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OCTOBER 15, 2013

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

Breast Cancer Symposium

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Trying to Improve Value in Cancer Care: An Experiment

Breast Cancer Radiotherapy and Cardiotoxicity: What Is the True Risk? By Caroline Helwick

By Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

vidence has long been accumulating that radiotherapy involving the heart can result in premature ischemic heart disease, but interest peaked last spring when a case control study published in The New England Journal of Medicine1 found an increased risk for cardiac-related deaths in breast cancer patients who received radiotherapy. Radiation oncologists speaking at the 2013 Breast Cancer Symposium in San Francisco, including Jay R. Harris, MD, Professor of Radiation Oncology at Harvard Medical School and Chief of Radiation Oncology at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, examined the results, put them into contemporary perspective, and provided a more reassuring view of radiotherapy for breast cancer in today’s practice.

Study Limitations The NEJM study was a population-based case control study involving 2,168 Scandinavian women treated between 1958 and 2001. It found that rates of major coronary events increased linearly with the mean dose Jay R. Harris, MD to the heart by 7.4% per gray (Gy) (P < .001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per Gy was similar in women with and without cardiac risk factors at the time of radiotherapy. The overall average of the mean doses to continued on page 10

Breast Cancer Symposium

Breast Cancer Care in the Era of Accountable Care Organizations

ne of the more significant problems in modern oncology practice is to provide increased value at a time when costs are spiraling upward, and new parameters of “success” are being introduced into the equation—most visibly, inside the Beltway in Washington, DC. Thus, oncologists will need to address the challenges of responding to the community’s evolving requirements.

Defining Value At its simplest, the value proposition in health care has been defined by Michael Porter and Elizabeth Teisberg1 with the following equation: Value = Outcomes/Cost This equation makes sense and is routinely used in planning the strategy of cancer care for our health-care system. This value proposition allows us to consider what is contributing to continued on page 134

Dr. Raghavan is President, Levine Cancer Institute, Charlotte, North Carolina.

By Caroline Helwick

MORE IN THIS ISSUE

repare for big changes ahead, Lawrence N. Shulman, MD, Senior Vice President for Medical Affairs at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School in Boston, told oncologists at the 2013 Breast Cancer Symposium.1 One change is the emergence of accountable care organizations (ACOs). Since accountable care orga-

nizations are already abundant in the Boston area, Dr. Shulman has gotten a close-up look and he had some words of advice for clinicians: “You have to become attractive to accountable care organizations if you want to stay in business,” he said.

The Accountable Care Organization Model

Dr. Shulman has concerns about how oncology will fit into this paradigm, but the outcomes could be positive he indicated. Oncology practices will be most “Partnerships are fruitful attractive to accountable care endeavors, but be sure the patient does not get stuck organizations if they can measure in the middle. Often, our and show competitive cost and good choices are not patientcentered. We are all trying, quality. but sometimes the system —Lawrence N. Shulman, MD makes it very difficult. We

Oncology Meetings Coverage 2013 Breast Cancer Symposium �� 1, 3, 8, 12, 16, 18 Best of ASCO �� 24, 25, 33, 38–41 International Lung Cancer Congress �� 45–47, 50 ASTRO Annual Meeting �� 104–107 Direct from ASCO �� 72–80 Jose Baselga, MD, on Future of Medical Oncology �� 110 Dermatologic Toxicities ��140 In Memoriam: Jane C. Weeks, MD �� 149 Letters to the Editor �� 148, 150

continued on page 20

October Is Breast Cancer Awareness Month

A Harborside Press® Publication

The ASCO Post | OCTOBER 15, 2013

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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

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

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

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com

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

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

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

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

Lynn D. Wilson, MD Yale University School of Medicine

Michael Buckley, Art Director Michael@harborsidepress.com

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Terri Caivano, Kristina O’Toole, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

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

Douglas W. Blayney, MD Stanford University Medical Center

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

Philip D. Bonomi, MD Rush University Medical Center

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

Richard Boxer, MD University of Wisconsin School of Medicine and Public Health

Michael P. Link, MD Stanford University Medical Center

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

International Editors

Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com

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

Wendy McGullam, Director of Production Wendy@harborsidepress.com

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

Frank Buchner, Chief Technology Officer Frank@harborsidepress.com

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD National Comprehensive Cancer Network

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

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

William T. McGivney, PhD Philadelphia, Pennsylvania

Jay S. Cooper, MD Maimonides Medical Center

James L. Mulshine, MD Rush University Medical Center

Jacek Jassem, MD Medical University of Gdansk, Poland

John Cox, DO Texas Oncology

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

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 wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@ harborsidepress.com.

