generation of oncologists. ASCO leadership also tries to provide the tools to help our members improve their own individual careers. It

is Chairman of the Board and has a central leadership role in shaping the Board’s wishes, plans, and strategy. I’m into my eighth year as ASCO’s CEO, and I’ve had the opportunity to work with a number of wonderful presidents. Each had his or her own style, personality, and vision for the Society, and every president has been a pleasure to work with. Moreover, each president has developed in ASCO service through participation on various committees and chairmanships and finally on the Board of Directors. Each president is powered by a great deal of knowledge about the inner workings of the Society. Serving as ASCO President was one of the highlights of my career. It also gave me a different perspective on serving the Society when I became CEO.

ASCO Takes the Lead in Quality What do you believe is the most important thing ASCO has accomplished since you’ve been CEO? If I were to isolate one initiative or accomplishment as my legacy, it would probably be participating in the initialtion, development, implementation, and eventually the success of CancerLinQ™. This massive data project stems from the Society’s commitment to harnessing the power of health information technology to measure and improve the quality of oncology care. That vision reaches back to a 1999 ASCO study on quality, which led to the Quality Oncology Practice Initiative (QOPI®). After a great deal of work, the QOPI program was formally rolled out to the membership in 2006. QOPI, in turn, led to CancerLinQ, which will allow us to analyze data in real time in the clinic. We will be able to capture outcomes, which will give this electronic system the ability to learn and rapidly refine our knowledge and clinical ­practice. ASCO’s total embrace of quality measurement and personal accountability for care has moved the discipline forward in many ways. CancerLinQ will help us accelerate the development of new knowledge, which will translate into a system that is constantly learning and evaluating itself. Being part of that exciting mission is as good as it gets. It’s important to note that although many entities and agencies, both public and private, are now engaging in quality measurement, it is ultimately up to the physicians to hold each other accountable for finding solutions to measuring outcomes and delivering quality care. ASCO has been at the forefront of this movement with its CancerLinQ project, and I am confident that in time, we will not only change the way oncology is practiced, but all of medicine. n

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Direct From ASCO

ASCO Celebrates 50 Years of Advancing Progress Against Cancer

F

ifty years ago, cancer was viewed as a monolithic and largely untreatable disease, with only a handful of hard-to-tolerate and mostly ineffective therapies available. Stigma and silence left many patients with cancer with little support or information. Determined to change this, a group of seven cancer physicians banded together with a single purpose—to improve the care of people with cancer. And with that, the American Society of Clinical Oncology (ASCO) was founded. Over the years, ASCO has held true to this vision as the Society and its members have established and advanced the field of modern clinical oncology. In many ways, the story of ASCO is the story of progress against cancer: As ASCO grew from its original seven members to more than 30,000 today, national funding for cancer research increased from less than $200 million to more than $5 billion annually. The number of drugs available to treat cancer grew from just a handful to more than 170. Most importantly, patients are living longer and better lives. On this historic year, as ASCO

proudly commemorates its 50th anniversary and decades of evolutionary change and growth, it also celebrates the significant progress that has been made against cancer. ASCO’s anniversary website, CancerProgress.Net, chronicles these achievements and more.

Advances” in the field. A key feature of the site, the interactive Cancer Progress Timeline developed under the guidance of an editorial board of 21 of the nation’s leading oncologists, has been updated with a fresh look and is now accessible on all mobile devices. Advances in seven types of care and 18 cancers are represented on the timeline, and this extensive record of cancer milestones can be downloaded in a variety of formats (such as PowerPoint slides, Word, or PDF) for use as hand-outs or in presentations.

Looking to the Future Celebrating Progress ASCO launched CancerProgress .Net nearly 3 years ago to mark the 40th anniversary of the signing of the U.S. National Cancer Act, which led to major new investments in cancer research and significant increases in cancer survival. The site provides a dynamic and interactive history of progress against cancer and expert perspectives on the future of care. In honor of the Society’s anniversary, the site will feature stories about ASCO’s evolution, an upgraded timeline of advances in cancer, aggregated news and views on ASCO’s anniversary and progress, social media features, and an opportunity to vote on the “Top Five

“As we look back over the past 50 years, however, let’s not forget that we still face important challenges—challenges that will require resources and innovation from both science and society,” said Clifford A. Hudis, MD, ASCO President. “We are on the threshold of major scientific breakthroughs in cancer prevention, detection, and treatment, and we must see these through.” To help accomplish this, the ASCO Board of Directors has created a vision document, “Help ASCO Shape the Future of Oncology: Envisioning Cancer Care in 2013,” to carry the practice of oncology into the next decades, including the transformation of cancer care through health information technology, the realization of precision medicine, and the use of quality measurement and improvement to increase the value of care. For more information on ASCO’s vision and to add your comments on the ideas presented, visit the Reports section of CancerProgress.Net.

Join the Celebration ASCO invites you to become part of this momentous occasion by touring the Society’s anniversary website CancerProgress.Net, or by following ASCO on ASCO Connection, Twitter, and Facebook. You can also help support the next 50 years of cancer progress by making a donation to the Conquer Cancer Foundation of the American Society of Clinical Oncology at ConquerCancerFoundation. org/donate. n © 2014. American Society of Clinical Oncology. All rights reserved.

Weigh in on which milestones of the last 50 years were the most important by voting on your “Top 5 Advances” at CancerProgress.Net/vote. Voting will continue through the 2014 ASCO Annual Meeting and results will be announced shortly thereafter.

ASCO, AACR, and Campaign for Tobacco-Free Kids Urge FDA Prohibition of Menthol Cigarettes

A

SCO has sent joint letters with both the American Association for Cancer Research (AACR) and the Campaign for Tobacco-Free Kids (CTFK) to the Food and Drug Administration (FDA) urging that the agency establish regulations to eliminate menthol in cigarettes. The agency is currently considering prohibiting menthol as a characterizing flavor of cigarettes.

Both letters call for establishing a uniform standard that sets a maximum menthol level, for which all cigarette manufacturers will have to comply. The ASCO/AACR letter goes one step further to “strongly recommend that the FDA ban the addition of menthol to cigarettes and other combustible tobacco products as a characterizing flavor,” a recommendation that is in-

cluded in ASCO’s 2013 tobacco cessation policy statement. “Additive flavors like menthol have a cooling effect that makes the inhaled cigarette smoke less harsh, and can lead to an increase in smoking, especially with young people,” said Frank L. Meyskens, Jr, MD, FACP, Chair of ASCO’s Cancer Prevention Committee. “Flavors that help aid addiction to

tobacco products should be prohibited… period.” The next step will be for the FDA to issue a proposed rule on banning menthol in cigarettes. Please follow ASCO in Action (http://www.asco.org/­advocacy) for the latest information. n © 2014. American Society of Clinical Oncology. All rights reserved.


The ASCO Post  |   JANUARY 15, 2014

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Direct From ASCO

ASCO Honors New Group of Members With FASCO Distinction

F

ormerly called the ASCO Statesman Award, the Fellow of the American Society of Clinical Oncology (FASCO) distinction recognizes ASCO members for their extraordinary volunteer service, dedication, and commitment to ASCO. Their efforts benefit ASCO, the specialty of oncology, and, most importantly, the patients they serve. Society volunteers regularly go be-

yond their daily practices and research to contribute their time, energy, and skills to ASCO committees, publications, and meetings. Those who are recognized with the FASCO status represent some of the most dedicated volunteers within the organization. “These are people who have given of themselves tirelessly over a long period of time. They represent the very best

of our organization,” said ASCO CEO Allen S. Lichter, MD, FASCO. Jonathan S. Berek, MD, MMS, Editor-in-Chief of ASCO Connection and a 2013 FASCO, said, “Working for ASCO is very meaningful because we, as volunteers, are able to foster improvements in all aspects of cancer discovery and care—and to contribute to the clinical, scientific, and social issues

that are critical to advance the causes of improved discovery, prevention, treatment, and delivery of essential cancer care.” n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Members Honored with FASCO Distinction.” ASCO Connection, September 2013: p 33. All rights reserved.

New FASCO Class

Gary I. Cohen, MD, FASCO

Jonathan S. Berek, MD, MMS, FASCO

Dean E. Brenner, MD, FASCO University of Michigan Comprehensive Cancer Center

Cancer Center at Greater Baltimore Medical Center

Michael P. Kosty, MD, FACP, FASCO

Neal J. Meropol, MD, FASCO

Ann H. Partridge, MD, MPH, FASCO

Stanford Women’s Cancer Center

Scripps Clinic

Case Western Reserve University

Dana-Farber Cancer Institute

Leon H. Dragon, MD, FACP, FASCO

NorthShore Kellogg Cancer Center

Julie Vose, MD, MBA, FASCO University of Nebraska Medical Center

Lee M. Ellis, MD, FASCO

The University of Texas MD Anderson Cancer Center

Peter Paul Yu, MD, FASCO Palo Alto Medical Foundation

Daniel F. Hayes, MD, FASCO University of Michigan Comprehensive Cancer Center

Robin Zon, MD, FACP, FASCO Michiana Hematology Oncology

Cancer.Net Launches New Brand of Printed Materials With Four Guides to Cancer

D

uring the second half of 2013, four new guides to cancer, known collectively as the ASCO Answers Guides to Cancer, were released on Cancer.Net, ASCO’s patient information website. The guides to breast, prostate, lung, and colorectal cancer were completely redesigned and reimagined to help newly diagnosed patients better understand their diagnosis and treatment options. These comprehensive, patientfriendly booklets not only contain the trusted information about diagnosis,

treatment, side effects, and psychosocial effects found on Cancer.Net, but also allow patients to record the specifics of their individual diagnosis and treatment plan. Throughout each guide are questions patients can ask their health-care team, as well as space to write down the answers and make other notes. There are also check boxes oncologists and nurses can use to help their patients keep track of the tests, procedures, and treatments they will be receiving. This feature allows patients to

easily go back and find the most pertinent information and talk about it with their friends and family members. The Cancer.Net Editorial Board played a key role in the development and review of the new guides, including Robert S. Miller, MD, FACP, current Cancer.Net Editor-in-Chief; Richard M. Goldberg, MD, Associate Editor, Gastrointestinal Cancers; Maha Hussain, MD, Associate Editor, Genitourinary Cancers; David H. Johnson, MD, FACP, Associate

Editor, Lung Cancer; Lidia Schapira, MD, Associate Editor, Psychosocial Oncology; and Diane Blum, MSW, former Cancer.Net Editor-in-Chief.

Introducing ASCO Answers The development and release of the new guides launched the larger ASCO Answers redesign and rebranding effort. ASCO Answers started as a collection of one-page fact sheets on common cancer types and cancer-related topcontinued on page 73


ASCOPost.com  |   JANUARY 15, 2014

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Direct From ASCO New Guides to Cancer continued from page 72

ics. Then in late 2012, the name ASCO Answers was broadened to include all of the printed patient education materials found on Cancer.Net. Now, when patients and caregivers pick up a fact sheet, guide, or booklet and see ASCO Answers, they will know immediately that they are holding a trusted, high-quality resource reviewed and approved by ASCO experts. As the ASCO Answers brand has expanded to include the guides and booklets, these materials have been updated with a fresh design and photos, many of which depict ASCO members in practice. By combining oncologist-approved information, a conversational tone, and a reassuring look and feel, the new ASCO Answers materials give patients and their caregivers the tools and resources they need to become active, informed participants in their cancer care.

Other ASCO Answers Guides In addition to the new guides to breast, prostate, lung, and colorectal cancer, other recently updated ASCO Answers materials include the Advanced Cancer Care Planning and Managing the Cost of Cancer Care booklets. Advanced Cancer Care Planning is a compassionate, authoritative resource that assists patients and their families/ caregivers in navigating the complex personal choices associated with an advanced cancer diagnosis. Managing the Cost of Cancer Care provides practi-

The Latest Gastrointestinal Cancer News for Patients

T

he 2014 Gastrointestinal Cancers Symposium is taking place now. Direct your patients to www.cancer.net/ gisymposium for summaries of the research being highlighted, including what the latest research means for their care. Your patients can also download or listen to a podcast with an ASCO expert explaining the importance of this research. n

© 2014. American Society of Clinical Oncology. All rights reserved.

cal guidance for patients and families to help them identify medical and associated costs and better cope with the financial impact of a cancer diagnosis.

Download or Order Materials The ASCO Answers guides to breast, prostate, lung, and colorectal cancer can be downloaded and

printed for individual use at no cost from Cancer.Net (www.cancer.net/ guides). Professionally printed copies of each guide can be purchased in packs of 50 from the ASCO University Bookstore (www.cancer.net/ estore). Advanced Cancer Care Planning , Managing the Cost of Cancer Care, and ASCO Answers fact sheets

are also available online (www.cancer .net/ascoanswers) and through the online bookstore in packs of 125. ASCO members receive a 20% discount, and all patient education materials ship for free. n © 2014. American Society of Clinical Oncology. All rights reserved.


The ASCO Post  |   JANUARY 15, 2014

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Direct From ASCO

The Conquer Cancer Foundation Celebrates 15 Years of Funding ASCO and Cancer Progress

W

hile ASCO celebrates its 50th anniversary in 2014, the Conquer Cancer Foundation is also marking a milestone: its 15th anniversary and longtime dedication to improving the lives of people who have been touched by cancer. To accelerate progress against

cancer, ASCO established the Foundation in 1999 to seek dramatic advances in the prevention, treatment, and cures of all types of cancer. Initially called The ASCO Foundation, the organization was renamed the Conquer Cancer Foundation in 2011 to reflect the passion for conquering cancer among its donors, many of whom are ASCO members. Although the Foundation has been

around for more than a decade, many people do not know that the Conquer Cancer Foundation provides funding for the majority of ASCO’s current programs. ASCO and the Foundation work in tandem to advance cancer care, and many of ASCO’s critical programs would not be possible without support from Conquer Cancer Foundation donors and their passion for fueling progress against cancer. In parallel with the growth of ASCO and the field of oncology, the Conquer Cancer Foundation has kept pace, expanding its portfolio of funding opportunities and working closely with donors to support ambitious new initiatives. Thanks to Foundation donors, collectively over the last 15 years the Foundation has been able to provide more than $1.3 million to fund physician training and education for oncologists in limited-resource countries and more

the world. We invite you to join us and ASCO in supporting the next 50 years of progress against cancer by making a gift at ConquerCancerFoundation.org /donate today. n

than $72 million to fund ASCO members conducting clinical cancer research. The Foundation is proud to celebrate 15 years of funding breakthrough cancer research, sharing cutting-edge knowledge with patients and physicians, and enhancing the quality of care for people with cancer around

Volume 29, Issue 15

May 20, 2011

© 2014. American Society of Clinical Oncology. All rights reserved.

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

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

What’s Hot in

JCO

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

www.jco.org

JCO.org Sunitinib Versus Sorafenib in Advanced Hepatocellular Cancer: Results of a Randomized Phase III Trial by Ann-Lii Cheng, et al

American Society of Clinical Oncology 2013 Top Five List in Oncology

ASCO Resources for Transitioning to ICD-10

A

SCO has developed resources to educate and assist oncology practices in transitioning to the 10th Edition of the Center for Medicare and Medicaid Services International Classification of Diseases (ICD-10) coding system.  Practices are encouraged to prepare for the transition before the October 1, 2014, deadline. On that date, ICD will fully replace ICD-9 and providers may no longer bill with ICD-9 codes. Therefore, it is important to take the time to educate oneself about ICD-10 and determine what impact it will have on your prac-

by Lowell E. Schnipper, et al

Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma In Situ: 15-Year Recurrence Rates and Outcome

tice. ASCO has provided online resources for transitioning to ICD-10 at www.asco.org/practice-research/icd -10/. In addition, CMS has developed an online ICD-10 implementation guide that provides step-by-step guidance on how to transition to ICD-10, which is available at implementicd10 .noblis.org/ If you have any questions regarding ICD-10, please contact ASCO via email at billingandcoding@asco.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

After a Recurrence, From the EORTC 10853 Randomized Phase III Trial by Mila Donker, et al

Oral Contraceptives and Risk of Ovarian Cancer and Breast Cancer Among High-Risk Women: A Systematic Review and Meta-Analysis by Patricia G. Moorman, et al

Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597 by Daniel D. Karp, et al


Up the AntiEGFR Start ERBITUX® (cetuximab) in 1st-Line I N D I C AT I O N S Head and Neck Cancer—ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck Colorectal Cancer—ERBITUX is indicated for the treatment of KRAS mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use, in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer EGFR=epidermal growth factor receptor.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks — Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy

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


START WITH THE EXTREME

Regimen

EXTREME=ERBITUX® (cetuximab) in first-line Treatment of REcurrent or MEtastatic head and neck cancer. EXTREME Regimen=EU-approved cetuximab combined with platinum-based therapy with 5-FU.

The First Regimen Approved in 30 Years With Extended Overall Survival for Recurrent Locoregional or Metastatic SCCHN EXTREME REGIMEN (n=222)1

vs

PLATINUM-BASED THERAPY WITH 5-FU (n=220)1

EXTENDED Median Overall Survival

(OS) (Primary Endpoint)

10.1 MONTHS

36% IMPROVEMENT IN OS*

7.4

MONTHS

HR=0.80 (95% CI: 0.64–0.98); p=0.034

IMPROVED Objective Response Rates (Reduced Tumor Size)†

20%

36%

PATIENTS

PATIENTS

OR=2.33 (95% CI: 1.50–3.60); p=0.0001

PROLONGED Median Progression-Free Survival

5.5

MONTHS

3.3

MONTHS

HR=0.57 (95% CI: 0.46–0.72); p<0.0001 * Relative improvement in median overall survival for the EXTREME regimen was ([10.1-7.4]/7.4) x 100%=36%.1 †

Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 CI=confidence interval; CT=platinum-based therapy with 5-FU; HR=hazard ratio; OR=odds ratio; SCCHN=squamous cell carcinoma of the head and neck.

The EXTREME Study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared EU-approved cetuximab + CT versus CT alone. Choice of platinum therapy (cisplatin or carboplatin) was up to the treating physician. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately 15% of the patients in the cisplatin-alone arm switched to carboplatin during the treatment period. In exploratory subgroup analyses of the EXTREME Study by initial platinum therapy (cisplatin or carboplatin), for patients (n=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 vs 7.3 months, respectively; HR=0.71 [95% CI: 0.54–0.93]). The difference in median progression-free survival was 2.1 months (5.6 vs 3.5 months, respectively; HR=0.55 [95% CI: 0.41–0.73]). The objective response rate was 39% and 23%, respectively (OR=2.18 [95% CI: 1.29–3.69]). For patients (n=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 vs 8.3 months; HR=0.99 [95% CI: 0.69–1.43]). The difference in median progression-free survival was 1.7 months (4.8 vs 3.1 months, respectively; HR=0.61 [95% CI: 0.42–0.89]). The objective response rate was 30% and 15%, respectively (OR=2.45 [95% CI: 1.10–5.46]).1 The EXTREME Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in these studies; these pharmacokinetic data, together with the results of the EXTREME Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in SCCHN.1

IMPORTANT SAFETY INFORMATION (continued) Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX


START WITH THE CRYSTAL

Regimen

CRYSTAL=Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer. CRYSTAL Regimen=EU-approved cetuximab + FOLFIRI; FOLFIRI=irinotecan, 5-fluorouracil, and leucovorin.

The First and Only Biomarker-Directed Therapy for Newly Diagnosed KRAS Mutation-Negative (Wild-Type) EGFR-Expressing mCRC1 ALL-RANDOMIZED PATIENT POPULATION1 CRYSTAL Regimen (n=608)

Median Overall Survival*

KRAS WILD-TYPE SUBPOPULATION1 P O S T- H O C A N A LY S I S

FOLFIRI alone (n=609)

CRYSTAL Regimen (n=320)

18.5

23.5

(95% CI: 18–21)

(95% CI: 17–20)

(95% CI: 21–26)

MONTHS

MONTHS

HR=0.88 (95% CI: 0.78–1.0)

Objective Response Rates (Reduced Tumor Size)‡

46%

19.5 MONTHS

(95% CI: 17–21)

HR=0.80 (95% CI: 0.67–0.94)†

38%

57%

IMPROVED

39%

PATIENTS

PATIENTS

PATIENTS

PATIENTS

(95% CI: 42–50)

(95% CI: 34–42)

(95% CI: 51–62)

(95% CI: 34–44)

PRIMARY ENDPOINT Median Progression-Free Survival

EXTENDED

19.6 MONTHS

FOLFIRI alone (n=356)

8.9

8.1

9.5

MONTHS

MONTHS

(95% CI: 8.0–9.4)

(95% CI: 7.6–8.8)

PROLONGED

8.1

MONTHS

MONTHS

(95% CI: 8.9–11.1)

(95% CI: 7.4–9.2)

HR=0.85 (95% CI: 0.74–0.99); p=0.0358

§

HR=0.70 (95% CI: 0.57–0.86)

In all randomized patients, overall survival was not significantly different at the planned, final analysis based on 838 events (HR=0.93 [95% CI: 0.8–1.1]; p=0.327). Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer. •The primary endpoint for the study was progression-free survival in the all-randomized patient population. * Post-hoc updated overall survival analysis based on an additional 162 events.1

Not significantly different.1 Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 § Based on the stratified log-rank test.1 CI=confidence interval; HR=hazard ratio; mCRC=metastatic colorectal cancer.

The CRYSTAL Study was a Phase 3, open-label, randomized, multicenter study of 1217 patients with EGFR-expressing mCRC. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI (the CRYSTAL Regimen) or FOLFIRI alone as first-line treatment. KRAS mutational status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had KRAS mutation-negative (wild-type) tumors. Post-hoc analyses of efficacy data were performed on patient subgroups defined by KRAS mutation status.1 The CRYSTAL Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in this study; these pharmacokinetic data, together with the results of the CRYSTAL Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in mCRC.1

IMPORTANT SAFETY INFORMATION (continued) Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

UP THE ANTI-EGFR


Dermatologic Toxicities ■ In clinical studies of ERBITUX (cetuximab), dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients —Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae —Sun exposure may exacerbate these effects Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3–4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy —Replete electrolytes as necessary Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX Adverse Reactions ■ The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

CONTACT your sales representative or call 1-800-805-1058 (8 AM-8 PM EST, M-F) to receive patient education materials, enrollment information, and forms

Phone 1-800-861-0048 or Fax 1-888-776-2370 8 AM to 8 PM EST, M-F Please see enclosed Full Prescribing Information, including Boxed WARNINGS. References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; March 2013. 2. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981;47(1):207-214. 3. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.

SCAN QR CODE for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2013 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US13BR00848-03-01

4/13

UP THE ANTI-EGFR


ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]

• i n combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, • in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy, • as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. 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. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 b 15 3 2 0 Infusion Reaction Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 c 43 2 21 1 Alanine Transaminase, high Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages d 87 17 10 1 Acneiform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.


Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux (cetuximab) in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). Table 2:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU 5-FU Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations b 44 11 27 8 Infection Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders c 70 9 2 0 Acneiform Rash Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). Table 3:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades 1–4b 3 and 4 1–4 3 and 4 Preferred Term % of Patients Blood and Lymphatic System Disorders Neutropenia 49 31 42 24 Eye Disorders Conjunctivitis 18 <1 3 0 Gastrointestinal Disorders Diarrhea 66 16 60 10 Stomatitis 31 3 19 1 Dyspepsia 16 0 9 0 General Disorders and Administration Site Conditions 14 2 <1 0 Infusion-related Reactionc Pyrexia 26 1 14 1 Infections and Infestations Paronychia 20 4 <1 0 Investigations Weight Decreased 15 1 9 1 Metabolism and Nutrition Disorders Anorexia 30 3 23 2 (Continued)

Table 3: (Continued)

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades 1–4b 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous Tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). Table 4:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya Erbitux plus BSC BSC alone (n=118) (n=124) Grades Grades Grades Body System Grades 3 and 4 1–4 3 and 4 Preferred Term 1–4b % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 c 18 3 0 0 Infusion Reactions Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 Infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.


The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of Erbitux. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Aseptic meningitis • Mucosal inflammation DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of 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, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, 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 cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

Geriatric Use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2013 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved. 1236886B3

Rev March 2013 693US13PBS02001

Don’t Miss These Important Reports in This Issue of The ASCO Post 693US13BR00848-01-03 UpTheAntiAd HalfPage/TrimSize: 10.5”x7”

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Daniel Morgensztern, MD, and Roy S. Herbst, MD, PhD, on Adjuvant Gefitinib in NSCLC see page 96

Lorenzo Cohen, PhD, on Stress and Tumor Biology see page 115

Laura P. Forsythe, PhD, MPH, and Mary McCabe, RN, MS, on Survivorship Care Planning see pages 128 and 129

Annie Parker, on Genetics and Breast Cancer: A Patient’s Perspective see page 112

Deborah Dudgeon, MD, FRCPC, on Assesing Patients for Palliative Care see page 119

Mark W. Dewhirst, DVM, PhD, on Hyperthermia for Cancer Treatment see page 142

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The ASCO Post  |   JANUARY 15, 2014

PAGE 82

Journal Spotlight Genitourinary Oncology

L-Type Amino Acid Transporters (LAT) Inhibition May Be a New Therapeutic Option for Metastatic Castration-Resistant Prostate Cancer By Matthew Stenger

L

-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mTOR complex 1 (mTORC1) signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer and are involved in increasing nutrients and stimulating cell growth. In a study reported in the Journal of the National Cancer Institute, Qian Wang, PhD, of the Origins of Cancer Laboratory, Centenary Institute, in Newton, Australia, and colleagues assessed the role of LAT3 function in prostate cancer.1 They found that inhibition of LAT transporters, and thus leucine uptake, may constitute a new strategy in metastatic castration-resistant prostate cancer.

Study Details In the study, LAT3 protein expression was assessed in human prostate cancer tissue microarrays, which contained samples from patients with prostatic intraepithelial neoplasia or Gleason-graded prostate cancer (n = 88) and from patients at different stages after neoadjuvant hormone therapy (n = 72). LAT function was inhibited using the leucine analog BCH in androgen-dependent and androgenindependent environments, and gene expression was analyzed by microarray. The effects of inhibition of LAT1 and LAT3 expression were examined in a PC-3 xenograft mouse model.

ATF4-Mediated Upregulation of Amino Acid Transporters LAT3 expression was detected at all stages of prostate cancer, with no differences in expression by Gleason grades. Compared with untreated patients (n = 123 cores), those undergoing neoadjuvant hormone therapy showed a decrease in LAT3 expression that became significant after 4 to 7 months (25.1% decrease; 4–7 month mean score = 1.571, 95% confidence interval [CI]  = 1.155–1.987, vs 0 month mean score = 2.098, 95% CI = 1.962–2.235, P = .0187). Inhibition of LAT function with BCH led to activating transcription factor 4 (ATF4)-mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc,

all of which were also regulated by the synthetic androgen R1881. ASCT1, ASCT2, and 4F2hc protein levels showed increased expression after leucine deprivation and in the presence of dihydrotestosterone, indicating that these proteins are regulated by both ATF4 and the androgen receptor.

M-Phase Cell-Cycle Genes Analysis to determine which gene sets and pathways are altered by BCH treatment showed substantial enrichment of gene sets involved in cellcycle regulation including spindle formation, microtubule cytoskeleton, M phase, mitosis, cell-cycle process, and cell-cycle phase genes and a sig-

Targeting Amino Acid Transport in Prostate Cancer ■■ Inhibition of LAT function led to ATF4-mediated upregulation of amino acid transporters that are also regulated by the androgen receptor. ■■ LAT inhibition suppressed M-phase cell-cycle genes regulated by E2F family transcription factors, including critical castration-resistant prostate cancer regulatory genes. ■■ LAT1 and LAT3 knockdown in xenografts inhibited tumor growth, cell-cycle progression, and spontaneous metastasis.

cell-cycle progression in androgenindependent prostate cancer cells and have been shown to be critical M-phase regulators of the cell cycle in metastasis. Western blot analysis showed that E2F1, E2F2, CDK1, UBE2C, and CDC20 protein levels

Targeting LAT transporters, thereby inhibiting leucine uptake, may offer a new therapeutic opportunity for metastatic [castration-resistant prostate cancer], affecting tumor growth and metastasis through inhibition of M-phase cell cycle and mTORC1 signaling pathways. —Qian Wang, PhD

nificant enrichment in binding sites for E2F transcription factor, the family members of which regulate the cell cycle and metabolism in cancers. Examination of genes showing significant changes after BCH treatment yielded 122 downregulated genes and 12 upregulated genes; of the 122 downregulated genes, which included transcription factors E2F1 and E2F2, 72 (59%) were related to the cell cycle and proliferation. Further analysis generated a network of downregulated genes from the E2F transcription factors, showing that approximately half of the genes are part of a common cell-cycle regulatory pathway. This analysis indicated that E2F transcription factors have a central role in the regulation of cell-cycle gene expression in prostate cancer. Three of the cell-cycle genes— CDK1 (CDC2), CDC20, and UBE2C (ubiquitin-conjugating enzyme E2C)—are upregulated and control

were slightly decreased in both PC-3 and LNCaP human prostate cancer cells after BCH treatment, with all proteins exhibiting a dramatic decrease after leucine deprivation.

BCH-Downregulated Genes Analysis of metastatic samples showed that the set of enriched genes in metastasis was highly similar to that inhibited by BCH treatment; these included M phase, mitosis, cell-cycle process, and cell-cycle phase genes. Analysis of transcription factor motif gene sets showed enrichment for genes with E2F binding sites, with 17 of 30 of the significantly enriched transcription factor motif gene sets being common to the metastasis-upregulated and BCHdownregulated genes. This analysis suggested that E2Fregulated cell-cycle genes are also crucial for metastatic castration-resistant prostate cancer. Overall, 91% of BCH-downregulated genes in me-

tastasis were significantly upregulated in metastatic patient samples, including E2F1, E2F2, CDK1, CDC20, and UBE2C; 83% of the BCH-upregulated genes were significantly downregulated in metastatic patient samples.

Knockdown of LAT1 and LAT3 The mouse xenograft model used to examine the role of LAT1 and LAT3 in castration-resistant prostate cancer tumor formation employed lentiviral shRNA constructs against either LAT1 or LAT3, which resulted in decreased transporter expression and decreased expression of cell cycle proteins including UBE2C, CDK1, and CDC20. Knockdown of both LAT1 and LAT3 caused a reduction in tumor take rate—ie, 70% for shLAT1 and 61% for shLAT3 cells compared with 83% for shControl cells. Xenografts expressing either shLAT1 or shLAT3 showed significantly decreased tumor growth compared with controls. Analysis of Ki-67 expression in the tumors showed a significant decrease in proliferation for both the shLAT1 and shLAT3 tumors compared with the shControl group. In addition, the xenografts showed decreased expression of CDK1 and UBE2C in shLAT1 and shLAT3 tumors, with CDC20 expression also decreasing in shLAT3 tumors. Organ harvesting showed that 8 of 14 mice with shControl tumors had metastases to the liver, lymph nodes, or lungs, compared with 3 of 13 with shLAT1 tumors (P =.1201) and 1 of 13 with shLAT3 tumors (P = .012) tumors. These findings suggest that depletion of LAT1 or LAT3 expression in prostate cancer cells may also suppress metastatic potential. The investigators concluded: “[W] e have shown that prostate cancer cells continued on page 83


ASCOPost.com  |   JANUARY 15, 2014

PAGE 83

Journal Spotlight

Inhibition of LAT Transporters and Leucine Uptake: A Step Forward for Therapeutic Strategies in Prostate Cancer By Elizabeth R. Kessler, MD, and E. David Crawford, MD

T

he seminal study by Wang and colleagues reported in the Journal of the National Cancer Institute1 and reviewed in this issue of The ASCO Post suggests a potential new therapeutic option in the treatment of advanced prostate cancer. The authors draw attention to the reliance of cancer cells on amino acids and the subsequent nutrient transporters that supply tumors with this metabolic fuel. The amino acid transporters, broken into various families, mediate the transport of amino acids, which then influence cellular signaling pathways. The current report shows the dependence of prostate cancer cells on amino acid uptake through the L-type amino acid transporter (LAT) family of transporters in order to proliferate through activation of the mammalian target of rapamycin complex 1 (mTORC1). The importance of the LAT transporters has been evaluated in preclinical experiments in multiple cancer cell lines,2 and this study expands upon previous work by Holst and colleagues3 illustrating the importance of LAT1 and LAT3 in prostate cancer growth and oncogenesis to now demonstrate the interplay between androgen receptor–dependent genes and the LAT transporters, the role of the transporters in castrateresistant disease, and the effect of inhibition of transport on tumor growth and metastasis. The authors suggest that targeting LAT transporters, and thus influencDr. Kessler is Assistant Professor in the Division of Medical Oncology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, and Dr. Crawford is Professor of Surgery and Radiation Oncology and Head of Urologic Oncology at the University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.

LAT Inhibition continued from page 82

use [androgen receptor] and ATF4 transcriptional pathways to maintain amino acid transporter levels during primary and metastatic prostate cancer. Targeting LAT transporters, there-

ing the uptake of leucine, affects tumor growth and metastasis through inhibition of the mTORC1 signaling pathway and M-phase cell-cycle signals. Consequently, these transporters are potential therapeutic targets in the treatment of advanced prostate cancer, including castrate-resistant disease.

Clinical Impact: Therapeutic Target Treatment options for metastatic prostate cancer have expanded markedly in the last few years. However, many of these newer therapies effec-

advanced prostate cancer. Importantly, this approach is different from the elegant modulation of the androgen receptor that we now rely on in the treatment of castrate-resistant disease. Analysis of microarray data in the study showed that many of the transporters are regulated by the androgen receptor signaling pathway as well as the activating transcription factor 4 (ATF4)-mediated amino acid pathway. Androgen deprivation has been shown to alter the expression levels of transporter genes, and ATF4 expression is increased in metastasis.

While all data reported by Wang and colleagues are preclinical, inhibition of amino acid transporters is an exciting potential therapeutic target in prostate cancer. —Elizabeth R. Kessler, MD, and E. David Crawford, MD

tively decrease circulating testosterone or strengthen androgen receptor blockade. As we improve the manipulation of the androgen axis, we have found that the response to subsequent therapies diminishes.4 This suggests that prostate cancer cells, much like any cancer cell, adapt to rely on varied growth mechanisms and continued mutagenesis for survival. Targeting the LAT transporters is a potential new mechanism to control

The data presented in the study suggest that there is interplay between amino acid transport and castrateresistant disease. Genes associated with the mTORC1 pathway and Mphase cell-cycle genes were altered in castrate-resistant tumor samples; and treatment with BCH, a LAT inhibitor, revealed that genes that are upregulated in castrate-resistant disease were effectively downregulated by treatment in cell culture.

by inhibiting leucine uptake, may offer a new therapeutic opportunity for metastatic [castration-resistant prostate cancer], affecting tumor growth and metastasis through inhibition of M-phase cell cycle and mTORC1 signaling pathways.”

Jeff Holst, PhD, of Origins of Cancer Laboratory, Centenary Institute, is the corresponding author for the Journal of the National Cancer Institute article. n Disclosure: The study authors reported no potential conflicts of interest.

In vivo experiments also supported the necessity of amino acids in prostate cancer development and metastasis, since knockdown of the LAT1 or LAT3 transporter reduced tumor formation, decreased the size of tumors, and decreased the number of noted metastases. Through in vivo knockdown of the transporter gene, or in vitro inhibition by BCH, the growth of prostate cancer was diminished, supporting the potential for success with pharmacologic inhibition in a clinical setting.

Clinical Impact: Biomarker Compared to a number of other malignant neoplasms, there is a paucity of biomarker data in advanced prostate cancer. To address this, the field is rightly focused on exploration and validation of biomarkers to help guide therapeutic decisionmaking. In addition to potential as a therapeutic target, the LAT family of transporters may also serve as a biomarker. LAT1 expression has been postulated as a biomarker in lung cancer5 and may serve as one in prostate cancer, as suggested by the altered expression of LAT1 in association with Gleason score. The gene expression of ATF4 was also upregulated by leucine deprivation and was found to be upregulated in the gene profiles of metastatic castrate-resistant samples, and this may indicate advanced malignancy. LAT inhibition repressed cell-cycle genes, yet these genes were found to be enriched in metastatic samples compared to primary prostate cancer tissue, and some of these genes were associated with poor survival. Additionally, neoadjuvant therapy altered LAT3 expression. Thus, LAT expression may offer more detail on the biology of a patient’s cancer. continued on page 84

Reference 1. Wang Q, Tiffen J, Bailey CG, et al: Targeting amino acid transport in metastatic castration-resistant prostate cancer: Effects on cell cycle, cell growth, and tumor development. J Natl Cancer Inst 105:1463-1473, 2013.


The ASCO Post  |   JANUARY 15, 2014

PAGE 84

Journal Spotlight

LAT Transporters and Leucine Update continued from page 83

Future Considerations The authors concluded that targeting LAT family transporters resulted in inhibition of growth factor and metabolic signaling pathways, inhibition in vivo of growth of prostate cancer tumors, and decreased expression of numerous genes associated with metastatic prostate cancer. The blockade of amino acid transporters, and leucine uptake, is an important potential tool in a field in need of additional mechanisms of treatment for castrateresistant disease. As our knowledge of the biology of castrate-resistant prostate cancer evolves, we will need to rely on identification and effective blockade of other pathways beyond the androgen receptor. Other than the multitargeted kinase inhibitor cabozantinib (Cometriq), there are few candidate pathway inhibitors under current investigation. Agents targeting the mTORC1 and PI3K pathways are in early-phase trials. While all data reported by Wang and colleagues are preclinical, inhibition of amino acid transporters is an exciting potential therapeutic target in prostate cancer. n

2. Fuchs BC, Bode BP: Amino acid transporters ASCT2 and LAT1 in cancer: Partners in crime? Semin Cancer Biol 15:254-266, 2005. 3. Wang Q, Bailey CG, Ng C, et al: Androgen receptor and nutrient signaling pathways coordinate the demand for

increased amino acid transport during prostate cancer progression. Cancer Res 71:7525-7536, 2011. 4. Noonan KL, North S, Bitting RL, et al: Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer pro-

gressing after enzalutamide. Ann Oncol 24:1802-1807, 2013. 5. Kaira K, Oriuchi N, Imai H, et al: Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer 98:742-748, 2008.

What if you could help the immune system respond to cancer cells? PD-L1 expression helps tumor cells evade the immune system programmed death-ligand 1 (PD-L1), which binds to the PD-1 and B7.1 receptors on Tumor expression of

T cells, deactivates T-cell–mediated cytotoxicity. This inhibits the immune

Disclosure: Drs. Kessler and Crawford reported no potential conflicts of interest.

References 1. Wang Q, Tiffen J, Bailey CG, et al: Targeting amino acid transport in metastatic castration-resistant prostate cancer: Effects on cell cycle, cell growth, and tumor development. J Natl Cancer Inst 105:1463-1473, 2013.

system and allows the tumor to continue to grow.1 Nearly all cancer types show increased expression of PD-L1.2

PD-1

Inactivated T cell

PD-L1 TCR

The ASCO Post Follow us on

@ASCOPost

B7.1

MHC

Tumor cell

PD-L1

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307-314. 3. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol. 2012;13:1129-1132.

© 2013 Genentech USA, Inc. All rights reserved. BIO0001911700 Printed in USA.


ASCOPost.com  |   JANUARY 15, 2014

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Announcements

Julie M. Vose, MD, MBA, FASCO, Elected ASCO President for 2015–2016 Term

J

ulie M. Vose, MD, MBA, FASCO, has been elected President of ASCO for a 1-year term beginning in June 2015. She will take office as PresidentElect during the ASCO Annual Meeting in Chicago in June 2014.