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

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.

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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 | OCTOBER 15, 2013

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Breast Cancer Symposium What Is on the Horizon in the Management of Breast Cancer? George Sledge, MD, and Monica Morrow, MD, Offer Their Perspectives By Caroline Helwick

n Keynote Lectures during the 2013 ASCO Breast Cancer Symposium, experts George Sledge, MD, and Monica Morrow, MD, offered their opinions and outlook on how the medical and surgical management of breast cancer may continue to evolve over the next 5 to 10 years.1 Dr. Sledge is Chief of Oncology at Stanford School of Medicine, Palo Alto, California. Dr. Morrow is Chief of the Breast Surgical Service at Memorial Sloan-Kettering Cancer Center, New York, and the Anne Burnett Windfohr Chair of Clinical Oncology.

Five emerging trends will shape breast cancer care within the next decade. —George Sledge, MD

Although many people envision the ideal future of breast cancer management as one that includes no surgery, this remains a fantasy for the foreseeable future.

Medical Management: Five Emerging Trends George Sledge, MD, first acknowledged that “making predictions is somewhat dangerous,” but said he feels confident that five emerging trends will shape breast cancer care within the next decade. These predictions are based on biology, technology, economics, and demography, all of which “intersect in the deep dark woods of the modern health-care system,” Dr. Sledge said. Prediction #1: “The era of HER2 is almost over.” “We will always have patients relapsing with HER2-positive disease, and this will require novel therapies. But from a public health standpoint, I believe the era of HER2 is almost over,” said Dr. Sledge. This prediction is based on the fact that with adjuvant T-DM1 plus pertuzumab (Perjeta), 3-year disease-free survival may exceed 92% (according to the schema for the current trials). Sur-

—Monica Morrow, MD

passing this 92% disease-free survival benchmark makes HER2-positive breast cancer akin to testicular cancer, no longer thought of as a “public health issue.” With long-term disease-free survival accomplished, the research questions then become about toxicity and cost-effectiveness of treatment, and phase III trials will be too expensive to explore these remaining “fill in the blank” questions, Dr. Sledge said. Prediction #2: “BRCA testing will become ubiquitous.” This will occur as a result of less expensive assays. The Supreme Court’s invalidation of the Myriad patent2 opened the door to market forces that will reduce the cost of testing to under $100, said Dr.

Looking Ahead: How Will Breast Cancer Management Change? ■■ The “era of HER2” is almost over, as disease-free survival rates climb. ■■ BRCA testing will become ubiquitous. ■■ Tumor proliferation and survival pathways will continue to be targeted. ■■ Targeting of dormant micrometastases will become important for reducing late recurrences.

■■ Cancer genomics will become affordable, but the implications for treatment will be concerning.

■■ Locoregional therapy will become more influenced by tumor biology, with favorable biology amenable to more conservative approaches.

■■ The need for surgery and radiotherapy will be redefined as more effective systemic treatments emerge.

■■ No longer will locoregional therapy be a “one size fit all” approach.

Sledge. “When price is no barrier, we will likely see a surge in BRCA testing (possibly in all breast cancer patients), and the downstream effects of this will be more imaging, more prophylactic surgery, and a modest reduction in systemic treatment because of interventions that occur before the medical oncologist is needed,” he noted. “Mendeliome testing [genome-wide] will be next, and this will affect everyone’s practice.” Prediction #3: “We will continue to target proliferation and survival pathways.” Recurrences are thought to be the result of proliferating micrometastases (especially in early recurrences) and activation of dormant cells (especially in late recurrences). “We haven’t gotten rid of this problem. It’s safe to say that targeting proliferation will continue to be important,” said Dr. Sledge. Novel pathway inhibitors, such as the experimental compound PD0332991 targeting cyclin-dependent kinases, affect cell-cycle progression and hold great promise. Prediction #4: “Cancer genomics will become ubiquitous, but we won’t like what we find.” The cost of genomic testing will fall enough to make assays readily usable in the clinic, but the implications of this for patient management are concerning. Recent

studies in breast cancer samples found driver mutations in at least 40 different cancer genes, with as many as six driver mutations in some tumors. This is daunting for treatment and for drug development. “In the history of cancer, we have never targeted six drivers intentionally,” he noted. Beyond the “top fliers,” like p53 and PI3 kinase, most are rare mutations. “To think of treating these tumors in a way that has been successful, like targeting kinases, means we will have to be very clever,” said Dr. Sledge. Just as discouraging is the prospect of designing trials of relevant treatments for what becomes an orphan disease. In addition, rapid emergence of compensatory mechanisms of resistance to virtually all drugs, along with the expense and toxicity of combining several biologics, will create further hurdles. Prediction #5: “We will need to do something different.” Relapses that occur beyond 5 years in estrogen receptor-positive patients are likely the result of dormant micrometastases. “This is a challenge for which we do not yet have good solutions,” said Dr. Sledge. The targeting of proliferating cells may not affect dormant cells; as agents are better able to suppress proliferating cells, dormant cells will become the major cause of breast cancer death and the remaining challenge in breast cancer, he predicted. Dormancy could be addressed by increasing the duration of hormonal therapy, an approach recently validated by large endocrine therapy trials; by improving the detection and prediction of dangerous dormancy (for instance, by advancements in imaging, plasma DNA and RNA assays); and by developing novel therapies specifically against dormant cells, possibly through immune modulation. “Novel ways of targeting stem cells might not work in the overtly metastatic setting, but could possibly be game-changing in the adjuvant setting,” he suggested.

Key Challenges in the Surgical Management of Breast Cancer “The ‘rules’ for surgery and radiotherapy in use for 30 years have served us well and have improved patient outcomes,” continued on page 6

The ASCO Post | OCTOBER 15, 2013

PAGE 6

Breast Cancer Symposium Breast Cancer Management continued from page 3

Dr. Morrow said in her presentation, “but very little of what we now believe about breast cancer biology was in place 30 years ago.” This new knowledge may alter locoregional management. “In the past, we believed that bigger is better and it cured more cancers. We

got slightly away from that after six randomized controlled trials showed that breast-conserving therapy was equivalent to mastectomy, but it has recently become clear that we haven’t totally gotten rid of the ‘bigger is better’ idea,” said Dr. Morrow. For example, the reigning thought for triple-negative breast cancer is

that “bigger surgery will perturb the bad biology,” in spite of several studies showing that the increased rate of local recurrence in triple-negative cancers is not improved through more extensive surgery, i.e., wider margins or mastectomy, Dr. Morrow noted. “Although many people envision the ideal future of breast cancer man-

agement as one that includes no surgery, this remains a fantasy for the foreseeable future,” she said. Instead, the immediate quest is to address key challenges: how to appropriately individualize surgery in response to advances in our understanding of tumor biology, and how to redefine surgery’s role in reducing disease burden in an

ASCOPost.com | OCTOBER 15, 2013

PAGE 7

Breast Cancer Symposium era of increasingly sophisticated imaging technology that allows visualization of diffuse microscopic disease in patients previously thought to have small, localized primary tumors.

Targeted Therapies Can Improve Local Outcomes It is increasingly apparent that tar-

geted therapy improves local therapy outcomes, as illustrated in patients with HER2-overexpressing tumors who receive adjuvant trastuzumab (Herceptin). But efforts to identify genetic signatures that define patients at higher risk of local recurrence after breast-conserving therapy than after mastectomy have been

unsuccessful, said Dr. Morrow. Encouragingly, emerging evidence suggests that within molecular subtypes, genetic profiling may reveal some of this risk and potentially allow for tailoring of local therapy. The implication of recent studies3,4 is that postmastectomy irradiation might be avoided in patients with

one to three involved nodes (or even four or more) and a low 21-gene recurrence score, she said.

Role of Surgery in Reducing Disease Burden The ACOSOG Z0011 trial5 was “a watershed in our thinking” regarding the need for surgical removal of all clinically evident disease in the multidisciplinary era, showing that T1/2 clinically node-negative patients with sentinel node metastases could safely avoid axillary completion dissection. “These results illustrate the ability to change standard surgical paradigms based on the use of multimodal therapy,” said Dr. Morrow. ACOSOG Z0011 and similar studies are opening the door to the possibility that less surgery in the breast—for example, removal of only the gross tumor without “obsessive concern for margins”—could result in high rates of local control in selected subgroups, Dr. Morrow suggested. On the other hand, the increasing use of magnetic resonance imaging preoperatively is leading to the identification of cancer not otherwise found, and this is increasing the mastectomy rate (without reducing reexcision rates), according to a recent meta-analysis she co-authored6.