“ASCO is a very diverse and multifaceted organization with so much to offer its membership. The recent enhancements in the educational offerings, quality improvement, broadened advocacy, and the potential for

comparative effectiveness research with CancerLinQ™ are just a few of the ASCO areas where I believe my experience and training will add to the current activities,” Dr. Vose said. “I am excited to serve the ASCO member-

ship as President and to make a difference for oncology professionals and our patients.” Dr. Vose is the Neumann M. and Mildred E. Harris Professorial Chair

Julie M. Vose, MD, MBA, FASCO

and Chief of the Oncology/Hematology Division in the Department of Internal Medicine at the University of Nebraska Medical Center, and the Associate Director of Clinical Research and Co-Chair of the Lymphoma Program at the Fred and Pamela Buffet Cancer Center. Since joining ASCO in 1991, she has served on the Board of Directors, as Chair of the Cancer Education Committee, and is the current Chair-Elect of the Integrated Media and Technology Committee, among other activities.

Blocking PD-L1 may restore the body’s adaptive immune response Genentech is investigating the strategy of inhibiting the interaction between tumor-expressed PD-L1 and its receptors on T cells; blocking this interaction may restore the body’s adaptive immune system to respond to cancer cells.1 Research is also under way to validate PD-L1 as a potential biomarker for cancer immunotherapy.3

Activated T cell

B7.1

ASCO is a very diverse and multifaceted organization with so much to offer its membership. —Julie M. Vose, MD, MBA, FASCO

TCR

MHC

Tumor cell death

PD-1

Explore the role of cancer immunotherapy and PD-L1 inhibition at ResearchCancerImmunotherapy.com

Since 2006, Dr. Vose has served as the Associate Director of Clinical Research and is Co-Chair of the Lymphoma Program at the Fred and Pamela Buffet Cancer Center. She is a member of the Board of Directors for the University of Nebraska Medical Center Physicians Group. She is Co-Chair of the Lymphoma Steering Committee for the National Cancer Institute and serves on the U.S. Food and Drug Administration Oncologic Drugs Advisory Committee. Additionally, four new members were elected to the ASCO Board of Directors and two new members to the ASCO Nominating Committee. See page 100 for information on these oth­ SCO’s er newly elected members of A Board of Directors and the ASCO Nominating Committee. n


The ASCO Post  |   JANUARY 15, 2014

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In the Clinic

Sorafenib in Differentiated Thyroid Carcinoma 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.

New Indication On November 22, 2013, sorafenib (Nexavar) was approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.1,2 Sorafenib was previously approved for treatment of renal cell carcinoma (2005) and hepatocellular carcinoma (2007). The current approval is based on the finding of significantly increased progression-free survival with sorafenib vs placebo in a phase III multicenter, double-blind trial in which 417 patients were randomly assigned to receive sorafenib at 400  mg twice daily orally (n  =  207) or placebo (n  =  209).2 Overall, 52% of patients were female, median age was 63

OF NOTE Sorafenib inhibits multiple intracellular and cell surface kinases thought to be involved in tumor cell signaling, angiogenesis, and apoptosis.

years (61% ≥ 60 years), 60% were white, 62% had Eastern Cooperative Oncology Group performance status of 0, and 99% had undergone thyroidectomy. Histologic diagnoses included papillary carcinoma in 57%, follicular carcinoma in 25%, and poorly differentiated carcinoma in 10%. Metastases were present in 96% of patients, with sites including lungs in 86%, lymph nodes in 51%, and bone in 27%. The median cumulative radioactive iodine activity administered prior to study entry was 400  mCi. Radioactive iodine refractoriness was indicated by target lesion with no iodine uptake on

radioactive iodine scan in 68%, tumors with iodine uptake and progression after radioactive iodine treatment within 16 months of enrollment in 12%, tumors with iodine uptake and multiple radioactive iodine treatments with the last treatment greater than 16 months prior to enrollment and disease progression after each of two radioactive iodine treatments within 16 months of each other in 7%, and cumulative radioactive iodine dose ≥ 600 mCi in 34%. Median progression-free survival was 10.8 months in the sorafenib group and 5.8 months in the placebo group (hazard ratio [HR] = 0.59, P < .001). Objective response occurred in 24% vs 0.5% of patients, and median response duration was 10.2 months in the sorafenib group. After progression, 75% of the placebo group crossed over to sorafenib treatment and 30% of the sorafenib group received open-label sorafenib. Median overall survival was not reached in the sorafenib group and was 36.5 months in the placebo group (HR = 0.88, P = .47).

How It Works Sorafenib inhibits multiple intracellular (c-CRAF, BRAF, and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, RET/PTC, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß), several of which are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. The drug results in decreased tumor cell proliferation in vitro, inhibits tumor growth of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma xenografts in immunocompromised mice, reduces tumor angiogenesis in models of hepatocellular carcinoma and renal cell carcinoma, and increases tumor apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma.

How It Is Given The recommended daily dose of sorafenib is 400 mg taken twice daily without food. Treatment should continue

Sorafenib in Thyroid Cancer ■■ In addition to previous indications in renal cell carcinoma and hepatocellular carcinoma, sorafenib (Nexavar) was recently approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment. ■■ The recommended daily dose of sorafenib is 400 mg taken twice daily without food, until loss of clinical benefit or unacceptable toxicity.

until loss of clinical benefit or unacceptable toxicity. Interruption of treatment is recommended in patients undergoing major surgical procedures, and interruption or discontinuation may be required for cardiac ischemia or infarction, hemorrhage requiring medical intervention, severe or persistent hypertension despite adequate antihypertensive therapy, gastrointestinal perforation, QTc prolongation, or severe drug-induced liver injury.

OF NOTE Sorafenib carries warnings/precautions for cardiac ischemia or infarction, bleeding, hypertension, dermatologic toxicities, gastrointestinal perforation, QT prolongation, drug-induced hepatitis, impairment of TSH suppression, and embryofetal toxicity.

When dose reductions are required, doses are reduced sequentially to 400 mg and 200 mg doses 12 hours apart, 200 mg twice daily, and 200 mg once daily. The product labeling provides specific recommendations for dose reductions for dermatologic toxicities. Concomitant use of strong CYP3A4 inducers (eg, rifampin, carbamazepine) should be avoided.

Safety Profile In the phase III trial, adverse events resulted in dose interruptions in 66% and dose reductions in 64% of sorafenib recipients and in treatment discontinuation in 14% of sorafenib recipients and 1% of placebo recipients. The most common adverse events of any grade in sorafenibtreated patients were palmar-plantar erythrodysesthesia syndrome (69% vs 8% with placebo), diarrhea (68% vs 15%), alopecia (67% vs 8%), weight loss (49% vs 14%), hypertension (41% vs 12%), fatigue (41% vs 20%), rash (35% vs 7%), and decreased appetite (30% vs 5%). Grade 3 adverse events occurred in 53% of sorafenib patients and 23% of placebo patients and grade 4 adverse events occurred in 12% and 7%; the most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (19% vs 0%), hypertension (10% vs 2%), diarrhea (6% vs 1%), weight loss (6% vs 1%), rash (5% vs 0%), and fatigue (5% vs 1%). Squamous cell carcinoma of the skin occurred in 3% of sorafenib patients. Alanine aminotransferase and aspar-

tate aminotransferase elevations were observed in 59% and 54% of sorafenib patients and in 24% and 15% of placebo patients, with grade 3 or higher elevations observed in 4% and 2% of sorafenib patients and in no placebo patients. Hypocalcemia (which was more common and severe in differentiated thyroid carcinoma patients than in renal cell carcinoma or hepatocellular carcinoma patients) occurred in 36% of sorafenib recipients and 11% of placebo recipients, with grade 3 or higher events occurring in 10% and 3%. Other laboratory abnormalities that have occurred in >  10% of sorafenibtreated patients in trials in differentiated thyroid carcinoma, renal cell carcinoma, and hepatocellular carcinoma include leukopenia, lymphopenia, hypokalemia, hyponatremia, and hypothyroidism. Thyroid suppression to thyroid-stimulating hormone (TSH) levels < 0.5 mU/L was present in 99% of patients at baseline. TSH elevations to > 0.5 mU/L were observed in 41% of sorafenib-treated patients and 16% of patients receiving placebo, with a median time to loss of adequate thyroid suppression of 4.6 months in the sorafenib group (range, 1–22 months). An increase in thyroid replacement medication was necessary to regain thyroid suppression. The sorafenib label includes warning/ precautions for cardiac ischemia or infarction, bleeding, hypertension, dermatologic toxicities, gastrointestinal perforation, QT prolongation, drug-induced hepatitis, impairment of TSH suppression, and embryo-fetal toxicity. Blood pressure should be monitored weekly during the first 6  weeks of treatment and periodically thereafter. ECGs and electrolytes should be monitored in patients at increased risk of ventricular arrhythmias. Liver function tests should be regularly monitored. Inadequate TSH suppression may promote thyroid cancer; TSH levels should be monitored monthly and thyroid replacement therapy adjusted. Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. n References 1. U.S. Food and Drug Administration: Sorafenib (Nexavar). Available at http:// www.fda.gov/drugs/informationondrugs/ approveddrugs/ucm376547.htm. 2. NEXAVAR® (sorafenib) tablets prescribing information. Bayer HealthCare Pharmaceuticals Inc, November 2013. Available at http://labeling.bayerhealthcare.com/ html/products/pi/Nexavar_PI.pdf.


ASCOPost.com  |   JANUARY 15, 2014

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Future of Oncology Overcoming Drug Development Challenges in the New Era of Cancer Care A Conversation With Manfred Lehnert, MD By Jo Cavallo

Manfred Lehnert, MD

W

hile the last 15 years have brought unprecedented advances in oncology drug development, the next 10 years promise to usher in even greater opportunities to realize the goal of precision medicine in the treatment of cancer, providing patients with more effective care and better outcomes. Reaching that goal will also entail overcoming unprecedented challenges, according to Manfred Lehnert, MD, Group Head, Oncology Clinical Research, Takeda Pharmaceuticals International, Inc. The ASCO Post talked with Dr. Lehnert about those challenges and how they can be overcome in the new era of cancer care.

New Paradigm What will be the paradigm for oncology drug development in the future? In the future—and that future is well underway—cancer will be predominantly classified by its genetic and molecular characteristics. As a result, there will be many hundreds if not thousands of distinct malignant entities, and common cancers, such as lung and breast, will largely cease to exist. This means that cancer will become a group of multiple orphan diseases, and this prospect is posing unprecedented challenges for the oncology community. My view is that collaboration among all the stakeholders, including research foundations, academic institutions, regulatory agencies, payers, patients, patient advocacy groups, physicians, and the biopharmaceutical industry, is vital for making the major progress we require and expect in the treatment of cancer. Takeda’s strong commitment to external collaboration includes models for more efficient ways to conduct clini-

cal studies and develop drugs in the new era of precision medicine in oncology. One example of that is the MATCH study, which the National Cancer Institute is launching. The study will screen about 3,000 patients with advanced cancers to find approximately 1,000 cancers with genetic mutations. The ultimate goal will be to determine which new therapies, including ones not yet approved for use, are made available by the pharmaceutical industry through collaborative arrangements. Another example is the WIN Consortium and the WINTHER project, through which an international consortium of members will use an algorithmbased bioinformatics tool to examine DNA and RNA data from dual biopsies of tumors and normal tissues and then provide relevant drug-target gene matches to improve treatments for patients in the trial. Drugs in the early stages of development will also be further investigated by this approach. These are two examples of what I believe is a new paradigm for drug development in oncology. Enterprises such as

early examples of efforts being made along those lines. Another important challenge to overcome is the redundancy that exists in the system when it comes to oncology drug development. For many actionable molecular targets, a half-dozen compounds may be in clinical development—compounds that often have only marginal differences. This redundancy is a waste of resources and slows down progress.

New Research Strategies How will drugs be investigated and tested for the specific molecular characteristics of each type of cancer in individual patients? This is one of our major new challenges. We have categorized cancer into about 200 distinct malignant diseases, but in the future, that number will be in excess of a thousand, which will impact many things including research and clinical care. For example, how will randomized phase  III clinical trials be executed? How much time will it take to complete

A major need and critical collateral of what we are talking about here is that we all need to aim for big improvements in outcome. Incremental improvements are no longer good enough. —Manfred Lehnert, MD

these highlight a critical need for close cooperation among academia, nonprofit organizations, and across industry.

Intellectual Property Issues In these types of collaborative efforts among pharmaceutical companies, who owns the patents on new medicines? The fundamental thinking and attitude needs to be that resolving the issue of intellectual property is a must in order to make major progress fast and to enable efficient oncology drug development. But intellectual property interests are not limited to the pharmaceutical industry. This issue also comes up in partnerships with major academic institutions, and traditionally it requires case-by-case discussions and negotiations for resolution. Ultimately, there needs to be a master framework to resolve this issue, and there are positive

such studies? How will we identify small subsets of patients with the molecular aberration targeted by a drug, and how will those patients be able to access appropriate trials? This is a major logistical effort, costly to do, and, importantly, it means that a majority of patients who have undergone testing will be disappointed because they don’t carry that mutation and do not qualify for the study. A major need and critical collateral of what we are talking about here is that we all need to aim for big improvements in outcome. Incremental improvements are no longer good enough. Big improvements are what cancer patients need and what they are waiting for. At the same time, these new approaches will allow the conduct of smaller randomized studies. In certain situations, randomized studies may not

be required at all, because the response rate and response durability will be so much better than historic data. As we get smarter at matching the right drug to the right molecular characteristics identified in the right patients, these needs and goals will be realized.

Drug Development Costs Will the process of individualizing treatment for patients add to the cost of drug development and approval? That is difficult to predict; it can go either way. A large part of the high development cost of drug research is driven by failure in phase III trials, because this is where most of the money gets spent. So we need to make sure that we dramatically increase the probability of success when a drug enters phase III trials, and I believe that the new science of oncology will enable us to do that. We need to perform rich scientific interrogation in early-phase development and apply an N-of-1 or single-subject approach to clinical trials. That is, we have to learn as much as we can about each patient, including the molecular makeup of the patient’s disease—ideally, before treatment and at the time of disease progression—and about the drug’s clinical and molecular effects. Early on in the process, we need to filter out the more likely winner compounds from the more likely losers. Again, large treatment effects and outcome improvements should be the key criteria. This should enable many more drugs to succeed in pivotal-phase development. While this strategy may help reduce cost, there will be added costs for molecular diagnostics, tissue processing, and compensation for study sites. There cannot be precision medicine without precision diagnostics, and the traditional business model of the diagnostic industry will need to change. Forming close partnerships between the biopharmaceutical industry and diagnostic companies early on, when there is still considerable risk for failure, will be absolutely critical for success. We have already started seeing that change: Some diagnostic companies are much more willing to accept higher risk and to partner with the biopharmaceutical industry in codeveloping a drug and a diagnostic assay. continued on page 92


NOW INDICATED

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (mPAC), in combination with gemcitabine.

ignite survival in first-line mPAC Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to

patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may

substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dosedependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • 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 • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)


Significant and clinically meaningful survival in first-line mPAC ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5 months months

(95% CI: 7.9-9.5)

6.7

months

(95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83) a

0.2

P<0.0001b

0.1 0.0 0 Patients at risk A+G: 431 G: 430

3

6

9

12

15

18

21

24

27

30

33

36

39

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. a

metastasis (yes vs no).

b

STUDY DESIGN The multinational, randomized, phase III MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with mPAC. The primary end point was OS.

T:14”

B:14.25”

S:13”

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%),

headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel 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, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages. For more information, please visit www.abraxane.com. ABRAXANE® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 09/13 US-ABR130068a

Geriatric • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary for metastatic adenocarcinoma of the pancreas; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.3)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. 2 DOSAGE AND ADMINISTRATION 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)]. 2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3. Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level

ABRAXANE (mg/m2)

Gemcitabine (mg/m2)

Full dose

125

1000

1st dose reduction

100

800

2nd dose reduction

75

600

Discontinue

Discontinue

If additional dose reduction required

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4. Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day Day 1 Day 8

ANC Platelet count ABRAXANE / Gemcitabine (cells/mm3) (cells/mm3) < 1500 OR < 100,000 Delay doses until recovery 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5. Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at No dose reduction next lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at next Grade 3 mucositis lower dose level or diarrhea

4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer. Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions ( 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)]. 5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)]. 5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine. 5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. 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. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 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 practice. In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%). 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.


ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients. Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm Gemcitabine ABRAXANE(125 mg/m2)/Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group. Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group. Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE (125 mg/m2) and gemcitabine (N=421) System Organ Class General disorders and administration site conditions

Gemcitabine (N=402)

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral edema

194 (46%)

13 (3%)

122 (30%)

12 (3%)

Pyrexia

171 (41%)

12 (3%)

114 (28%)

4 (1%)

Asthenia

79 (19%)

29 (7%)

54 (13%)

17 (4%)

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

Diarrhea

184 (44%)

26 (6%)

95 (24%)

6 (1%)

Vomiting

151 (36%)

25 (6%)

113 (28%)

15 (4%)

Skin and subcutaneous tissue disorders

Alopecia

212 (50%)

6 (1%)

21 (5%)

0

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%)

Nervous system disorders

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

3 (1%)

Dysgeusia

68 (16%)

0

33 (8%)

0

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%) 6 (1%)

Gastrointestinal disorders

Metabolism and nutrition disorders

T:14”

52 (12%)

18 (4%)

28 (7%)

Cough

72 (17%)

0

30 (7%)

0

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

1 (<1%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

0

Depression

51 (12%)

1 (<1%)

24 (6%)

0

B:14.25”

S:13”

Hypokalemia Respiratory, thoracic and mediastinal disorders

Psychiatric disorders a

Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal. Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema

Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose. Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent. Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died. 6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. 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. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. 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. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). 8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made 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 ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.


The ASCO Post  |   JANUARY 15, 2014

PAGE 92

Future of Oncology Drug Development Challenges continued from page 87

Cancer Cures

Over the next decade, will more winner-targeted therapies result in more cancer cures? For advanced cancers, I think we

will more likely see the transformation of acute life-threatening diseases to more chronic ones, where patients live a long, high-quality life. There also may be a small subset of certain B:7.5”is on the horizon. cancers where cure T:7” observations with For example, recent S:6.5” anti–PD-1 antibodies and CTLA-4 in-

hibitors in the treatment of advanced melanoma suggest that a proportion of patients may have durable responses that last for years. It remains to be seen whether this is a cure—at some point, the cancer cells might learn to evade the checkpoint blockade. In many cases, there may be effec-

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)]. • Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)]. • Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)]. Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE®

is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

tive second, third, fourth, and fifth lines of treatment available, which collectively lead to long-term outcome benefit. This too has major implications for drug development. One consequence is that survival may no longer be a practical primary endpoint for measuring clinical efficacy benefit, because it may simply take too long to get to that endpoint. Also, survival may get confounded by multiple lines of subsequent treatments. So we need robust and clinically meaningful surrogate early endpoints, and they need to become acceptable to regulatory agencies as a basis for approval. In addition, payers will need to change their cost-effectiveness models and criteria because they are largely based on survival as an outcome measure. n Disclosure: Dr. Lehnert is Group Head, Oncology Clinical Research, Takeda Pharmaceuticals, Inc.

Contact

The ASCO Post

U.S. Patent Numbers: See www.celgene.com. ABR_PANC_HCP_BSv006 9_2013

Editorial Correspondence T:10”

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S:9.5”

James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

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ASCOPost.com  |   JANUARY 15, 2014

PAGE 93

ASH Annual Meeting Hematology

Meta-Analysis Upholds Benefit in Progression-Free Survival, but Not Overall Survival, With Lenalidomide Maintenance By Caroline Helwick

M

ultiple myeloma patients derived a benefit from maintenance lenalidomide (Revlimid) treatment in terms of progression-free but not overall survival, according to a meta-analysis of four key trials presented at the 2013 American Society of Hematology (ASH) Annual Meeting.1 The study does little to settle the debate over the value of maintenance in prolonging survival. “The subset of patients benefitting the most from lenalidomide maintenance is not yet defined, and the risks and benefits should be discussed with all patients,” said Preet Paul Singh, MD, from Mayo Clinic, Rochester, Minnesota, who presented the findings.

Four Randomized Trials The Mayo Clinic investigators performed the systematic review and meta-analysis of existing outcome data— including updated findings presented at this meeting—to evaluate the role of lenalidomide given continuously following induction or transplant until relapse. They included four random-

ized controlled trials involving 1,935 patients: the Intergroupe Francophone du Myelome (IFM) 2005-02 trial, the Cancer and Leukemia Group B (CALGB) 100104 trial, Celgene’s

estimate among the trials. “All four studies showed an improvement in progression-free survival, with an overall 51% reduction in risk of progression (P < .001),” Dr. Singh re-

The subset of patients benefitting the most from lenalidomide maintenance is not yet defined, and the risks and benefits should be discussed with all patients. —Preet Paul Singh, MD

MM-015 trial, and the Fondazione Neoplasie Sangue Onlus–sponsored RV-MM-PI209. Patients received lenalidomide at 10 mg daily (increased to 15 mg daily in some trials, if tolerated) after induction or transplant, continued until progression. The Mayo Clinic researchers found no heterogeneity for estimates of progression-free survival but considerable heterogeneity for the overall survival

Meta-Analysis of Lenalidomide Maintenance in Myeloma ■■ A meta-analysis and systematic review of four randomized trials of newly diagnosed multiple myeloma patients found a 51% reduction in the risk of recurrence with maintenance lenalidomide (P < .001) following induction or transplant. ■■ A trend toward an overall survival benefit was observed in the metaanalysis (HR = 0.77, P = .07). Two individual studies showed a benefit, and two did not. ■■ The risk of secondary primary malignancies was increased by 62% (P = .006).

ported. “There was a small [nonsignificant] improvement in overall survival with lenalidomide maintenance, with two studies showing a benefit and two not showing one, resulting in a modest 23% reduction in risk (P = .071).” In the individual studies, a survival benefit was demonstrated in CALGB 100104 (hazard ratio [HR]  = 0.61, P = .008) and RV-MM-PI209 (HR  = 0.620, P = .018), but not in MM-015 (HR = 0.79, P = .251) and IMF 200502 (HR = 1.06, P = .664).

Additional Data In patients who actually received a transplant (analyses from IFM 2005-02 and CALGB 100104), a nonsignificant 18% reduction in risk was observed (P  = .462). It should be noted that this estimate did not include survival data from the transplant arm of the RVMM-P1209 study, and will be updated

when complete results of this study are published. The odds of achieving a very good partial response or better were 28% higher in the maintenance arm, but again this lacked statistical significance (P = .329). Secondary primary malignancies were significantly increased with lenalidomide maintenance, he said. The increase was 62% (P = .006), and there was no heterogeneity among the studies. Other complications were also increased, including a 4.9-fold increased risk of neutropenia (P < .001), a 2.7fold increase in thrombocytopenia (P  < .001), a 2.3-fold risk in fatigue (P = .01) and a 3.2-fold increase in venous thromboembolism (P = .02). Before making a recommendation for using or not using lenalidomide, Dr. Singh suggested “waiting for longer follow-up and subgroup analyses, once complete data are available from all the trials.” n

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

Reference 1. Singh PP, Kumar S, LaPlant B, et al: Lenalidomide maintenance therapy in multiple myeloma: A meta-analysis of randomized trials. 2013 American Society of Hematology Annual Meeting. Abstract 407. Presented December 9, 2013.

For More on This Topic See pages 1 and 45-50 for more on lenalidomide maintenance therapy in multiple myeloma.

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The ASCO Post  |   JANUARY 15, 2014

PAGE 94

Health-Care Policy

ASCO Statement on Annual Report to the Nation on the Status of Cancer

C

lifford A. Hudis, MD, FACP, President of ASCO, commented recently on the Annual Report to the Nation on the Status of Cancer, coauthored by the National Cancer Institute, the American Cancer Society, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries.

These improvements in lung cancer survival specifically can be attributed to better supportive care and new drugs, some based on exciting advances in molec-

Building on this year’s report related to patients in the United States, even more work is needed to accelerate the pace of progress worldwide.

Significant Advances Against Difficult Cancers “Our mission at ASCO is to conquer cancer and the Annual Report to the Nation demonstrates the progress we are making. The continuing decrease in overall cancer death rates is a clear indicator that our societal investments are paying off, in particular for those patients with cancers that have been traditionally most challenging to treat, such as lung cancer.

—Clifford A. Hudis, MD, FACP

ular biology made possible by the research infrastructure we have built and supported over the years. The successful translation of these findings into clinically relevant treatments has been possible only because of

IOM Makes Clinical Data Available for Research By Jo Cavallo

I

n 1979, Congress mandated that an epidemiologic study be launched to evaluate the frequency and type of adverse health conditions experienced by military personal as a result of their exposure to Agent Orange and other herbicides used during the Vietnam War. Called the Air Force Health Study (AFHS), data from a health questionnaire and physical examination and over 86,000 biospecimens were collected from 2,758 subjects over 20 years in six cycles—in 1982, 1985, 1987, 1992, 1997, and 2002—from airmen who participated in the spraying missions and were exposed to the herbicides and a comparison cohort of airmen who served in Southeast Asia, but were not involved in herbicide-spraying operations. Once the study was completed in 2006, Congress directed that both the clinical data and biospecimens be transferred to the Institute of Medicine for safekeeping and to provide guidance on the future use of the information gathered. Now, the clinical data and biospecimens, which include serum, whole blood, adipose tissue, semen, stool smears, and urine, are being made available to researchers for further scientific study. David Butler, PhD, Scholar and Director of the Medical Follow-up Agen-

decades of clinical trials that led to significant advances in targeted therapies in lung and a number of other cancers. At the same time, the availability of effective screening

cy at the IOM, said “For cancer research, some of the most fruitful uses might be in looking for biomarkers of susceptibility in the development of different cancers over time. These data give researchers an opportunity to look at health outcomes over 20 years and ask, is there something different about the specimens of people who developed a specific cancer from those who didn’t develop that cancer?” To obtain access to the data and biospecimens, researchers must first submit a letter of intent to the IOM. A review committee will then evaluate the scientific merits of the proposal, and if accepted, investigators will be required to submit a formal proposal detailing specifically how the data and biospecimens will be used. All proposals will also have to be approved by both the investigator’s and the National Academies’ Institutional Review Boards. Complete details of the AFHS study and the data and biospecimens collected can be found in the IOM report, Disposition of the Air Force Health Study.1 n Reference 1. Institute of Medicine: Disposition of the Air Force Health Study. Released February 24, 2006. Available at www. iom.edu/Reports/2006/Dispositionof-the-Air-Force-Health-Study.aspx. Accessed December 11, 2013.

options for those at high risk for developing lung cancer may yield even greater reductions in mortality—by finding more patients with early stage, curable disease— in the coming years.”

Prevention A Key to Future Progress Even better than treatment is prevention when possible. As we approach the 50th anniversary of the first Surgeon General’s Report on Smoking and Health, we are reminded that tobacco control remains the most important tool to further decrease global lung cancer and overall cancer mortality rates. However, increasingly we must focus on other effective prevention strategies, including, for example, vaccination against some viral infections and energy balance, as obesity-associated cancers represent a growing challenge. Building on this year’s report related to patients in the United States, even more work is needed to accelerate the pace of progress worldwide.” n

Statement by ASCO President Clifford A. Hudis, MD, FACP, on ACS Report

“T

he American Cancer Society [recently] issued a report showing a 20% decline in cancer death rates between 1991 and 2010, and estimating that 1.3 million deaths have been averted as a result of the decline.  “This is tremendous progress and a direct result of our nation’s

that the cuts are harming their ability to conduct cancer research. “While the recently passed budget allows for the reversal of some of the most drastic cuts, the truth is that our nation is gradually abandoning its historical commitment to leading cancer research globally. Given what the field of

ASCO joins others in the cancer research and care community in calling for a $32 billion budget for NIH to sustain and enhance the search for new cures. commitment to cancer research and care. This 20% decline in death rates shows the progress we’ve made using the earlier generations of cancer treatments. Now, based on accelerating understanding of cancer, we are poised to make even greater progress. Frustrating, this potential is limited by decreasing funding for the National Institutes of Health— funding has fallen steadily for a decade in real terms—and by increasing barriers to clinical research with oncologists nationwide reporting

oncology has accomplished despite more limited resources, imagine what we could do with sustained or increased funding. To support accelerating improvements in cancer care and the kinds of statistics released this week, ASCO joins others in the cancer research and care community in calling for a $32 billion budget for NIH to sustain and enhance the search for new cures.” n —Clifford A. Hudis, MD, FACP ASCO President


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The ASCO Post  |   JANUARY 15, 2014

PAGE 96

Perspective Thoracic Oncology

Adjuvant Gefitinib in Patients With NSCLC: Bad Idea or Wrong Patient Selection? By Daniel Morgensztern, MD, and Roy S. Herbst, MD, PhD

D

espite optimal surgical resection and adjuvant chemotherapy with cisplatin-based doublets, the 5-year overall survival for patients with early-stage non–small cell lung cancer (NSCLC) remains suboptimal. In the International Association for the Study of Lung Cancer (IASLC) staging project, the 5-year overall survival ranged from 36% to 73% in patients with pathologic stages IIB to IA, respectively.1 The Lung Adjuvant Cisplatin Evaluation (LACE) pooled analysis of five large trials involving 4,584 patients showed a 5-year overall survival benefit from chemotherapy of 5.4%.2 Furthermore, the updated analyses of two of the largest adjuvant trials showed less than a 50% 5-year overall survival.3,4 Therefore, novel therapies are still needed in this patient population in an attempt to improve survival.

ceptor (EGFR) mutations, of whom 7 received gefitinib and 8 received placebo. Among the 96 patients with KRAS mutation, gefitinib was associated with a detrimental effect on disease-free survival.

Lessons From the BR.19 Trial The BR.19 study was the third study showing a lack of benefit from gefitinib in patients with wild-type EGFR, with the spectrum now including all three clinical NSCLC settings: early-stage, locally advanced, and metastatic. This is in contrast to erlotinib (Tarceva), which was associated with improved

Unlike the use of targeted therapy drugs in unselected patients, a better understanding of the tumor biology and the use of molecular predictors for response may provide the best treatment available for each patient, with an increased probability of survival improvement in resected NSCLC.

BR.19 Study Findings The National Cancer Institute of Canada (NCIC) BR.19 study—recently reported by Goss and colleagues in the Journal of Clinical Oncology and reviewed in the December 15 issue of The ASCO Post—planned to randomly assign 1,242 patients with completely resected NSCLC stages IB, II, or IIIA to gefitinib (Iressa) or placebo, with overall survival as the primary endpoint.5 The study, however, was closed early after the results of two randomized studies showed that gefitinib did not result in survival improvement in patients with advanced NSCLC6 and was potentially detrimental after chemoradiotherapy followed by docetaxel in patients with stage III disease.7 Among the 503 patients enrolled between 2002 and 2005, 251 were randomly assigned to gefitinib and 252 to placebo for 2 years. Only 87 patients received prior adjuvant chemotherapy since the study started before its establishment as a standard of care. Adjuvant gefitinib was not associated with improved overall survival or disease-free survival either for the total population or for the 15 patients with activating epidermal growth factor reDr. Morgensztern is Associate Professor of Medical Oncology and Dr. Herbst is Chief of Medical Oncology at Yale Cancer Center, New Haven, Connecticut.

56 who received adjuvant gefitinib or erlotinib and 111 who did not receive adjuvant EGFR tyrosine kinase inhibitors. The 2-year disease-free survival was higher for the group receiving adjuvant EGFR tyrosine kinase inhibitors, although it did not reach statistical significance (89% vs 72%, hazard ratio  = 0.53, P  =  .06), likely due to the small patient population. The RADIANT trial, which randomly assigned patients with resected NSCLC and EGFR-positive tumors, defined by immunohistochemistry or fluorescence in situ hybridization, complet-

—Daniel Morgensztern, MD, and Roy S. Herbst, MD, PhD

overall survival in patients with metastatic disease.8 For the most part, the BR.19 trial predated the common use of adjuvant chemotherapy. Furthermore, in patients with advanced disease, chemotherapy has been shown to be clearly superior to gefitinib in patients with wild-type EGFR.9 Therefore, the role for adjuvant EGFR tyrosine kinase inhibitors is still not clarified.

Other Key Studies While attempts to improve survival in patients with resected NSCLC are likely to involve targeted drugs, a significant benefit can only be achieved with the use of molecular predictors. In a study reported by Janjigian and colleagues,10 167 patients with resected NSCLC harboring activating EGFR mutations were evaluated, including

ed the accrual of 945 patients in 2010, with the results expected soon. However, neither immunohistochemistry nor fluorescence in situ hybridization is an established predictor for benefit from EGFR tyrosine kinase inhibitors. Therefore, although the results of RADIANT and other adjuvant EGFR tyrosine kinase inhibitor studies are eagerly awaited, it is unclear how they will affect treatment decisions, particularly if the number of patients with EGFR mutations from these studies does not allow the detection of a statistically significant benefit. It may be interesting to evaluate whether some of the potential predictors of benefit from EGFR tyrosine kinase inhibitors in patients with wild-type EGFR metastatic disease, such as VeriStrat11 and the gene signature from the Biomarker-integrated Approaches of Targeted Therapy for Lung

Cancer Elimination (BATTLE) trial,12 can be used as predictors for efficacy in patients with earlier-stage disease. n For more on the NCIC CTG BR.19 study, see The ASCO Post, December 15, 2013, page 42.

Disclosure: Drs. Herbst and Morgensztern reported no potential conflicts of interest.

References 1. Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer Staging Project. J Thorac Oncol 2:706-714, 2007. 2. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation. J Clinical Oncol 6:3552-3559, 2008. 3. Butts CA, Ding K, Seymour L, et al: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer. J Clin Oncol 28:29-34, 2010. 4. Arriagada R, Dunant A, Pignon JP, et al: Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatinbased chemotherapy in resected lung cancer. J Clin Oncol 28:35-42, 2010. 5. Goss GD, O’Callaghan C, Lorimer I, et al: Gefitinib versus placebo in completely resected non-small-cell lung cancer. J Clin Oncol 31:3320-3326, 2013. 6. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall-cell lung cancer. Lancet 366:1527-1537, 2005. 7. Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer. J Clin Oncol 26:2450-2456, 2008. 8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer. Lancet Oncol 11:521-529, 2010. 9. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947957, 2009. 10. Janjigian YY, Park BJ, Zakowski MF, et al: Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol 6:569-575, 2011. 11. Lazzari C, Novello S, Barni S, et al: Randomized proteomic stratified phase III study of second-line erlotinib (E) versus chemotherapy (CT) in patients with inoperable non-small cell lung cancer (PROSE). J Clin Oncol 31:LBA8005, 2013. 12. Kim ES, Herbst RS, Wistuba II, et al: The BATTLE trial. Cancer Discov 1:44-53, 2011.


REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

For patients with relapsed or refractory mantle cell lymphoma

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS™ program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving REVLIMID with dexamethasone. For more information, please visit www.REVLIMID.com or call 1-888-423-5436. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Important Safety Information and Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.

REVLIMID® is a registered trademark of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 10/13 US-REV130052a


Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide 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 the fetus Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. 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 REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide 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 REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID 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 REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.


Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after assessment of the individual patient’s underlying risk factors. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for chronic lymphocytic leukemia (CLL) and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop Revlimid upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.

ADVERSE REACTIONS B:14.5”

T:13.75”

S:13”

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. Any suspected fetal exposure to REVLIMID must be reported 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 whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis.

Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.


The ASCO Post  |   JANUARY 15, 2014

PAGE 100

Announcements

ASCO Announces Election Results for Terms Beginning June 2014

I

n addition to the election of Julie M. Vose, MD, MBA, FASCO, as President of the American Society of Clinical Oncology (ASCO) for a 1-year term beginning in June 2015 (see page 85), ASCO has announced four new members who were recently elected to the ASCO Board of Direc-

tors and two new members recently elected to the ASCO Nominating Committee.

Newly Elected ASCO Board Members The following physicians will begin 4-year terms as members of ASCO’s Board

of Directors starting in June 2014: Linda D. Bosserman, MD, FACP, has been elected to a Community Oncologist seat. She is President of the Wilshire Oncology Medical Group, Inc., in Los Angeles, California. Since joining ASCO in 1990, Dr. Bosserman has served on the

Quality Care Symposium Planning Committee and Practice Guidelines Implementation Network. She was a member of the White House Physician Forum on Health Reform in 2009. David Khayat, MD, PhD, FASCO, has been elected to an International On-

T:7”

REVLIMID [lenalidomide] capsules, for oral use

Platelet counts

The following is a brief summary for Mantle Cell Lymphoma; refer to full prescribing information for complete product information

Thrombocytopenia during treatment in MCL When Platelets

Recommended Course

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM

Fall to <50,000/mcL

Interrupt REVLIMID treatment and follow CBC weekly

Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2).

Return to ≥50,000/mcL

Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily

Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

1 INDICATIONS AND USAGE 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID.

Neutropenia during treatment in MCL When Neutrophils

Recommended Course

Fall to <1000/mcL for at least 7 days Interrupt REVLIMID treatment and follow OR CBC weekly Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL

Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily

Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MCL: See Section 2.4. 2.4 Starting Dose for Renal Impairment in MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MCL Category

Renal Function (Cockcroft-Gault)

Dose in MCL

Moderate Renal Impairment

CLcr 30-60 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2). 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)]. 4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.5)].

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Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)].

Absolute Neutrophil counts (ANC)


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Announcements

Linda D. Bosserman, MD, FACP

David Khayat, MD, PhD, FASCO

Walter J. Curran, Jr, MD, FACR

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions 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 REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID 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 REVLIMID 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 Lenalidomide 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 REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)].

Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)]. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of

Cosmos Communications

cer Institute and the French Federation of Medical Oncologists. Walter J. Curran, Jr, MD, FACR, has been elected to a Radiation Oncologist seat. He is the Executive Director of the Winship Cancer Institute of Emory University and the Lawrence W. Davis Professor and Chairman of the Department of Radiation continued on page 102

patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)]. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)]. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. 5.5 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. 5.6 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.7 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.8 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop Revlimid upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.9 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account

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Blood Donation Patients must not donate blood during treatment with REVLIMID 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 REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID 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 REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.

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cologist seat. He is the Head of the Department of Medical Oncology at PitiéSalpêtrière Hospital, in Paris, France. Since joining ASCO in 1987, he has served as Chair of the International Affairs Committee, on the Cancer Education Committee, and as Associate Editor of the Journal of Clinical Oncology (JCO). He has served as President of the French National Can-


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Announcements

ASCO Election Results continued from page 101

Oncology. Since joining ASCO in 1988, Dr. Curran has served on the Cancer Research Committee, the Cancer.Net Editorial Board, and the Conquer Cancer Foundation Advanced Clinical Research Award in Glioma Subcommittee. He is a founding principal investigator of the NCI-funded co-

operative group NRG Oncology and the Founding Chair of the NRG Oncology Foundation Board. Charles D. Blanke, MD, FACP, FRCPC, FASCO, has been elected to an Undesignated Specialty seat. He is a Professor of Medicine at

Charles D. Blanke, MD, FACP, FRCPC, FASCO

the Oregon Health & Science University Knight Cancer Institute in the Division of Hematology and Medical Oncology. Since joining ASCO in 1995, Dr. Blanke has served as Chair of the Cancer Education Committee, Co-Chair of the Gastrointestinal Cancers

Symposium Program Committee, and on the JCO Editorial Board. He is the current Chair of the Southwest Oncology Group.