Looking Forward: One Size Does Not Fit All Looking to the future, Dr. Morrow said, there is a need to recognize that small differences in local recurrence (< 5%) are unlikely to impact survival, and that adding more treatment adds toxicity, making it necessary to ask what old treatments can be reduced as new ones are added. She predicted an increasing appreciation that both local and distant outcomes vary according to breast cancer subtypes. Studies will need to evaluate the benefit of less extensive surgery and radiotherapy, as well as effective new systemic therapies, in the face of favorable biology, she said. Unfortunately, “The low rate of locoregional recurrences, coupled with the reluctance of physicians to enter patients into trials of less therapy, will make progress difficult,” she added. Dr. Morrow further suggested that patient-reported outcome measures add important information to the overall framing of preferencecontinued on page 8

The ASCO Post | OCTOBER 15, 2013

PAGE 8

Breast Cancer Symposium Dr. Larry Norton, Honored at 2013 Breast Cancer Symposium, Calls For A Return to the ‘Exploration of Concepts’ By Caroline Helwick

arry Norton, MD, of Memorial Sloan-Kettering Cancer Center, is the recipient of the 2013 Gianni Bonadonna Breast Cancer Award, which he received at the 2013 Breast Cancer Symposium. The Symposium

ogy at Memorial Sloan-Kettering Cancer Center, New York. Among Dr. Norton’s many accomplishments is the refinement of a mathematical approach to studying cancer. During the 1970s, Dr.

Coevolution of Clinical and Basic Science

is sponsored by ASCO, the American Society of Breast Surgeons, the American Society of Radiation Oncology, the National Consortium of Breast Centers, and the Society of Surgical Oncology. Dr. Norton is Deputy Physicianin-Chief for Breast Cancer Programs, Medical Director of the Evelyn H. Lauder Breast Center, and the Norna S. Sarofim Chair in Clinical Oncol-

Norton collaborated with Richard Simon, ScD, at the National Cancer Institute, to formulate the NortonSimon Hypothesis. The hypothesis contends that the rate at which a tumor shrinks in response to therapy is proportional to its growth rate. This led to the concept of dose-dense drug delivery, which maximizes the killing of cancer cells while minimizing toxicity.

In accepting the award, Dr. Norton commented on what he called “the coevolution of clinical and basic science in oncology.” “Having been involved in cancer research since the 1960s, I have witnessed immense changes in all aspects of the mission. Some are obvious, mostly related to the vast expansion of our knowledge of biology and chemistry and the revolutionary advances in our ability—via electronic means—of storing and sharing information,” he said. “But others are more obscure although equally important,” he continued. “One is our willingness to openly discuss societal needs, such as reducing the costs of care, on an at-least-equal footing, with the needs of individuals, such as the personal benefits of earlier diagnosis of disease,” he continued. “Another is the evolution of a complex system of producing, testing, and distributing new cancer treatments (and linked diagnostics) that might now, as times have changed, become suboptimal for further progress. This may be illustrated by a contrast between the invention of postsurgical adjuvant dose-dense doxorubicin plus cyclophosphamide followed by paclitaxel plus trastuzumab and contemporary opportunities in the same space,” he said.

Breast Cancer Management

References 1. Sledge G, Morrow M: How will we be treating breast cancer in 5 to 10 years? 2013 Breast Cancer Symposium September 9, 2013. 2. Supreme Court Ruling, June 13, 2013. http://www.supremecourt.gov/ opinions/12pdf/12-398_1b7d.pdf. Accessed September 23, 2013. 3. Mamounas EP, Tang G, Fisher B et al: Association between the 21-gene recurrence score assay and risk of lo-

coregional recurrence in node-negative, estrogen receptor-positive breast cancer: Results from NSABP B-14 and NSABG B-20. J Clin Oncol 28:1677-1683, 2010. 4. Mamounas EP, Tang G, Paik S et al. Prognostic impact of the 21-gene recurrence score on disease-free and overall survival of node-positive, ER-positive patients with breast cancer treated with adjuvant chemotherapy: Results from NSABP B-28. 2012 AACR-CTRC-San Antonio Breast Cancer Symposium. Ab-

Having been involved in cancer research since the 1960s, I have witnessed immense changes in all aspects of the mission. Some are obvious, … but others are more obscure although equally important, [such as] our willingness to openly discuss societal needs, … on an atleast-equal footing with the needs of individuals…. —Larry Norton, MD

continued from page 7

sensitive decisions and should be incorporated into future trials. “Looking ahead, the one thing that is clear is that the ‘one size fits all’ approach to local therapy that has served us well for the past 30 years is not the path to future success,” Dr. Morrow concluded. n Disclosure: Drs. Sledge and Morrow reported no potential conflicts of interest.

A New, Older Mindset New clinical trial designs, new approaches to the collection and analysis of real-world clinical experiences, new business models for early therapeutic research and development, and new sources of funding for these endeavors may be “imperative” innovations, he said, but an even more sweeping change may be vital to the future of optimal cancer care: “a return to an older mindset—the exploration of concepts rather than an exclusive focus on the testing of agents.” Dr. Norton said the accomplishment of this new mindset, “especially in a time of limited governmental resources, an exigent commercial environment, and the emergence of evidence-based decision tools as rules rather than guidelines,” will be a major challenge.

Fellowship Award In conjunction with Dr. Norton’s award, the 2013 Gianni Bonadonna Breast Cancer Research Fellowship was awarded to Aki Morikawa, MD, PhD, of Memorial Sloan-Kettering Cancer Center, in recognition of her research on brain metastases in patients with breast cancer. She will be conducting her Fellowship under the tutelage of Dr. Norton and Andrew D. Seidman, MD, also of Memorial Sloan-Kettering. n stract 1. Presented September 13, 2011. 5. Giuliano AE, Hunt KK, Ballman KV et al. Axillary dissection vs. no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305:569575, 2011. 6. Houssami N, Turner R, Morrow M. Preoperative magnetic resonance imaging in breast cancer: meta-analysis of surgical outcomes. Ann Surg 257(2):249255, 2013.

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Breast Cancer Symposium Radiotherapy and Cardiotoxicity continued from page 1

the whole heart was 4.9 Gy. “It is important to note the major limitations of the study, mainly, it is a case control study and this does not provide the highest level of evidence. Also, there were limitations in design,” said Dr. Harris.

The investigators developed virtual simulations of radiotherapy dose based on computed tomography scanning of patients with “typical anatomy,” which they used to construct an idealized radiation field; with this they estimated the doses to the heart and the left anterior descending artery. David E. Wazer, MD, Radiation Oncologist-in-Chief and Professor and

Chairman of Radiology at Tufts Medical Center, Boston, agreed with Dr. Harris’ concerns. “Radiation oncologists looked at this study critically, because the patients were treated in a different era. They were subject to two-dimensional treatment planning, which we in the United States have not done for at least 15 years,” he said. “Even more unsettling was that the heart dose was

estimated based on extrapolating from a ‘typical patient,’ whatever that is. And what was surprising to a lot of us was that the mean heart dose was so much higher than in our experience.”

Absolute Increase in Risk Is Minor Dr. Harris emphasized that despite the proportional relationship between

Contemporary Studies Dispute Findings of Radiation-Induced Cardiotoxicity

t the 2013 Breast Cancer Symposium, studies suggested that with current radiotherapy techniques the mean radiation doses to the heart are much lower—and thus radiotherapy is presumably much safer—than findings suggested by an article published in The New England Journal of Medicine last spring.1

field treatment planning is much lower than the published reports of patients treated prior to 2001—1.06 Gy vs 4.9 Gy,” she noted. David E. Wazer, MD, Radiation Oncologist-in-Chief at Tufts Medical Center, Boston, discussed the paper at the meeting and commented, “These

Mean Heart Doses Lower Than Reported Geraldine M. Jacobson, MD, MPH, and colleagues from West Virginia University, Morgantown, reviewed the treatment plans of 78 patients (86 breasts) treated in 2012/2013, which were computed tomography–based, field-in-field forward planning with heart blocking .2 Patients received hypofractionation (16 x 2.66 Gy, no boost) or standard fractionation (46.8–50.4 Gy +/– 10 Gy boost) radiotherapy. They found the average mean heart doses were 1.45 Gy for the left breast

Geraldine M. Jacobson, MD, MPH

and 0.70 for the right. Averages were 1.16 Gy and 0.48 Gy, respectively, under hypofractionation and 1.60 Gy and 0.84 Gy, respectively, under standard fractionation. Mean heart doses for the left vs right breasts were significantly different (P = .002), and breast doses and mean heart doses were significantly correlated (P = .026), Dr. Jacobson reported. “Mean heart dose in patients treated at our institution with heart avoidance and three-dimensional [3D] field-in-

David E. Wazer, MD

findings undermine the credibility of the NEJM paper as to its relevance in current practice. The investigators showed that using contemporary planning, left and right breast mean heart doses are all less than 25% of the values reported in that paper.” A second study presented at the meeting examined heart exposure in 100 patients treated with 3D conformal radiotherapy for left-sided breast cancer and also found mean doses to be lower (2.89 Gy) than those reported by Darby et al (4.9 Gy), and that the median volume of heart exposed to doses higher than 5 Gy is also low (17%).3 “This is not to say that radiation oncologists are not concerned about the heart, or that there is not a real potential for injury,” he said.