Newly Elected Members of ASCO Nominating Committee Two newly elected ASCO Nominating Committee members will serve 3-year terms beginning in June 2014:

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both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Allergic Reactions [see Warnings and Precautions (5.5)] • Tumor lysis syndrome [see Warnings and Precautions (5.6)] • Tumor flare reactions [see Warnings and Precautions (5.7)] • Hepatotoxicity [see Warnings and Precautions (5.8)] • Second Primary Malignancies [see Warnings and Precautions (5.9)] 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. 6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. 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. Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 (N=134)

Grade 3/4 AEs2 (N=134)

n (%)

n (%)

General disorders and administration site conditions Fatigue 45 (34) Pyrexia$ 31 (23) Edema peripheral 21 (16) Asthenia$ 19 (14) General physical health deterioration 3 (2) Gastrointestinal disorders Diarrhea$ 42 (31) Nausea$ 40 (30) Constipation 21 (16) Vomiting$ 16 (12) Abdominal pain$ 13 (10) Musculoskeletal and connective tissue disorders Back pain 18 (13) Muscle spasms 17 (13) Arthralgia 11 (8) Muscular weakness$ 8 (6) Respiratory, thoracic and mediastinal disorders Cough 38 (28) Dyspnea$ 24 (18) Pleural Effusion 10 (7) Hypoxia 3 (2) Pulmonary embolism 3 (2) Respiratory distress$ 2 (1) Oropharyngeal pain 13 (10) Infections and infestations Pneumonia@ $ 19 (14) Upper respiratory tract infection 17 (13) Cellulitis$ 3 (2) Bacteremia$ 2 (1) Staphylococcal sepsis$ 2 (1) Urinary tract infection$ 5 (4)

9 (7) 3 (2) 0 4 (3) 2 (1) 8 (6) 1 (<1) 1 (<1) 1 (<1) 5 (4) 2 (1) 1 (<1) 2 (1) 2 (1) 1 (<1) 8 (6) 2 (1) 2 (1) 2 (1) 2 (1) 0 12 (9) 0 2 (1) 2 (1) 2 (1) 2 (1) (continued)

Cosmos Communications

System Organ Class/Preferred Term

All AEs1 (N=134)

Grade 3/4 AEs2 (N=134)

n (%)

n (%)

Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma. General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency

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System Organ Class/Preferred Term

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma


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Gregory H. Reaman, MD, FASCO, is the Associate Director of the U.S. Food and Drug Administration’s Office of Hematology and Oncology Products, a Professor of Pediatrics at The George Washington University School of Medicine and Health Sciences, and an Adjunct Professor of Oncology and Pediatrics at Georgetown University School of Medi-

cine. Since joining ASCO in 1978, he has served on the Board of Directors, the Cancer Survivorship Committee, and as Chair of the Membership Committee. David R. Spriggs, MD, is Head of the Division of Solid Tumor Oncology and the Winthrop Rockefeller Chair of Medical Oncology at Memorial Sloan-Kettering Cancer Center andT:7” a Professor of Medicine

Cosmos Communications K

Gregory H. Reaman, MD, FASCO

In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 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 adverse reactions in nursing infants from lenalidomide, 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 in pediatric patients below the age of 18 have not been established. 8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age. Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions 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 REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID 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 REVLIMID. The first test should be performed within 1 ja

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or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID 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. Lenalidomide caused thalidomide-type limb defects in monkey offspring. 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. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

at Weill Cornell Medical College. Since joining ASCO in 1986, he has served on the Scientific Program Committee, Chair of the Grants Selection Committee, and as an Associate Editor of JCO. Dr. Spriggs will serve as the 2016– 2017 Chair of the Nominating Committee. n

David R. Spriggs, MD


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Dermatologic Events in Oncology Diagnosing and Treating Chronic Mucocutaneous Graft-vs-Host Disease By Jonathan A. Cotliar, MD

C

hronic graft-vs-host disease is a major cause of late, nonrelapse death following allogeneic hematopoietic stem cell transplantation. In addition, chronic graft-vs-host disease results in

significant functional impairment and decreased quality of life for long-term survivors of stem cell transplant. The incidence of chronic graft-vs-host disease is rising withT:7”wider availability of

10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. 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. REVLIMID treatment must be discontinued during this evaluation. Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm

peripheral blood stem cells as a graft source, but other factors such as prior acute graft-vs-host disease, older transplant recipient age, and male recipients of stem cells from female donors also

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID 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 REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)].

8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)].

• Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. 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)].

8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route.

• REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.

10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg. In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted.

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can 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 REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID 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 REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. 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 REVLIMID 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)].

Cosmos Communications K

Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)]. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Secondary Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, 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 REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for:

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved. REV_MCL_HCP_BSv. 06/13 REV_MCL_HCP_BSv.DRAFT 1 ja

Q1

Q2

Clinical Manifestation Approximately 60% to 70% of allogeneic stem cell transplant recipients will develop chronic graft-vs-host disease. Nearly one-third of chronic graft-vs-host disease develops de novo, with the remaining two-thirds split evenly among those whose disease occurs as either a continuous progression from acute graftvs-host disease or after a quiescent period following previous acute graft-vs-host disease. Chronic graft-vs-host disease can be categorized as classic (with only typical chronic skin lesions) or overlap (presence of both acute and chronic cutaneous graft-vs-host disease lesions along with diarrhea and liver dysfunction). Nearly all cases of chronic graft-vshost disease involve the skin and/or mucous membranes. This may manifest as oral or conjunctival dryness, dental caries, periodontitis, or gingivitis. Oral lesions may resemble lichen planus, characterized by reticulated white patches or plaques with the ability to ulcerate and cause significant pain and weight loss from anorexia. Ocular lesions may cause dryness, photophobia, and excessive tearing; severe cases can lead to corneal epithelial sloughing and cicatricial conjunctivitis. Vulvovaginal involvement can be associated with urinary and sexual dysfunction. Skin involvement is the hallmark of chronic graft-vs-host disease, and lesions can be classified as either sclerotic or nonsclerotic. Nonsclerotic lesions commonly follow a lichen planus–like morphology T:9.875”

Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)].

predispose individuals to the development of chronic graft-vs-host disease. While the pathophysiology of acute graft-vs-host disease has been described, chronic graft-vs-host disease involves a less understood biologic pathway. The end result is a complex multisystem disorder characterized by immunodeficiency, immune dysregulation and, ultimately, impaired organ function. Previously, the 100-day demarcation was used to delineate acute from chronic graft-vs-host disease. However, in the era of nonmyeloablative hematopoietic stem cell transplantation and common use of donor lymphocyte infusions, this demarcation no longer exists

Dr. Cotliar is Associate Professor of Dermatology, General Internal Medicine, and Geriatrics at Northwestern University Feinberg School of Medicine, Chicago.


ASCOPost.com  |   JANUARY 15, 2014

PAGE 105

Dermatologic Events in Oncology (Fig. 1); they are violaceous, flat-topped, and slightly scaly. Sclerotic lesions are indurated, poorly circumscribed, and may appear hyperpigmented. Progressive sclerotic skin lesions, whether focal or generalized, may result in significant impairment of activities of daily living and deconditioning. Severe sclerosis can lead to involvement of soft tissue and muscle, can cause nerve entrapment, and may ultimately result in chronic skin ulceration (Fig. 2). Loss of skin adnexal structures can lead to permanent alopecia, nail loss, and impairment of sweating. More rare cutaneous morphologies include morbilliform lesions, eczematous forms, and ichthyotic lesions.

Assessment Unlike acute graft-vs-host disease, there is no standardized grading schema to assess chronic cutaneous graft-vs-host disease. However, a National Institutes of Health (NIH)-developed scoring guide1 assesses the severity of skin lesions based on the amount of body surface area involved along with the presence of sclerotic features. The most severely affected individuals are those with a body surface

GUEST EDITOR

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.

Fig. 1: With a lichen planus–like morphology, nonsclerotic lesions associated with graft-vs-host disease are violaceous, flat-topped, and scaly.

area >  50% and sclerosis that impairs mobility, causes ulcerations, or results in severe pruritus. A recently validated grading system to assess oral chronic graft-vs-host disease involvement is based on the presence and extent of erythema, hyperkeratosis, ulceration, and number of mucoceles; patients are stratified as mild, moderate, or severe.2

Treatment Recommendations For lichen planus–like skin lesions, high potency topical steroids (clobetasol, fluocinonide) applied twice daily and emollients applied after bathing are preferred initial treatment for patients who don’t require systemic treatment, or may be used in conjunction with systemic treatment if indicated. Triamcinolone 0.1% cream used once or twice daily is optimal for maintenance topical therapy. Sclerotic skin lesions respond poorly to topical steroids, though there is some anecdotal evidence supporting the use of calcipotriene cream or ointment as a mechanism to soften sclerotic skin. For oral lesions, fluocinonide gel or tacrolimus 0.1% ointment can be applied twice daily to lips or mucosal surfaces, including eroded areas. Dexamethasone solution can be swished and spit for oral mucosal lesions, but close observation for the development of candidiasis as a result is warranted. Viscous lidocaine can similarly be used to swish and spit, and may provide pain relief to allow for oral

Fig. 2: Severe sclerosis associated with graft-vs-host disease can lead to involvement of soft tissue and muscle, can cause nerve entrapment, and may ultimately result in chronic skin ulceration.

intake of foods and liquids. Physical therapy to maintain range of motion and strength for patients with sclerotic graft-vs-host disease is vital. Aggressive wound care for sclerotic skin lesions can preclude the development of ulcerations, which, if severe, predispose to serious skin and soft-tissue infections. Algorithms for first-line systemic treatment of chronic graft-vs-host disease are controversial, though most patients are initiated on prednisone at a dose of 1 mg/kg/d. In many patients, a calcineurin inhibitor is either started at the same time, or during an attempt to taper the steroid dose. Recent NIH guidelines3 suggest starting systemic treatment if there is severe involvement of one organ, or if three separate organs are involved to any extent. Cyclophosphamide, azathioprine, methotrexate, and sirolimus (Rapamune) are accepted second-line agents for patients that fail systemic steroids; failure is defined as either: (1) progression of chronic graft-vs-host disease despite 2 weeks of systemic steroids at a dose of 1  mg/ kg/d, (2) no improvement after 4 to 8 weeks of sustained therapy, or (3) inability to taper steroid dose. Imatinib (Gleevec) has shown modest benefit for patients with sclerotic graft-vs-host disease, and it is currently under investigation in this setting. Extracorporeal photopheresis has become an additional second-line treatment for chronic graft-vs-host disease patients,

and offers potential benefit without further immunosuppression. Pentostatin, rituximab (Rituxan), thalidomide (Thalomid), mycophenolate mofetil, tumor necrosis factor inhibitors, and alefacept (Amevive) are also used when first-line treatment fails. In addition, sclerotic skin lesions may be amenable to either PUVA (psoralen plus ultraviolet A [UVA]) or UVA1 phototherapy at a dermatologist’s office. n

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

References 1. Filipovich AH, Weisdorf D, Pavletic S, et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945-956, 2005. 2. Bassim CW, Fassil H, Mays JW, et al. Validation of the National Institutes of Health chronic GVHD Oral Mucosal Score using component-specific measures. Bone Marrow Transplant. September 2, 2013 (early release online). 3. Perez-Simon JA, Encinas C, Silva F, et al. Prognostic factors of chronic graftversus-host disease following allogeneic peripheral blood stem cell transplantation: the national institutes health scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant 14:11631171, 2008.

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PAGE 106

News Clinical Trials

Activation of Innovative Lung Cancer Master Protocol Officially Announced, Enrollment to Begin in March By Margot J. Fromer

A

t a recent meeting in Washington, DC, Friends of Cancer Research and the Engelberg Center for Health Care Reform at the Brookings Institution officially announced activation of the Lung Cancer Master Protocol, a new research strategy that has the potential to hurdle or bypass known clinical trial roadblocks and barriers.1 This first-of-its-kind clinical trial design has generated considerable anticipation in the cancer research community.

Study Background and Rationale Cancer clinical trials are time-consuming (requiring up to 15 years), expensive ($50–$100  million each), bogged down in bureaucratic and regulatory red tape, and notoriously difficult to fill. For in-

Master Protocol Steering Committee Members ■■ Roy Herbst, MD, PhD (Co-Chair), Yale Cancer Center ■■ Ellen V. Sigal, PhD (Co-Chair), Friends of Cancer Research ■■ Jeffrey S. Abrams, MD, National Cancer Institute ■■ Jeff Allen, PhD, Friends of Cancer Research ■■ David Chang, MD, PhD, Amgen ■■ Andrea Ferris, MBA, LUNGevity ■■ David Gandara, MD, University of California, Davis ■■ Richard B. Gaynor, MD, Eli Lilly ■■ Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center ■■ Pasi A. Jänne, MD, PhD, DanaFarber Cancer Institute ■■ Vali Papadimitrakopoulou, MD, The University of Texas MD Anderson Cancer Center ■■ Eric Rubin, MD, Merck ■■ Regina Vidaver, PhD, National Lung Cancer Partnership ■■ Jack Welch, MD, PhD, National Cancer Institute ■■ Janet Woodcock, MD, Center for Drug Evaluation and Research, U.S. Food and Drug Administration ■■ Steven W. Young, Addario Lung Cancer Medical Institute

stance, in 2012, only 1,864 patients with lung cancer out of the 226,000 diagnosed that year were enrolled in a trial. At the moment, there are 1,320 open trials for lung cancer, costing upwards of $70  billion—and the vast majority will not result in drug approval. In fact, of 20 recent trials for late-stage disease, only two resulted in approval. These trials face logistical problems as well. If they incorporate biomarkers, which is the best way to focus on patients most likely to respond, then the pool of potential subjects shrinks. For example, the ALK marker appears in fewer than 7% of non–small cell lung cancer (NSCLC) patients. Other biomarkers have even smaller numbers. The Lung Cancer Master Protocol investigators hope to avoid this problem with their new model. “NSCLC almost always has multiple and often independent mutations—thus many potential therapeutic targets,” said Vali Papadimitrakopoulou, MD, Professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston. “Squamous cell carcinoma is really an orphan disease because there have been no substantial therapeutic developments and no approved targeted drug therapies. Therefore, we think that genotype- or phenotype-driven subgroup selection in a clinical trial would improve operational efficiency and provide homogeneous patient populations and consistency in eligibility from arm to arm.” Genotype and phenotype screening at the outset and grouping similar types in multiple small studies reduces the overall screen failure rate. “Multitarget screening can increase the ‘hit rate’ and provide for uninterrupted accrual. This, in turn, will create a path to approval for safer and more effective drugs, while replacing ineffective ones,” said Dr. Papadimitrakopoulou.

Trial Design Each drug used in the Master Protocol trial is required to have demonstrated biologic activity in a responsive patient group against a measurable target and to use a validated predictive biomarker assay that then becomes suitable for a pivotal trial. This master plan for second-line therapy for advanced squamous cell carcinoma is a multiarm, randomized, controlled

phase  II/III registration protocol. Each arm opens and closes independently of the others and is powered for overall survival. Positive results at varying interim analyses determine whether an arm proceeds to phase III. The primary objective for phase  II is a 40% improvement in progression-free survival and for phase III, a 2.25-month extension in progression-free survival. The trial will be powered to assess over-

sample. This maximizes the amount of information available from each tissue sample, as well as the likelihood that any one patient will be successfully matched to a biomarker-defined arm. Equally significant is that it can avoid testing the same patients many times over. Companies participating in the master trial will enroll patients from the large pool of screened candidates in an appropriate trial arm. The main purpose of the screening is

Multitarget screening can increase the ‘hit rate’ and provide for uninterrupted accrual. This, in turn, will create safer and more effective drugs, while replacing ineffective ones. —Vali Papadimitrakopoulou, MD

all survival, and secondary objectives are toxicity and response rate for both phase II and phase III Exploratory objectives include additional predictive blood and tumor biomarkers, resistance biomarkers at progression, and creation of a tissue and blood repository from patients with refractory squamous cell carcinoma.

How It Got Started The Master Protocol project all started 8 months previously at a Friends of Cancer Research workshop, where a group of stakeholders (federal health and regulatory agencies, academic research centers, and patient advocacy organizations) reached consensus about this new idea. The committee was chaired by Roy S. Herbst, MD, PhD, and Ellen V. Sigal, PhD. Because of its unique design, the trial can accelerate the way new biomarker-defined therapies are tested—the master trial will start with five of them. It also represents an opportunity for patients with rare mutations for whom few clinical trials are available or accessible. About 1,250 patients will be screened annually, and about 500 to 1,000 assigned to trial substudies each year. Participants at that meeting agreed to overall trial design (endpoints, patient population, biomarker screening, controls, statistical analysis), the most significant of which is the ability to screen for many alterations from the same tissue

to achieve rapid accrual. The master protocol is flexible enough to accommodate amendment of individual study arms, which avoids the need to initiate separate new trials. For the initial trial, five compounds have been selected: • Rilotumumab (Amgen), a human monoclonal antibody against human hepatocyte growth factor/scatter factor. • A fibroblast growth factor receptor tyrosine kinase inhibitor (AstraZeneca) • MED14736 (Medimmune), a human IgG1 monoclonal antibody targeting programmed cell death 1 ligand. • Palbociclib (Pfizer), a cyclin-dependent kinase 4 and CDK6 inhibitor. • An inhibitor of phosphoinositide 3-kinase (Genentech).

Participants, Challenges, and Hesitations A number of groups are involved in the Master Protocol: • The National Cancer Institute (NCI) Thoracic Malignancy Steering Committee provides initial approval of the master Investigational New Drug (IND). • Foundation for the National Institutes of Health (FNIH), a public-private biomedical research partnership, will hold the master IND, as well as contracts with trial sites, labs, and pharmaceutical companies. continued on page 107


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Issues in Oncology

Developing Intermediate Endpoints in Immunotherapy By Margot J. Fromer

“T

he immune system holds tremendous potential for longterm sustained antitumor activity,” said James P. Allison, PhD, Immunology Chair, The University of Texas MD Anderson Cancer Center, Houston, as he opened a panel discussion at a meeting cosponsored by the Friends of Cancer Research and the Brookings Institution, in Washington, DC.1 He added that the approach may be amenable to treating resistant tumors, and it is probably less toxic than conventional treatment. Moreover, there is transformational clinical potential. That said, “some patients do well on immunotherapy—durable responses for 10 years or more—and some don’t,” he added.