Studies Shows No Increased Risk of Heart Disease Also reported at the Breast Cancer Symposium was a large populationbased study from the Netherlands, which showed that women who received radiotherapy for ductal carcinoma in situ (DCIS) had no increased risk of cardiovascular disease compared

to the general population or to patients with DCIS treated with surgery alone.4 Naomi B. Boekel, MSc, of Netherlands Cancer Institute, Amsterdam, described 10,468 women treated between 1989 and 2004, of whom 28% received radiotherapy. After a median follow-up of 10 years, the diagnosis of cardiovascular disease was similar between patients receiving surgery alone (9%) or surgery plus radiotherapy (8%), and between patients who received left- sided radiotherapy (7%) vs right-sided (8%). “This is a powerful paper with a large cohort and remarkably detailed data,” Dr. Wazer noted. “Its one weakness is that follow-up was just 10 years, but it’s a fantastically valuable dataset that we hope will be reanalyzed after 5 more years.” A recent paper from Europe used strain rate imaging (a sensitive echocardiographic technique that evaluates wall motion) and revealed that if the left ventricle is included in the incident beam path, wall motion abnormalities can be detected shortly after radiotherapy is delivered, and they persist for at least 14 months.5 Results from a study led by Lori J. Pierce, MD, of the University of Michigan, were “more reassuring,” he continued. The study compared singlephoton emission CT myocardial perfusion scans pre- and post-treatment and quantified doses to the heart and coronary arteries.6 Radiotherapy was not associated with any clinically significant defects. “They used sophisticated 3D treatment planning and kept the heart out of the incident, ie, primary beam. The average mean dose to the heart was relatively high (2.82 Gy) but it was being delivered in very low doses on a daily basis. No correlation was found for low doses delivered to cardiac structures and perfusion, the summed stress defects scores or ejection fraction. They saw no clinically

significant defects after radiotherapy, and this is reassuring. If we are meticu-

Lori J. Pierce, MD

lous with our treatment planning, we can have a positive effect with respect to cardiac injury,” Dr. Wazer concluded. n

Disclosure: Drs. Jacobson, Wazer, and Boekel reported no potential conflicts of interest.

References 1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013. 2. Jacobson GM, Wen S, Zhang J, et al: Mean radiation dose to the heart in patients with breast cancer. 2013 Breast Cancer Symposium. Abstract 56. Presented September 7, 2013. 3. Lonardi F, Gioga G, Coeli M, et al: Heart exposure in 100 consecutive, unselected patients treated with adjuvant 3D conformal radiotherapy for left-sided breast cancer. 2013 Breast Cancer Symposium. Abstract 103. Presented September 8, 2013. 4. Boekel NB, Schaapveld M, Gietema JA, et al: Cardiovascular morbidity and mortality in patients treated for ductal carcinoma in situ of the breast. 2013 Breast Cancer Symposium. Abstract 58. Presented September 7, 2013. 5. Erven K, Florian A, Slagmolen P, et al: Subclinical cardiotoxicity detected by strain rate imaging up to 14 months after breast radiation therapy. Int J Radiat Oncol Biol Phys 85:1172-1178, 2013. 6. Chung E, Corbett JR, Moran JM, et al: Is there a dose-response relationship for heart disease with low-dose radiation therapy? Int J Radiat Oncol Biol Phys 85:959964, 2013.

ASCOPost.com | OCTOBER 15, 2013

PAGE 11

Breast Cancer Symposium radiotherapy dose and heart disease, the absolute increase was small. For a 50-year-old women without cardiac risk factors, the lifetime increased risk was 0.5% after 0.5 Gy, 0.2% after 1 Gy, and just 0.5% after 3 Gy delivered to the heart. Today, for most node-negative women having breast-conserving therapy, the mean heart dose is only about 1 Gy, although though higher doses (still only about 2 Gy) are more common for women with left-sided postmastectomy radiotherapy, according to Dr. Harris. Dr. Harris further emphasized that current mean heart doses result in a mor-

Radiotherapy to the Heart in Breast Cancer Patients

tion oncologists. Radiation oncologists should operate on the principle that there is no totally safe radiation dose to the heart, and we should keep the heart dose as low as possible.” A number of maneuvers, such as using cardiac blocks, prone techniques and deep inspiration breath holds, make radiation delivery much safer

now. “In virtually all our patients we have eliminated direct cardiac radiation,” he pointed out. n

Disclosure: Drs. Harris and Wazer reported no potential conflicts of interest.

References 1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in

women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013. 2. Early Breast Cancer Trialists’ Collaborative Group: Effect of radiotherapy after breast-conserving surgery on 10-year 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.

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tality risk that is minor, compared to the survival benefit from radiation. In the latest Oxford Overview, radiotherapy after mastectomy and axillary dissection provided an 11.4% absolute gain in 10-year recurrence-free survival and a 9.4% gain in 15-year breast cancer mortality in patients with one to three positive nodes.2 “The survival benefit seen for radiotherapy in these trials includes the deleterious effects on the heart seen with doses as high as 10 Gy,” he noted. “This means that using current techniques that spare the heart, radiotherapy will provide even greater benefit.” Dr. Harris concluded, “While the NEJM article has major limitations, it is a very important publication for radia-

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The ASCO Post | OCTOBER 15, 2013

PAGE 12

Breast Cancer Symposium Ductal Carcinoma In Situ

Single-Institution Study Evaluates Routine Use of Perioperative MRI in Patients With Ductal Carcinoma In Situ By Alice Goodman

erioperative MRI for patients with ductal carcinoma in situ (DCIS) was not associated with a reduction in locoregional recurrence or contralateral breast cancer development in

Melissa L. Pilewskie, MD

a large single-center study reported at the 2013 ASCO Breast Cancer Symposium. The study also was presented at a premeeting presscast. According to the investigators, there are no guidelines for appropriate use of MRI around the time of surgery, and the results of this study suggest that it should not routinely be ordered in the perioperative setting because it was not associated with improved outcomes. “There was no association between

the use of perioperative breast MRI and decreased rates of locoregional recurrence and contralateral breast cancer for both the entire cohort and women who did not receive radiotherapy. This adds to the evidence we already have, which indicates that MRI is not necessary for every patient with DCIS, “ said first author Melissa L. Pilewskie, MD, of Memorial Sloan-Kettering Cancer Center. Dr. Pilewskie said that MRI screening comes with a high cost and a fairly high false positive rate leading to additional tests and workups. She added that there are situations where perioperative MRI may be useful, such as in patients with clinical symptoms or physical exam findings not explained by mammogram.

Study Details The retrospective study was based on a prospectively maintained database of 2,321 women with DCIS who underwent surgery between 1997 and 2010 at Memorial Sloan-Kettering Cancer Center. Of that group of women, 596 had an MRI before or imme-

EXPERT POINT OF VIEW

“T

his is an important large retrospective single-institution study …[conducted in the context of a] tremendous increase in use of MRI for invasive and noninvasive breast cancer,” said Steven J. O’Day, MD, who moderated a presscast held just prior to the 2013 Breast Cancer Symposium. “The study grounds us and shows us that we should be sure we are actually making a difference with the use of new technology. The authors are not saying that MRI can’t be used perioperatively Steven J. O’Day, MD or postoperatively, but they question its routine use in DCIS, because it is not an independent predictor of improving locoregional recurrence (LRR) or contralateral breast cancer (CBC) outcomes,” he added. Dr. O’Day is Director of Clinical Research at the Beverly Hills Cancer Center and Adjunct Member of the John Wayne Cancer Institute in Los Angeles. Dr. O’Day called for additional prospective studies to establish the optimal role of MRI in ductal carcinoma in situ and invasive breast cancer. n Disclosure: Dr. O’Day reported no potential conflicts of interest.

See additional expert comments on page 14

diately following surgery, while 1,725 women did not. At a median follow-up of 59 months, no significant difference in the 5-year locoregional recurrence rates was observed between those who had an MRI vs those who did not

(8.5% vs 7.2%, respectively). Women who had an MRI were younger, more likely to be premenopausal, have a family history of breast cancer, have a clinical presentation, continued on page 15

Radiation Therapy Is Safe in the Management of Ductal Carcinoma In Situ: No Increase in Risk of Cardiovascular Disease By Alice Goodman

adiation therapy as part of the management of ductal carcinoma in situ (DCIS) did not increase the risk of cardiovascular disease 10 years after treatment, according to a large retrospective study presented at a press conference held just prior to the 2013 Breast Cancer Symposium.1 Longer follow-up is required to establish with certainty the lack of increased cardiotoxicity risk, but the study provides a degree of reassur-

ance to physicians and patients who have opted for radiation therapy in addition to surgery in the treatment DCIS.