Existing Agents and Challenges Immunotherapeutic agents work successfully to varying degrees. But there are challenges. They require a variety of developmental approaches and strategies to produce antitumor responses because immunotherapy is not all the same. • Cytokines interact with immune cells to modulate a particular type of response. Interleukin-2 (IL-2 [Proleukin]) is the best-known example of these agents and was approved for the treatment of metastatic renal cell

Lung Cancer Master Protocol continued from page 106

• A drug selection committee of independent experts will determine which biomarkers and drugs will be studied. • Pharmaceutical companies will be represented. • A Global Trial Oversight committee, including members of the Food and Drug Administration (FDA), NCI, FNIH, patient foundations, and industry) will evaluate site management and data collection. • SWOG will be responsible for operational monitoring, quality control, and tissue and data flow. Next steps for the project include writing the protocol, developing the governance structure, establishing a data set expectations, and determining overall cost and staffing. This should be done within 2 to 3 months, and enrollment is slated to begin in March 2014, according to ­David Gandara, MD, Director, Tho-

carcinoma in 1992. • Therapeutic vaccines induce or amplify a host immune response to a specific tumor antigen. • Cellular therapies include active transfer of live immune cells (tumorinfiltrating lymphocytes or peripheral blood T cells) engineered to rec-

tors,” said Ramy Ibrahim, MD, Senior Medical Director, Oncology Clinical Development, MedImmune, Washington, DC. He added that because some tumors co-opt these checkpoints to induce immune tolerance to their own cells, “checkpoint blockade” enables an anti-

The immune system holds tremendous potential for long-term sustained antitumor activity. —James P. Allison, PhD

ognize tumor-specific targets—for instance, sipuleucel-T (Provenge), approved in 2010 for the treatment of metastatic castration-resistant prostate cancer. • Immune-modulating antibodies enhance natural immune responses or overcome tumor-induced immune tolerance. “Some agents bind to and inhibit negative regulators of T-cell activity that normally serve as “checkpoints” to maintain self-tolerance, while others stimulate positive T-cell co-recep-

tumor response. The first of these agents to be tested was ipilimumab (Yervoy), which inhibits cytotoxic T-lymphocyte antigen-4 (CTLA-4) and was approved for treatment of metastatic melanoma in 2011. A similar class of checkpoint inhibitors that inhibit the T-cell co-receptor programmed cell death protein 1 (PD1) or its ligand (PD-L1) has raised significant interest. Using the immune system to fight cancer has been of interest for a long time, said Dr. Ibrahim, “but we do not

racic Oncology Program, University of California Davis. “In NSCLC, ‘all-comer’ clinical trial designs are rarely successful, so we need early codevelopment of drugs and their associated biomarkers. Through master protocols for both early-stage adjuvant therapy and advanced disease, we can account for the tumor heterogeneity and genomic complexity of NSCLC. However, we believe that this approach will transcend lung cancer and this particular group of patients. By using a Master Protocol, ‘the future is now’,” he said.”

ogy, Yale University Cancer Center, and Co-Chair of the Master Protocol Steering Committee (see sidebar), said that it is much easier to get a pharmaceutical company into a group plan for a small, early trial than it is to persuade them to provide drugs and proprietary information for a large late-stage one. However, we are entering a new world of genomic profiling, and this type of intercompany cooperation will be essential. Dr. Herbst added a caveat: “Many companies often think they can do these kinds of studies alone, and they worry about losing autonomy, so the idea of a master trial is a challenge for them,” he said. “We hope to show this design will be a ‘win-win,’ adding efficacy and speed to the process.” “We tried to address industry concerns early,” said Ellen V. Sigal, PhD, Founder and Chair, Friends of Cancer Research. “At the March [2013] planning meeting, we assured the original 20 companies that expressed interest that FDA supports the

Industry Concerns There remain concerns about the workability of such a large endeavor: competition among pharmaceutical companies, their need to protect proprietary information, and the logistics of such a large and complex trial. However, Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, Chief of Medical Oncol-

sufficiently understand its response to cancer, and we lack a methodology of research that recognizes the unique features of immunotherapy.” There are many challenges in such research. For example, conventional pharmacokinetic approaches cannot guide dosing decisions because pharmacodynamic effects may be prolonged. Dose escalation until toxicity does not work. “We need new phase I designs for dosing,” said Dr. Ibrahim. Dose-ranging comparative studies may not better inform dose selection. Sometimes, if there is an early dramatic signal of activity, a trial might progress too quickly from phase I to phase III. Furthermore, animal models may not adequately mimic the human immune response to cancer, and there are too few immune-based biomarkers that correlate with an effective response. Because the immune system is dynamic and multifactorial, a successful approach must facilitate recognition of tumor cells by immune effector cells, as well as overcome the immunosuppressive tumor microenvironment. In other words, the target is the immune system itself and not the cancer. Finally, different immunotherapies require different criteria to assess response rate, progression-free survival, and other parameters. continued on page 110

idea and has put its statisticians at our disposal so it can make approval decisions based on trial data. We also will have a neutral third party monitoring the trial to assure that drugs from the participating companies will not be compared directly with one another.” Drug companies also can be enticed to participate by means of access to NCI’s network of comprehensive cancer centers that have much experience conducting trials. n For more on the Lung Cancer Master Protocol, see The ASCO Post, November 1, 2013, page 65. Disclosure: Drs. Papadimitrakopoulou, Gandara, Herbst, and Sigal reported no potential conflicts of interest.

Reference 1. 2013 Friends-Brookings Conference on Clinical Cancer Research. Session Two: Lung Cancer Master Protocol Activation Announcement. Presented November 7, 2013.


Amgen is researching ways to help T cells target cancer.

Find it T cell

Reference: 1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011;19:1008-1016. Š2013 Amgen Inc. All rights reserved. 11/13 74385-R2-V7


Fight it ONCOLYTIC IMMUNOTHERAPY

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Amgen. Leading the way in the study of Oncolytic Immunotherapy.


The ASCO Post  |   JANUARY 15, 2014

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Issues in Oncology

Intermediate Endpoints in Immunotherapy continued from page 107

Surrogate Endpoints Clinical trials have long relied on intermediate or surrogate endpoints to predict long-term survival. But immunotherapy doesn’t “try out” the same way as cytotoxic drugs. “Unconventional responses [for example, tumor shrinkage sooner than expected] to immunotherapy are relatively frequent and shouldn’t be ignored,” said Axel Hoos, MD, PhD, Vice President of Oncology, GlaxoSmithKline, Philadelphia. “We need to develop immunerelated response criteria that incorporate both early and delayed response, as well as tumor volume that increases before it recedes.” Drug companies use surrogate endpoints to decide whether they will continue testing a particular drug. Perhaps even more important, without an accurate surrogate, a trial that might have ended successfully could be prematurely terminated. This is what happened with a trial of tremelimumab, an anti-CTLA-4 antibody that was discontinued in 2008. Dr. Hoos said that immune-related responses must be incorporated into surrogate endpoints, such as: • Calculating the overall clinical benefit rate (for example, response and stable disease for 6 months or more). • Taking a baseline measurement several months after the initiation of therapy rather than at the beginning. This allows for the time it takes for a tumor to respond. • “Milestone survival”: the proportion of trial participants alive at a designated point that is late enough to surpass late-onset immune response but early enough for accelerated approval. Tai-Tsang Chen, PhD, Lead Statistician, Bristol-Myers Squibb, New York, described immune checkpoint modulators as offering the possibility of longterm survival and delayed clinical effect.

Log-rank analysis is not sufficient as the sole characterization of overall survival because it does not capture longterm survival effect, he said. The time to final analysis may be lengthened based on the kinetics of survival effect. But milestone survival (for example, 2 years) can be used as an intermediate endpoint to quantify long-term survival in the assessment of survival benefit. There are advantages and disadvantages, said Dr. Chen. The former include earlier assessment of benefit and risk, greater statistical power when the delayed clinical effect is present, predictable timing of analysis, and the

sponses plus durable stable disease in patients whose disease had been progressing. Because stability sometimes reflects the natural course of a disease, a clinical trial should require evidence of measurable progressive disease before patients begin the study drug. Gated progression-free survival is a modified approach to traditional progression-free survival and is assessed 2 or 3 months after treatment begins rather than at the time of treatment initiation. This minimizes the effect of early and/or pseudo progressions, thus allowing time for a full immunologic response. However,

We need to develop immune-related response criteria that incorporate both early and delayed response, as well as tumor volume that increases before it recedes. —Axel Hoos, MD, PhD

ability to use overall survival as both intermediate and final endpoints. Disadvantages include not maintaining study integrity after the milestone analysis (unblinding prior to final overall survival analysis), as seen in all interim analyses not accounting for the totality of overall survival data, and the danger of making false-positive or false-negative errors in a registration trial when prior data do not lend themselves to appropriate milestone selection.

Other Endpoints Other surrogate endpoints take into account unusual response patterns and delayed treatment effect. They can be used to characterize the activity of checkpoint modulators or to accelerate their development. Clinical benefit rate is the rate of partial responses plus complete re-

it requires a protocol in which patients are kept on the investigational treatment past initial radiographic progression. This may be appropriate only for patients with refractory disease and for whom there are no other treatment options. Tumor growth rate constants, which are now exploratory, can be used as a potential measure of efficacy. Analysis of changes in tumor growth rate may translate into survival improvement. Growth rates can be calculated from the tumor burden data usually collected for progression-free survival assessment. They are particularly relevant for treatments that induce low levels of response, as well as for describing effects beyond response.

The Future Much of the data demonstrating delayed treatment effects and unusu-

ally long-lasting responses come from a single agent: ipilimumab. Trials with therapeutic vaccines and early clinical results from PD-1 and PD-L1 inhibitors show similar effects, suggesting that the phenomenon might occur in 5% to 10% of patients. Such positive intermediate results could reduce the chance of prematurely ending a trial and increase the likelihood of accurately characterizing the activity profile of new immunotherapies. It also can reduce the time to marketing by serving as a basis for accelerated approval. A major question for the future concerns randomized trials. Are they at all ethical when early immunotherapy trials have shown significant and reproducible evidence of efficacy? Randomized trials with survival endpoints may not be feasible when multiple drugs in the same class are developed simultaneously by several companies (eg, PD-1/PD-L1). Single-arm registration trials might be appropriate for adoptive cell transfer approaches or therapies with high response rates. It is unclear, though, what endpoints would be appropriate if a therapy induced a long-term benefit but a low response rate. Validated endpoints that reflect mechanism of action are needed. n Disclosure: Dr. Allison is an inventor of intellectual property owned by the University of California, Berkeley, and licensed to BristolMyers Squibb; he is also a recipient of royalties from Bristol-Myers Squibb and founder of Jounce Therapeutics. Dr. Ibrahim works for and owns stock in AstraZeneca. Dr. Hoos is Vice President, Oncology, for GlaxoSmithKline. Dr. Chen reported no potential conflicts of interest.

Reference 1. 2013 Friends-Brookings Conference on Clinical Cancer Research. Session One: Facilitating Development of Immunotherapies: Intermediate Endpoints for Checkpoint Blockade. Presented November 7, 2013.

Friends of Cancer Research Launches New Online Forum: Engaging Innovation

F

riends of Cancer Research recently announced the launch of the online forum Engaging Innovation (www. focr.org/EngagingInnovation). With this site, the group will host leaders from regulation, research, drug development, treatment, and advocacy,

encouraging them to share insights and innovations in an ongoing dialogue about the most critical issues in the fight against cancer. The forum’s inaugural entry is an interview and video with Francis ­Collins, MD, PhD, Director of the National In-

stitutes of Health. Dr. Collins sat down with Friends of Cancer Research to talk about personalized medicine, research funding, sequestration, and opportunities for young scientists in America. Friends of Cancer Research invites members of the oncology research

community to add to the conversation with comments, contributions, and engagement. Readers can pitch their ideas for future contributors on Twitter via @CancerResrch using #EngageInnovation or e-mail Friends at info@ focr.org. n


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

1:1 Randomization

Blinded Rindopepimut Group 1 Bevacizumab Naïve (n=70)

1st or 2nd relapse EGFRvIII-positive glioblastoma

+

Bevacizumab Blinded KLH Control

+

Bevacizumab

Treat until tumor progression, intolerance, or withdrawal of consent

Rindopepimut

Group 2 Bevacizumab Refractory

+

Bevacizumab

(n=25)

KLH=keyhole limpet hemocyanin.

N=95

Key Inclusion Criteria

Key Exclusion Criteria

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

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

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

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

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

• History, presence, or suspicion of metastatic disease

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

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

All rights reserved.

J2A

7/13


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Patient’s Corner

Cancer Is in My Soul

After my mother, sister, and cousin died of breast cancer, I knew our family wasn’t just victim to random bad luck. But in 1980, no one had yet connected the genetic dots. By Annie Parker, as told to Jo Cavallo

T

he threat of getting cancer began for me before I was born. In 1950, when my mother was pregnant with me, she was diagnosed with breast cancer and refused treatment until after she gave birth, so I have always felt that cancer was woven into my soul. For the first year of my life, I was raised by my grandmother and aunt while my mother recovered from a mastectomy and cobalt treatment that left her too ill to care for an infant. Because cancer was still a closeted disease in the 1950s, I never learned that my mother had breast cancer until after she passed away from secondary lung cancer when I was 13. Until my mother’s death, I remember having a very happy childhood that was filled with lots of love and laughter. But cancer affects the whole family, and after my mother died life wasn’t the same. My sister Joanie and brother Doug moved out of the house, and my father, brokenhearted over my mother’s death, sank into a depression and died 3 weeks before my wedding in 1969.

doctor refused to consider a genetic basis for the breast cancer that had taken so many beloved family members and that had now come for me. After undergoing a radical mastectomy, I became obsessed with trying to learn what the common thread could be that bound together my family’s destiny with cancer. But back then there was no Internet or social media to turn to for information or to discover that a woman named MaryClaire King, PhD [American Cancer Society Research Professor, Departments of Medicine and Genome

It took a lot of soul-searching to decide to become so public about both my family’s and my own experience with cancer. But I hope our story brings solace to others facing a similar circumstance and encouragement to persevere when circumstances seem hopeless.

More Than Bad Luck Because Joanie was 10 years older than I am, she became my surrogate mom, and I went to her with all my problems. When she was diagnosed with breast cancer in 1978 and died a year later of ovarian cancer, I was inconsolable. During that year, my cousin Carolyn was also diagnosed with breast cancer and passed away. They were both just shy of their 40th birthday. Although breast cancer wasn’t commonly linked to genetics in the 1970s, I instinctively knew there had to be something more at work here than simple bad luck, which was what my gynecologist kept suggesting to reassure me that I wouldn’t be next on the list. Even after I was diagnosed with cancer in my left breast in 1980 at the age of 29, my

When my ovarian cancer was finally diagnosed in 1988, it had spread to the peritoneum. At that point, I needed a complete hysterectomy and 12 months of grueling chemotherapy. Finally, in 1994, 4 years after Dr. King’s discovery that a single gene on chromosome 17q21—which she named BRCA1—was responsible for inherited breast and ovarian cancers, my oncologist called and said he wanted me to be tested for the gene mutation. In fact, I was one of the first people to be tested in North America

—Annie Parker

Sciences, at the University of Washington, Seattle] was researching an inherited susceptibility to breast and ovarian cancers.

The Answer at Last Although news about Dr. King’s work and the possibility that there could be a genetic basis for breast and ovarian cancers had started to seep into the medical literature by the late 1980s, when I went to my gynecologist complaining about bloating, vaginal bleeding, and back pain, I was told that my symptoms were the result of stress from my recent divorce. I was advised to see a psychiatrist.

for the BRCA gene mutation, and the Tech Museum of Innovation in San Jose, California, had a whole exhibit devoted to my testing. They even sent a film crew up to Toronto to film me and family members. I got my answer 2 years later. (Today, gene sequencing takes less than 3 weeks.) I did indeed carry the BRCA1 gene mutation. My reaction was jubilation because finally I had the answer I had searched for all my adult life. At last I knew for sure that what had doomed my mother, sister, cousin, and me to cancer wasn’t random bad luck but an inherited susceptibility, as I had always suspected.

Cancer Is My Life In 2005, I was diagnosed with an unknown primary cancer that had attached to my liver. Even though there is no apparent connection between this latest cancer and the BRCA gene mutation, I instinctively feel there must be a link. All I know for sure is that cancer is my life. Despite the immeasurable pain of losing so many family members—and nearly my own life—to cancer, the disease has made me the person I am today. It’s a cliché, I know, but I really do live every day as if it were my last because I know that at any moment the course of my life can change. And that’s true for everyone. I recently got to tell my life story in a movie called Decoding Annie Parker [see “Decoding Annie Parker: Hunting the Breast Cancer Gene,” The ASCO Post, November 15, 2013]. I hope it gives other people facing a cancer diagnosis the courage to overcome their fear and the knowledge that they are not alone. It has been especially gratifying for me to meet with oncologists and researchers at screenings of the movie who have said that the film gave them a new appreciation and understanding of what goes on in the lives of their patients after they leave the doctor’s office. Their words and kindness have been humbling. It took a lot of soul-searching to decide to become so public about both my family’s and my own experience with cancer. But I hope our story brings solace to others facing a similar circumstance and encouragement to persevere when circumstances seem hopeless. n Annie Parker is writing an autobiography. Her book and the film, Decoding Annie Parker, are scheduled for commercial release in spring 2014. Ms. Parker lives in Toronto, Ontario, Canada.

Delivered to your inbox every weekday evening. Visit ASCOPost.com to learn more.


ASCOPost.com  |   JANUARY 15, 2014

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Journal Spotlight Hematology

Donor KIRDL1-R245 Allele Predicts Improved Survival and Reduced Progression in Pediatric Allogeneic Stem Cell Transplant By Matthew Stenger

K

iller-cell immunoglobulin-like receptors (KIRs) that regulate natural-killer cells are highly polymorphic, and some KIR2DL1 alleles (ie, KIR2DL1-R245) encode receptors characterized by stronger signaling function than others (ie, KIR2DL1-C245). In a study reported in the Journal of Clinical Oncology, Rafijul Bari, PhD, of St. Jude Children’s Research Hospital, Memphis, and colleagues investigated whether outcomes of pediatric allogeneic hematopoietic stem cell transplantation are affected by donor KIR2DL1 polymorphism.1 They found that patients receiving a donor graft with the functionally stronger KIR2DL1-R245 allele had significantly improved overall survival and progression-free survival.

Study Details The study involved 313 pediatric patients undergoing allogeneic hematopoietic stem cell transplantation at St. Jude Children’s Research Hospital between January 1, 2000, and January 1, 2010. Donor KIR2DL1 functional allele typing was retrospectively performed using a single nucleotide polymorphism assay. The functionally stronger KIR2DL1 allele has arginine at amino acid position 245 (KIR2DL1-R245), and the functionally weaker allele has cysteine at the same position (KIR2DL1-C245). Patients had a median age of 9.9 years at transplantation (range, 1 month to 18.6 years). The primary diagnoses included 231 hematologic malignancies (lymphoid in 116 patients, myeloid in 115; total 74%), 25 solid tumors (embryonal tumors in 19 patients, bone sarcomas in 6; total 8%), and 57 nonmalignant diseases (marrow failure in 10 patients, genetic diseases in 47 patients; total 18%). Of 256 patients with cancer, 143 (56%) were in remission and 113 (44%) had persistent disease at the time of transplantation. A total of 175 patients (56%) received a conditioning regimen including totalbody irradiation. The majority (77%) of regimens were myeloablative, defined as total-body irradiation ≥ 5 Gy in single dose or ≥ 8 Gy fractionated, busulfan (Busulfex, Myleran) > 9 mg/kg, or melphalan > 150 mg/m2. Grafts were obtained from matched-sibling donors in 27% of recipients, matched-unrelated donors in 31%, and haploidentical donors in 41%. Among the 313 donors, 215 (69%)

were homozygous for KIR2DL1-R245 (RR; RR), 22 (7%) were homozygous for KIR2DL1-C245 (CC; CC), and 76 (24%) were heterozygous for KIR2DL1-R245/C245 (RC; RC). KIR2DL1-R245 was associated with centromeric  A–containing haplotypes and KIR2DL1-C245 with centromeric  B haplotypes (P  <  .00001). There was no significant difference among the three allelic groups for any other demographic or transplantation variables.

Survival Compared with the patients who received a CC donor graft, the risk of death after hematopoietic stem cell transplantation was significantly lower in those who received an RR graft (hazard ratio [HR] = 0.4, P < .0001) or an RC graft (HR = 0.42, P = .0013), with the estimate of survival probability in patients receiving an RR or RC graft being significantly greater than that in patients receiving a CC graft (P  =  .0004). There was no difference in survival associated with RR vs RC grafts. CC grafts were associated with the worst survival rates among 256 patients with malignancy (P = .001) and among

Predicting Outcome in Stem Cell Transplant Recipients ■■ Patients who received a donor graft containing the KIR2DL1-R245 allele had better survival and lower cumulative incidence of disease progression than patients receiving a donor graft containing only the functionally weaker KIR2DL1-C245 allele. ■■ The effect of KIR2DL1 allelic polymorphism was similar in patients with acute myeloid leukemia and those with acute lymphoblastic leukemia among all three allele groups. ■■ Patients who received a KIR2DL1-R245 graft with HLA-C receptor-ligand mismatch had the best survival and lowest risk of disease progression.

survival on univariate analysis. In multivariate analysis adjusting for these factors, survival remained significantly longer in patients receiving an RR (HR = 0.4, P  <  .0001) or RC graft (HR = 0.44, P = .0024) vs a CC graft.

Progression-Free Survival On univariate analysis, progressionfree survival in 256 patients with cancer was significantly greater in those with an RR (HR = 0.42, P  =  .0003) or RC graft (HR = 0.48, P  =  .0075) vs a CC graft, with no difference observed between RR and RC groups. RR and RC grafts were also associated with signifi-

Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic [hematopoietic stem cell transplantation]. These findings have substantial implications for prognostication and donor selection. —Rafijul Bari, PhD, and colleagues

231 with hematologic malignancy (P = .0007). Patients with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) had similar survival probabilities in all three donor KIR2DL1 allele groups (all P ≥ .71). The effects of donor KIR2DL1 alleles were comparable in the sibling donor, unrelated donor, and haploidentical donor hematopoietic stem cell transplantation subgroups, in T-cell–depleted and T-cell– replete graft subgroups, and in the myeloablative hematopoietic stem cell transplantation subgroup. Differences between the RR and RC vs CC grafts were not significant in the nonmyeloablative subgroup. In addition to donor KIR2DL1 polymorphism, primary disease, T-cell depletion, and conditioning intensity were also significantly associated with

cantly prolonged progression-free survival among the 231 patients with hematologic malignancies (P = .01). There was no significant difference in risk of progression between AML and ALL patients according to the three donor KIR2DL1 allele groups (all P  ≥ .54). On multivariate analysis, progression-free survival remained significantly longer in the RR group (HR = 0.38, P= .0001) and RC group (HR = 0.45, P= .0049) vs the CC group.

Graft vs Host Disease Grade II to IV graft-vs-host disease was present in 25% of the RR group, 32% of the RC group, and 27% of the CC group, with no significant correlation between graft-vs-host disease and donor KIR2DL1polymorphism.

Effects of Receptor-Ligand Mismatch Among the 231 patients with hematologic malignancies, the 5-year survival rate was 48% in those in the RR or RC groups who were HLA-C receptor-ligand mismatched (P  <  .001 vs CC group), compared with 31% among those in the RR or RC groups who were not HLA-C receptor-ligand mismatched (P = .02 vs CC group) and 0% in the CC group with or without receptor-ligand mismatch. The cumulative incidence of disease progression was lowest in patients in the RR or RC groups who were HLA-C receptorligand mismatched (P  <  .001 vs CC group; P = .02 for RR or RC group patients who were not HLA-C receptorligand mismatched vs CC group). The investigators concluded, “Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic [hematopoietic stem cell transplantation]. These findings have substantial implications for prognostication and donor selection.” n Disclosure: The study was supported in part by the National Institutes of Health, the Assisi Foundation of Memphis, and the American Lebanese Syrian Associated Charities. Drs. Bari and Wing Leung (also of St. Jude Children’s Research Hospital) hold the patent for the single nucleotide polymorphism assay used for killer-cell immunoglobulin-like receptor allele typing. Dr. Leung is the corresponding author for the Journal of Clinical Oncology article. For full disclosures of the study authors, visit jco. ascopubs.org.

Reference 1. Bari R, Rujkijyanont P, Sullivan E, et al: Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 31:3782-3790, 2013.


The ASCO Post  |   JANUARY 15, 2014

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Announcements

Bill & Melinda Gates Foundation Names Susan Desmond-Hellman New CEO

T

he Bill & Melinda Gates Foundation has selected Susan Desmond-­Hellmann, MD, MPH, as its next Chief Executive Officer. Currently the Chancellor of the University of California, San Francisco (UCSF), Dr. Desmond-Hellmann will assume

her role on May 1, 2014. “We chose Sue because of her scientific knowledge and deep technical expertise on the foundation’s issues, as well as the organizational and leadership skills required to lead a large, growing and dynamic global organization. Sue shares our

commitment and passion to create a more equitable world,” said Melinda Gates, Co-Chair of the Foundation. “I am honored by the opportunity that Bill and Melinda have extended to me. I’m excited to join such a dynamic and ambitious organization, with such a

clear and focused mission—improving the lives of the world’s most vulnerable,” said Dr. Desmond-Hellmann. “Sue’s background in public health policy, research and development, and higher education, make her an exceptional fit for this role. She impressed us as an innovator and an outstanding leader and manager,” said Bill Gates, Co-Chair of the Foundation.

Palbociclib in combination with letrozole vs letrozole alone for first-line treatment of postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer

Susan Desmond-Hellmann, MD, MPH

Primary endpoint: progression-free survival

(PD-0332991)

Study 1008

2:1 R A N D O M I Z A T I O N

N=450

Postmenopausal women with ER+/HER2- breast cancer; no prior systemic anticancer treatment for advanced disease

Palbociclib 125 mg QD (21 days on/7 days off) + Letrozole 2.5 mg QD

Placebo (21 days on/7 days off) + Letrozole 2.5 mg QD

Palbociclib in combination with fulvestrant vs fulvestrant alone in the treatment of women with HR+/HER2- locally advanced or metastatic breast cancer Primary endpoint: progression-free survival N=417

Study 1023

Palbociclib

2:1 R A N D O M I Z A T I O N

NOW ENROLLING

Palbociclib Clinical Trials

Two phase 3, randomized, double-blind, multicenter studies of Palbociclib, an oral CDK4/6 inhibitor

Women of any menopausal status with HR+/HER2- breast cancer who progressed on or after prior endocrine therapy

125 mg QD (21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

Placebo

(21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

For more information about these trials, including secondary endpoints and eligibility criteria, please visit www.pfizercancertrials.com and www.clinicaltrials.gov (PALOMA-2: NCT01740427; PALOMA-3: NCT01942135). Palbociclib (PD-0332991) is an investigational compound.

These trials are part of the clinical trial program.

(Cyclin-Dependent Kinase inhibitor in cancer)

This information is current as of November 2013. CDK=cyclin-dependent kinase 8500270947-H © 2013 Pfi zer Inc. All rights reserved.

Dr. Desmond-Hellmann is an oncologist and recognized leader on issues of higher education, public health, drug development, regulatory innovation and health policy. She has led UCSF since August 2009, when she became the first woman to serve as the university’s chancellor, overseeing all aspects of the university and medical center’s strategy, academic programs and operations. Prior to her tenure at UCSF, she was President of Product Development at Genentech, where she led the development and introduction of two of the first gene-targeted therapies for cancer, bevacizumab (Avastin) and trastuzumab (Herceptin). Dr. Desmond-Hellmann will take over from Jeff Raikes, who announced his retirement from the Foundation in September 2013 after 5 years at the helm.

Bill & Melinda Gates Foundation Guided by the belief that every life has equal value, the Bill & Melinda Gates Foundation works to help all people lead healthy, productive lives. In developing countries, it focuses on improving people’s health and giving them the chance to lift themselves out of hunger and extreme poverty. In the United States, it seeks to ensure that all people—especially those with the fewest resources—have access to the opportunities they need to succeed in school and life. Based in Seattle, the Foundation is led by CEO Jeff Raikes and Co-Chair William H. Gates Sr, under the direction of Bill and Melinda Gates and Warren Buffett. n


ASCOPost.com  |   JANUARY 15, 2014

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Integrative Oncology Stress and Tumor Biology: Insights Into Managing Stress to Help Improve Cancer Care By Lorenzo Cohen, PhD, Anil K. Sood, MD, PhD, Sarah Prinsloo, PhD, and Alejandro Chaoul, PhD, The University of Texas MD Anderson Cancer Center, Houston

S

tress is ubiquitous in our society, especially for people diagnosed with a life-threatening illness. There is a common misconception that stress is derived

Lorenzo Cohen, PhD

from a particular negative event. However, the event itself (the stressors, such as cancer diagnoses and treatment) does not causes stress. Rather, the cause is the response to the stressor, known as the “fight-or-flight” response. Dr. Cohen is Professor in the Departments of General Oncology and Behavioral Science, and Director of the Integrative Medicine Program, and Dr. Sood is Professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston. Dr. Prinsloo is a Population Sciences Fellow in the Integrative Medicine Program and Dr. Chaoul is Assistant Professor in the Department of General Oncology and Director of Education in the Integrative Medicine Program at The University of Texas MD Anderson Cancer Center, Houston.

Although it is not always possible to control the stressors encountered in life, it is possible to learn how to control reactions to stressors. Ensuring that patients manage stress effectively is critical to improving patient outcomes. Although research indicates that stress and depression are associated with poorer cancer survival,1 controversy surrounds the interpretation that psychosocial and biologic factors indeed may contribute interdependently to disease processes.2

Physiologic Effects of Stress Stress generally occurs when an event or situation (stressor) places demands on an individual or tests coping abilities. Normal physiologic responses evolved evolutionarily to help organisms deal with threats. For example, to escape from a predatory threat, automatic physiologic responses include increased heart rate, faster and shallower breathing, increased perspiration, and the shunting of blood to muscles. Under such conditions, other body systems tend to decrease function. For example, digestion is decreased to enable the expenditure of additional energy on systems that will best help the body deal with the stressor. To counterbalance the sympathetic nervous system and hypothalamic-pituitary-adrenal response once the acute stressor is over, the parasympathetic system engages, decreasing heart rate, slowing breathing, and relaxing muscles, allow-

GUEST EDITOR

I

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 SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. Barrie R. Cassileth, MS, PhD 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. 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.

ing return to the prestressor balanced state of function and resting under parasympathetic tone. Stressors in life are many and varied, but typically they are characterized by an event that is challenging, harmful, induces fear, or represents loss. Although the acute physiologic reaction associated with the “fight or flight” response has been evolutionarily helpful for survival and is adaptive, when these situations occur frequently and the demands on the system exceed coping abilities, stress becomes chronic. Under

these conditions, one lives in a constant sympathetic state, and excessive demands on the system ensue. These biobehavioral factors can result in maladaptive physiologic responses including prolonged increases in sympathetic nervous system and hypothalamic-pituitary-adrenal axis activity.3 The brain also responds in the “fight or flight” fashion and, in fact, may be viewed as the major orchestrator of the response. The brain usually shifts into a high-alert brain-wave activity state

Learn More About

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

www.mskcc.org/aboutherbs

continued on page 116


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Integrative Oncology Stress and Tumor Biology continued from page 115

while the stressor is present and then shifts back to more relaxed activity once the stressor is gone (usually slower; parasympathetic tone). Under chronic stress, it becomes more difficult for the brain to switch between sympathetic and parasympathetic arousal, so that the brain and the rest of the body rarely have the opportunity to recover. Over time, the body will struggle to recover after a stressful event, even if the stressor is no longer present. Unmanaged chronic stress can speed the aging process through telomere shortening,4 and increases the risk for heart disease,5 sleeping difficulties,6 digestive problems,7 and even depression.8 Moreover, chronic stress can also cause patients to forgo healthy eating and exercise habits that help prevent cancer and other disease.

Stress and the Tumor Microenvironment The health-damaging effects of chronic stress are well documented in the medical literature, and research indicates that chronic stress affects almost every biologic system.9 With regard to cancer, there is little convincing evidence that chronic stress affects cancer initiation. However, there is extensive evidence that chronic stress can promote cancer growth and progression.10-12 The underlying mechanisms for such effects are complex and involve chronic activation of the sympathetic nervous system and the hypothalamicpituitary-adrenal axis.13-15 Sustained elevations from these pathways (eg, norepinephrine, cortisol) can result in diverse effects including stimulation of cancer invasion, angiogenesis, inflammation, reduced anoikis, and even reduced efficacy of chemotherapeutic agents.16-18 The underlying signaling pathways19 offer opportunities for designing new therapeutic approaches to disrupting the effects of stress biology on cancer biology. These include both biobehavioral and pharmacologic approaches (eg, beta-blockers).

Screening and Treating Chronic Stress According to the National Comprehensive Cancer Network (NCCN), distress is: a multifactorial unpleasant emotional experience of a psychological (cogni-

tive, behavioral, emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms and its treatment. Distress extends along a continuum, ranging from common normal feelings of vulnerability, sadness, and fears to problems that can become disabling, such as depression, anxiety,

panic, social isolation, and existential and spiritual crisis.20

The NCCN Clinical Practice Guidelines in Oncology suggest that all patients be screened with the single-item “distress thermometer.”20 The distress thermometer asks patients to rate their distress using a scale ranging from 0 (“no distress”) to 10 (“extreme dis-

tress”). Patients also indicate their source of distress by checking off issues listed on a 34-item problem list. The list includes practical problems, family problems, emotional problems, spiritual/religious concerns, and physical problems. While some distress is normal, it is not benign and must be addressed, as


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Integrative Oncology failure to do so may compromise health and quality-of-life outcomes. The NCCN recommends that those scoring ≥ 4 on the distress thermometer be referred to a mental health-care professional for further evaluation. A number of different approaches can be used to manage distress in patients with cancer including behavior-

al, pharmacologic, or a combined approach. Cognitive-behavioral therapy, cognitive-behavioral stress management, and antidepressants or anxiety medications have all been found to help in treating anxiety and depression in cancer patients. In fact, a recent study of cognitive-behavioral stress management found that this technique

led to decreases in inflammatory gene expression, with previous studies reporting improvements in mood, quality of life, and ability to find meaning in the illness experience, among other benefits.21,22 Although these approaches will be useful for some patients, many seek strategies to manage their distress that

are outside the conventional areas of psychiatry and clinical psychology. Mind-body practices constitute one method of increasing brain flexibility to help maintain a healthy balance between sympathetic and parasympathetic arousal.

Mind-Body Practices A key ingredient to managing chronic stress is to have patients engage in behaviors that decrease sympathetic and increase parasympathetic arousal—that is, clinicians should encourage patients to learn how to relax in stressful situations. Mind-body practices are one way to achieve this goal. Research shows that mind-body practices have a positive effect on all body systems, improving quality of life, reversing the harmful effects of stress, and creating fundamental changes in brain function.23-31 Mind-body practices to help manage stress include meditation, various forms of yoga, and practices such as tai chi and qigong. These practices may be understood as movement-based meditations. They affect neurotransmitters (eg, glutamate, GABA) and neuromodulators (eg, dopamine, serotonin, epinephrine), which are essential in maintaining a healthy balance between sympathetic and parasympathetic arousal, thereby helping to manage the stress response.32 Mind-body practices can help decrease chronic stress by bringing balance to the body and, ultimately, to patients’ lives.33 It is clear from multiple studies of mind-body interventions that it is important for patients to participate in some kind of program and/or to include a mind-body practice in their lives to manage stress and improve their quality of life. There are many types of mindbody programs that can be useful.

Meditation Meditation has been described as “a wakeful hypometabolic physiologic state”34 in which the practitioner is extremely relaxed yet alert and focused. Although meditation methods can vary, most types of meditation share common features such as focused, controlled regulation of breathing and control over thoughts and feelings, whether the goal is to inhibit and/ or acknowledge and release external thoughts and feelings. Given the continuous attentionbased processes involved in initiating and maintaining a meditative state, meditation has been proposed to be an attentional training exercise. Among continued on page 118


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Integrative Oncology Stress and Tumor Biology continued from page 117

other benefits, it helps bring awareness to the relationship between the mind and body, acknowledging the constant dialogue and bidirectional effect that the mind and body have on one another. Meditation and meditative movement practices may help the brain invoke the parasympathetic response to chronic stress, to thereby balance the sympathetic strain. Most brain activity is electrical. Electrical rhythms are classified into groups according to the speed with which they relay information. Delta is the slowest brainwave and is predominant in

mone systems, neurotransmitters (neuromodulators) and even gene expression, thus improving aspects of quality of life, and creating fundamentally beneficial changes in the way the brain works. The neurologic effect of mind-body practices demonstrates the brain’s profound ability to change itself through experience. This new frontier of medicine reveals the importance of managing chronic stress and underscores how influential behavior is on how the brain works and on overall health and well-being. Mind-body practices are one such healthy behavior with which to achieve balance and teach the brain flexibility.

Patients often ask which mind-body program is the best for reducing stress and improving quality of life. The answer is the one they will do every day and make a part of their life. —Lorenzo Cohen, PhD, Anil K. Sood, MD, PhD, Sarah Prinsloo, PhD, and Alejandro Chaoul, PhD

sleep states; theta can equal a state similar to daydreaming; alpha is associated with relaxation; and beta is associated with attention and intellectual activity. Brain research demonstrates that the mechanisms of meditation induce electrical frequencies that are thought to be, in part, the switch between hyperarousal and relaxation. For example, under meditation conditions, the brain often shows changes in activity in the alpha wave.35,36 Alpha triggers mental relaxation and is an idle rhythm of the brain as it waits for cues from other parts of the body and the environment. This and other brain electrical rhythms affect neuromodulators, such as dopamine and serotonin, which are also essential to maintain a healthy balance between sympathetic and parasympathetic arousal and to manage the stress response. Mind-body practices, therefore, help regulate relaxation in the body through a bidirectional conversation between electrical and chemical messages in the brain and the translation of those messages throughout the body. A feedback loop follows, where the brain receives signals from the rest of the body about the current state of arousal. As meditation with awareness continues, the body continues to relax and improve the balance across functional systems. Consequently, these practices can help regulate chronic stress, facilitating the integration of the mind and body.

Overall Health Effects Mind-body research indicates that these practices have an effect on all physiologic systems, such as immune and hor-

Patients often ask which mind-body program is the best for reducing stress and improving quality of life. The answer is the one they will do every day and make a part of their life. Mind-body techniques are many and varied. Encourage your patients to find a mind-body approach that works for them and to practice it daily. n Disclosure: Drs. Cohen, Sood, Prinsloo, and Chaoul reported no potential conflicts of interest.

References 1. Satin J, Linden W, Phillips MJ: Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer 115:5349-5361, 2009. 2. Metcalfe C, Davey Smith G, Macleod J, et al: The role of self-reported stress in the development of breast cancer and prostate cancer: A prospective cohort study of employed males and females with 30 years of follow-up. Eur J Cancer 43:1060-1065, 2007. 3. McEwen BS: Protective and damaging effects of stress mediators. N Engl J Med 338:171179, 1998. 4. Epel ES, Blackburn EH, Lin J, et al: Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A 101:1731217315, 2004. 5. Torpy JM, Lynm C, Glass RM: JAMA patient page. Chronic stress and the heart. JAMA 298:1722, 2007. 6. Cohen S, Janicki-Deverts D, Miller GE: Psychological stress and disease. JAMA 298:1685-1687, 2007. 7. Chang L: The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome. Gastroenterology 140:761765, 2011. 8. Hammen C: Stress and depression. Annu

Rev Clin Psychol 1:293-319, 2005. 9. Chrousos GP, Gold PW: The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244-1252, 1992. 10. Lutgendorf SK, Sood AK, Antoni MH: Host factors and cancer progression: Biobehavioral signaling pathways and interventions. J Clin Oncol 28:4094-4099, 2010. 11. Sloan EK, Priceman SJ, Cox BF, et al: The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70:7042-7052, 2010. 12. Lutgendorf SK, Sood AK, Anderson B, et al: Social support, psychological distress, and natural killer cell activity in ovarian cancer. J Clin Oncol 23:7105-7113, 2005. 13. Antoni MH, Lutgendorf SK, Cole SW, et al: The influence of bio-behavioural factors on tumour biology: Pathways and mechanisms. Nat Rev Cancer Mar 6:240-248, 2006. 14. Lutgendorf SK, Sood AK: Biobehavioral factors and cancer progression: Physiological pathways and mechanisms. Psychosom Med 73:724-730, 2011. 15. Lutgendorf SK, DeGeest K, Dahmoush L, et al: Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun 25:250-255, 2011. 16. Thaker PH, Han LY, Kamat AA, et al: Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12:939-944, 2006. 17. Armaiz-Pena GN, Cole SW, Lutgendorf SK, et al: Neuroendocrine influences on cancer progression. Brain Behavior and Immunity 30:S19-S25, 2013. 18. Sood AK, Armaiz-Pena GN, Haider J, et al: Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest 120:1515-1523, 2010. 19. Armaiz-Pena GN, Allen JK, Cruz A, et al: Src activation by beta-adrenoreceptors is a key switch for tumour metastasis (vol 4, pg 1403, 2013). Nat Commun 4:1403, 2013. 20. National Comprehensive Cancer Network: NCCN Clinical Practice Guildines in Oncology: Distress management, version 1.2010. Available at www.nccn.org. Accessed March 15, 2010. 21. Antoni MH, Lutgendorf SK, Blomberg B, et al: Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics. Biol Psychiatry 71:366372, 2012. 22. Traeger L, Penedo FJ, Benedict C, et al: Identifying how and for whom cognitivebehavioral stress management improves emotional well-being among recent prostate cancer survivors. Psychooncology 22:250-259, 2013. 23. Dusek JA, Otu HH, Wohlhueter AL, et al: Genomic counter-stress changes induced by the relaxation response. PLoS ONE 3:e2576, 2008. 24. Carlson LE, Doll R, Stephen J, et al: Ran-

domized controlled trial of Mindfulness-based cancer recovery versus supportive expressive group therapy for distressed survivors of breast cancer. J Clin Oncol 31:3119-3126, 2013. 25. Mustian KM, Sprod LK, Janelsins M, et al: Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol 31:3233-3241, 2013. 26. Chandwani K, Nagendra HR, Raghuram NV, et al: A randomized, controlled trial of yoga in women with breast cancer undergoing radiotherapy. J Clin Oncol 2013 (in press). 27. Chandwani KD, Thornton B, Perkins GH, et al: Yoga improves quality of life and benefit finding in women undergoing radiotherapy for breast cancer. J Soc Integr Oncol 8(2):43-55, 2010. 28. Chen Z, Meng ZQ, Milbury K, et al: Qigong improves quality of life in women undergoing radiotherapy for breast cancer results of a randomized controlled trial. Cancer 119:16901698, 2013. 29. Milbury K, Chaoul A, Biegler K, et al: Tibetan sound meditation for cognitive dysfunction: Results of a randomized controlled pilot trial. Psychooncology. May 9, 2013 (early release online). 30. Wells RE, Yeh GY, Kerr CE, et al: Meditation’s impact on default mode network and hippocampus in mild cognitive impairment: A pilot study. Neurosci Lett 556:15-19, 2013. 31. Holzel BK, Carmody J, Vangel M, et al: Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Res 191:36-43, 2011. 32. Jindal V, Gupta S, Das R: Molecular mechanisms of meditation. Mol Neurobiol 48:808-811, 2013. 33. Davidson RJ, McEwen BS: Social influences on neuroplasticity: Stress and interventions to promote well-being. Nat Neurosci 15:689-695, 2012. 34. Wallace RK, Benson H, Wilson AF: A wakeful hypometabolic physiologic state. Am J Physiol 221:795-799, 1971. 35. Saggar M, King BG, Zanesco AP, et al: Intensive training induces longitudinal changes in meditation state-related EEG oscillatory activity. Front Hum Neurosci 6:256, 2012. 36. Berkovich-Ohana A, Glicksohn J, Goldstein A: Studying the default mode and its mindfulness-induced changes using EEG functional connectivity. Soc Cogn Affect Neurosci. November 5 2013 (early release online).

Learn More About The University of Texas MD Anderson Cancer Center’s Integrative Medicine Program at www.mdanderson.org/ integrativemed


ASCOPost.com  |   JANUARY 15, 2014

PAGE 119

Palliative Care in Oncology Assessing Patients for Palliative Care

A Conversation With Deborah Dudgeon, MD, FRCPC By Jo Cavallo

Deborah Dudgeon, MD, FRCPC

I

n 2012, ASCO issued a provisional clinical opinion addressing the integration of palliative care services into standard oncology practice at the time a patient is diagnosed with metastatic or advanced cancer and for patients with uncontrolled symptoms.1 However, despite ASCO’s provisional clinical opinion and numerous studies showing the benefits of palliative care for patients and their caregivers, including one by researchers at Icahn School of Medicine at Mount Sinai, 2 palliative care services remain underutilized for patients with cancer. “Patients need early identification of their palliative needs, and those needs might be in the realm of symptoms that are not well controlled, both physical and psychological. But evaluations also need to be made of any other issues that are impacting patients’ quality of life,” said Deborah Dudgeon, MD, FRCPC, W. Ford Connell Professor of Palliative Care Medicine at Queen’s University in Kingston, Ontario, Canada, and Senior Scientific Lead for Person-Centred Perspective for the Canadian Partnership Against Cancer. As the former head of Palliative Care for Cancer Care Ontario, Dr. Dudgeon helped to integrate palliative care into the 14 regional cancer centers in Ontario and also helped to develop a Web-based tool patients could use to describe the intensity of their symptoms—such as their level of pain—to their physicians for further evaluation and management. The ASCO Post talked with Dr. Dudgeon about assessing patients for palliative care and dispelling the long-held association of palliative care with only end-of-life hospice care.

Expertise and Teamwork

Integration of Care

When should patients with cancer be considered for palliative care, and who is best qualified to treat their symptoms? Patients have many palliative needs and often present to a physician with symptoms of pain, shortness of breath, and other issues even before a cancer diagnosis is made. They need a physician with the expertise to manage their symptoms. My own feeling is that all physicians need to have a basic level of knowledge about palliative care and that we, as oncologists, need to have the next level of knowledge, because many of our patients present with symptoms, both from the disease and from the treatments we give, including pain, fatigue, shortness of breath, weight loss, nausea, and vomiting. Then there is the need for the third level of care by palliative care experts who have more training and experience in managing symptoms that are refractory to simpler measures.

Should palliative care be integrated into standard oncology care for all patients? Yes. We talk about a simultaneous model of care, so it’s not a question of whether a patient should receive either palliative care or cancer care that is oriented toward the disease. There needs to be an integration of palliative care with disease-oriented management to optimize people’s quality of life throughout the course of their diagnosis, treatment, and recovery. The balance of where to focus changes over time, but both needs have to be addressed simultaneously.

Emotional Issues How can palliative care be used to help patients cope with the emotional turbulence of living with a terminal disease? Traditionally, palliative care has always tried to address the needs of the whole patient, including any psychosocial issues they may have. It is important for oncologists to identify early on any emotional or mental health issues pa-

Ideally, you want palliative care to be provided by the primary physician who is managing the patient’s standard oncology care. But the integration of palliative care into standard oncology care is very much about teamwork. —Deborah Dudgeon, MD, FRCPC

Ideally, you want palliative care to be provided by the primary physician who is managing the patient’s standard oncology care. But the integration of palliative care into standard oncology care is very much about teamwork. The type of care and who manages the care depends in part on the complexity of the individual patient’s disease and symptoms. Patients should be assessed for palliative care needs throughout the course of their illness, for any issue that is negatively impacting their quality of life and their ability to cope with having cancer. It is important for oncologists to be aware of available supportive services, including psychological, social, and spiritual resources, so they can refer patients to the appropriate expert for care, to help patients cope with emotional, mental health, and existential issues resulting from their diagnosis.

tients have and then refer them to the appropriate specialist on the health-care team, such as a social worker, psychologist, or psychiatrist, if the oncologist is unable to manage those symptoms.

Screening Tool Please describe the screening technique you developed to measure the palliative care needs of patients based on the level of physical and psychological symp-

toms they are experiencing. When I was the head of Palliative Care for Cancer Care Ontario, we used the Edmonton Symptom Assessment System, which is designed to assist in screening for the intensity of nine common symptoms experienced by cancer patients—ie, pain, fatigue, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath—to develop a Web-based tool for patients who came into our cancer centers. Patients enter the level of severity of their symptoms on a 0-to-10 scale using a touch-screen computer every time they visit the cancer center; the information is captured electronically and printed to show to the clinician for evaluation. The printout includes a history of the patients’ symptoms over time so the clinician can see changes in the number of symptoms and levels of their severity and determine the best course of palliative management. My understanding is that the 14 cancer centers utilizing this technology are getting about 27,000 patient inputs a month, so it is a very useful tool for oncologists to screen for palliative care needs. Following an in-depth assessment, they can then work out a management plan to address a patient’s symptoms.

Palliative vs Hospice Care Are more physicians and patients now making the distinction between the roles of palliative care and end-of-life hospice care? Not completely, but it is getting better. I think there are still a lot of people that tend to view palliative care as synonymous with end-of-life care, which is reserved for when treatment stops working and the cancer is no longer controllable. There is certainly a greater understanding among most cancer professionals about the difference between the two, but it is not universal. continued on page 120

GUEST EDITOR

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. In July 2013, Dr. Von Roenn was named ASCO’s Senior Director of Education, Science and Professional Development Department. n

Jamie H. Von Roenn, MD


The ASCO Post  |   JANUARY 15, 2014

PAGE 120

News Immunotherapy

Science Magazine Names Cancer Immunotherapy as Scientific Breakthrough of the Year By Jo Cavallo

W

hile acknowledging that the full potential of cancer immunotherapy remains unclear, the editors of the journal Science said that the approach of using the immune system to attack tumors marks a turning point in the treatment of cancer. 1 The successes of cancer immunotherapy in clinical trials in 2013, which were decades in the making, displayed such promise as a treatment strategy, it rose to the top of the journal’s list of the year’s 10 most important scientific breakthroughs. Other scientific achievements singled out by Science include breakthroughs in solar cell technologies, genome-editing techniques, and vaccine design strategies. “This year there was no mistaking the immense promise of cancer immunotherapy,” Tim Appenzeller, Science’s News Editor, said in a statement. “So far, this strategy of harnessing the immune system to attack tumors works only for some cancers and a few patients, so it’s important not to overstate the immediate benefits. But many cancer specialists are

Deborah Dudgeon, MD, FRCPC continued from page 119

The benefits of utilizing standard oncology care with early palliative care after a diagnosis were demonstrated in a study of newly diagnosed patients with advanced lung cancer published in The New England Journal

convinced that they are seeing the birth of an important new paradigm for cancer treatment.”

Steady Progress

A few years earlier, a Japanese biologist discovered that a molecule expressed in dying T cells, which he Early Pioneers called programmed death 1 (PD-1), Science credited many of today’s also put the brake on T cells. The advances in cancer immunotherapy to first clinical trial of an anti–PD-1 anthe early work of French researchers tibody began in 2006 in 39 patients in the late 1980s. Their identification and five different cancers. Two years of a new protein later, five of the receptor on the participants, all This year there was no with refractory surface of T cells, called cytotoxic disease, saw their mistaking the immense T-lymphocyte antumors shrink. promise of cancer tigen 4 (CTLA-4), Then in 2010, led to the discovSteven ­Rosenberg, immunotherapy. ery by cancer imMD, PhD, of the —Tim Appenzeller munologist James Surgery Branch Allison, PhD, in the National Chair of Immunology at The Univer- Cancer Institute’s Center for Cansity of Texas MD Anderson Cancer cer Research, published encouragCenter and Executive Director of its ing results from his study of chimeMoon Shots Program immunothera- ric antigen receptor (CAR) therapy, py platform, that CTLA-4 prevented in which a patient’s T cells are geT cells from launching full-force im- netically engineered to attack tumune attacks. Nearly a decade later, in mor cells. And research led by Carl 1996, Dr. Allison showed that block- June, MD, Director of Translational ing CTLA-4 in mice could unleash T Research at the Abramson Cancer cells against their tumor cells, shrink- Center at the University of Pennsyling them dramatically. vania, of a type of CAR cell called of Medicine.3 The study found that introducing palliative care soon after a diagnosis not only improved quality of life for patients but also actually extended the length of their life. So we now have evidence showing that early integration has other value besides just quality of life. n Disclosure: Dr. Dudgeon reported no

potential conficts of interest.

References 1. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880-887, 2012. 2. Adelson K, Paris J, Smith CB, et al:

CTL019 in patients with leukemia has shown durable remissions in some patients. The result from the success of clinical studies of immunotherapy is encouraging pharmaceutical companies to develop antibodies, such as anti–PD1. And in 2011, the U.S. Food and Drug Administration approved ipilimumab (Yervoy), an anti–CTLA-4 antibody for metastatic melanoma.

New Chapter in Cancer Research There is still a lot of uncertainty regarding how many and which patients will benefit from immunotherapies and for which cancers they will be most effective, according to the editors of Science. Still, the ongoing scientific investigations into identifying biomarkers that might offer answers and researching ways to make these therapies more potent, they said, show that a new chapter in cancer research has begun. n Reference 1. Couzin-Frankel J: Cancer immunotherapy. Science 342:1432-1433, 2013.

Standardized criteria for required palliative care consultation on the solid tumor oncology service. 2013 ASCO’s Quality Care Symposium. Abstract 37. Presented November 1, 2013. 3. Temel J, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small cell lung cancer. N Engl J Med 363:733-742, 2010.

The ASCO Post Like us on Facebook facebook.com/TheASCOPost


In postmenopausal women with advanced HR+, HER2-negative breast cancer,

When your patients need MORE...

There is a treatment regimen that has more than doubled median PFS after failure of a nonsteroidal aromatase inhibitor1

Abbreviations: HR+, hormone receptor-positive; PFS, progression-free survival.


AFINITOR plus exemestane Combination Therapy Gives You More: Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

55%

HR=0.45 [95% CI, 0.38-0.54]

reduction in risk of progression or death1

Log-rank P value: <0.0001

PFS curves began to diverge

at 6 weeks

(the first tumor assessment) 1,2

PFS Probability (%)

80

Median PFS

7.8 months

60

40

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

20

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

Exemestane plus placebo (n/N=200/239)

Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2.

62% reduction in risk of progression or death1

Independent central assessment confirmed benefit1 •

Median PFS was 11.0 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

Overall survival (OS) results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted (HR=0.77 [95% CI, 0.57-1.04]).1 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information) Noninfectious Pneumonitis: •

Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed If symptoms are moderate, patients should be managed with dose interruption until symptoms improve The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve

• •

For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR The development of pneumonitis has been reported even at a reduced dose


MORE THAN DOUBLES MEDIAN PFS

over exemestane alone1

Proven PFS benefit across all preplanned patient subgroups1,2 Median PFS Across Preplanned Patient Subgroups2 AFINITOR plus exemestane

Placebo plus exemestane

Median PFS (months) 8.3 6.8

2.9 4.0

8.1 6.8

3.9 2.8

6.8 9.9

2.8 4.2

8.3 6.9

4.1 2.8

12.9 6.9

5.3 2.8

8.2 7.0

3.2 3.5

8.1 6.9 8.2

4.4 3.0 3.0

8.1 7.0

2.8 4.1

8.1 6.9

3.3 2.8

11.5 6.7 6.9

4.4 3.5 2.6

Subgroups (n) All (724)

Age <65 (449) ≥65 (275) Sensitivity to prior hormonal therapy YES (610) NO (114) Presence of visceral metastasis YES (406) NO (318) Baseline ECOG PS 0 (435) 1 or 2 (274) Bone-only lesions at baseline YES (151) NO (573) Prior chemotherapy YES (493) NO (231) No. of prior therapies used in the adjuvant setting or to treat advanced disease 1 (118) 2 (217) ≥3 (389) Prior hormonal therapya YES (398) NO (326) Progesterone receptor status Positive (523) Negative (184) No. of organs involved 1 (219) 2 (232) ≥3 (271)

Excluding anastrozole and letrozole.

a

Favors placebo plus exemestane

Favors AFINITOR plus exemestane

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Hazard Ratio

Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status.

Prescribe AFINITOR plus exemestane upon first progression on letrozole or anastrozole therapy1 Important Safety Information) Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR •

Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment •

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.


Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: •

Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed If symptoms are moderate, patients should be managed with dose interruption until symptoms improve The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR The development of pneumonitis has been reported even at a reduced dose

In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed •

Renal Failure: •

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR

Geriatric Patients:

Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended •

Vaccinations:

• The use of live vaccines and close contact with In the randomized advanced hormone those who have received live vaccines should receptor-positive, HER2-negative breast cancer be avoided during treatment with AFINITOR study, the incidence of deaths due to any cause within 28 days of the last AFINITOR Embryo-Fetal Toxicity: • dose was 6% in patients ≥65 years of age • Fetal harm can occur if AFINITOR is compared to 2% in patients <65 years of age administered to a pregnant woman. Women of • Adverse reactions leading to permanent childbearing potential should be advised to use discontinuation occurred in 33% of patients a highly effective method of contraception • ≥65 years of age compared with 17% in while using AFINITOR and for up to 8 weeks patients <65 years of age after ending treatment • • Careful monitoring and appropriate Adverse Reactions: dose adjustments for adverse reactions • The most common adverse reactions (incidence are recommended ≥30%) were stomatitis (67%), infections Laboratory Tests and Monitoring: (50%), rash (39%), fatigue (36%), diarrhea • (33%), and decreased appetite (30%) Elevations of serum creatinine, proteinuria, • glucose, lipids, and triglycerides, and • The most common grade 3/4 adverse reactions reductions of hemoglobin, lymphocytes, (incidence ≥2%) were stomatitis (8%), infections Infections: neutrophils, and platelets, have been reported (5%), hyperglycemia (5%), fatigue (4%), dyspnea • AFINITOR has immunosuppressive properties • Renal function (including measurement of blood (4%), pneumonitis (4%), and diarrhea (2%) and may predispose patients to bacterial, urea nitrogen, urinary protein, or serum Laboratory Abnormalities: fungal, viral, or protozoal infections (including creatinine), blood glucose, lipids, and • The most common laboratory abnormalities those with opportunistic pathogens). Localized hematologic parameters should be evaluated (incidence ≥50%) were hypercholesterolemia and systemic infections, including pneumonia, prior to treatment and periodically thereafter (70%), hyperglycemia (69%), increased aspartate mycobacterial infections, other bacterial • When possible, optimal glucose and lipid transaminase (AST) concentrations (69%), anemia infections, invasive fungal infections such as control should be achieved before starting a (68%), leukopenia (58%), thrombocytopenia aspergillosis or candidiasis, and viral patient on AFINITOR (54%), lymphopenia (54%), increased alanine infections, including reactivation of hepatitis B transaminase (ALT) concentrations (51%), and Drug-Drug Interactions: virus, have occurred hypertriglyceridemia (50%) • Avoid coadministration with strong CYP3A4 • Some of these infections have been severe (eg, • The most common grade 3/4 laboratory inhibitors (eg, ketoconazole, itraconazole, leading to respiratory or hepatic failure) or fatal abnormalities (incidence ≥3%) were clarithromycin, atazanavir, nefazodone, • Physicians and patients should be aware of the lymphopenia (12%), hyperglycemia (9%), saquinavir, telithromycin, ritonavir, indinavir, increased risk of infection with AFINITOR anemia (7%), decreased potassium (4%), nelfinavir, voriconazole) • Treatment of preexisting invasive fungal increased AST (4%), increased ALT (4%), • Use caution and reduce the AFINITOR dose to infections should be completed prior to and thrombocytopenia (3%) 2.5 mg daily if coadministration with a starting treatment moderate CYP3A4 and/or PgP inhibitor is • Be vigilant for signs and symptoms of infection Please see Brief Summary of Prescribing required (eg, amprenavir, fosamprenavir, and institute appropriate treatment promptly; Information on adjacent pages. aprepitant, erythromycin, fluconazole, interruption or discontinuation of AFINITOR verapamil, diltiazem) To learn more, please visit should be considered • Avoid coadministration with strong CYP3A4 www.AFINITOR.com. • Discontinue AFINITOR if invasive systemic inducers (eg, phenytoin, carbamazepine, fungal infection is diagnosed and institute rifampin, rifabutin, rifapentine, phenobarbital); appropriate antifungal treatment References: 1. AFINITOR [prescribing information]. East Hanover, however, if coadministration is required, NJ: Novartis Pharmaceuticals Corp; 2012. 2. Data on file. AFINITOR Oral Ulceration: CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals increase the AFINITOR dose from 10 mg daily Corp; March 2012. • Mouth ulcers, stomatitis, and oral mucositis have up to 20 mg daily, using 5-mg increments occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients •

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

© 2013 Novartis

8/13

AFB-1066531


AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

T:14”

B:14.25”

S:13”

Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.


The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 Pneumonitisd 19 4 0.2 0.4 0 0 Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median duration of treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.


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A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reducti