Late Effects of Radiation The study comes at a time when some experts question the classification of DCIS as a cancerous lesion. Recently, a working panel convened by the National Cancer Institute called for the removal of the word

Radiation in Ductal Carcinoma In Situ ■■ The first large population-based study to examine the cardiotoxicity of radiation in patients with DCIS found no associated increased risk of developing cardiovascular disease or death 10 years after treatment.

■■ Longer follow-up is needed to establish the cardiac safety of radiation in this setting.

“cancer” with regard to nonlethal cancers that include DCIS.2 However, in about 5% of patients, DCIS can herald the eventual development of invasive breast cancer. Since, currently, it is not possible to determine which patients with DCIS will progress to invasive disease, DCIS is typically treated with surgery plus or minus radiation therapy to control local recurrence. The present study sought to determine whether radiation as part of DCIS management increases the risk of cardiovascular disease in light of concerns about the late effects of radiation. This is the first large populationbased study to evaluate long-term effects of radiotherapy for DCIS on both the incidence of cardiovascular disease and associated deaths. The authors compared the 10-year risk of

developing cardiovascular disease in patients with DCIS treated with radiation and surgery vs those treated with surgery alone vs the general population. “The late effects of radiation are of great importance. Over time, radiation techniques have been adjusted to reduce exposure to the heart, and currently, radiation exposure for DCIS is relatively low,” said lead author of the study Naomi B. Boekel, MSc, a PhD student at the Netherlands Cancer Institute in Amsterdam, Netherlands. “We found no increased risk of [cardiovascular disease] morbidity and mortality after radiation compared to surgery alone in patients with DCIS. However, longer follow-up of about 5 to 10 years is needed.” continued on page 15

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Learn more at GRANIXhcp.com Indication » GRANIXTM is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatmentemergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Prescribing Information on adjacent page.

The ASCO Post | OCTOBER 15, 2013

PAGE 14

Breast Cancer Symposium EXPERT POINT OF VIEW ON DUCTAL CARCINOMA IN SITU

n an e-mail interview, E. Shelley Hwang, MD, an expert who has coauthored several papers on ductal carcinoma in situ (DCIS), weighed in on the two abstracts about manage-

ment of DCIS featured in this issue of The ASCO Post—one presented by Melissa L. Pilewskie, MD (perioperative MRI in DCIS, page 12)1 and the other, by Naomi B. Boekel, MSc

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(radiation therapy in DCIS, page 12).2 Dr. Hwang is Professor of Surgery and Chief of Breast Surgical Oncology at Duke University Medical Center in Durham, North Carolina.

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Perioperative MRI Adds Little Value in DCIS Regarding Dr. Pilewskie’s abstract on perioperative MRI, Dr. Hwang said, “I agree that the routine use of MRI in the setting of DCIS is not indicated, and this study supports that view. We,

E. Shelley Hwang, MD

and others, have reported that use of MRI is associated with a higher likelihood of mastectomy, regardless of MRI findings, and this has recently been substantiated in a meta-analysis by Houssami and colleagues. These observations indicate that the routine use of MRI to guide surgical therapy adds little value to mammography alone. Further, there is danger of harming patients by inappropriate screening at low or intermediate breast cancer risk.” Dr. Hwang pointed out that other potential uses for MRI warrant further exploration. “For example, we are participating in a national study sponsored by the Alliance cooperative group, which will determine the value of MRI in assessing response of DCIS to medical, as opposed to surgical treatment. Such trials may, in the future, help determine which cases of DCIS are most likely to require aggressive treatment and which may be amenable to surveillance alone,” she explained.

Radiation in DCIS and Cardiovascular Concerns Turning to Ms. Boekel’s paper on the cardiovascular safety of radiation therapy in the setting of DCIS, Dr. Hwang cited some concerns. “The most reassuring observation from this study is that patients undergoing radiation for left-sided DCIS [involves radiation to a portion of the heart] had the same cardiovascular mortality as those undergoing rightsided radiation,” she stated. “However, it is important to note that these recontinued on page 15

ASCOPost.com | OCTOBER 15, 2013

PAGE 15

Breast Cancer Symposium MRI in DCIS continued from page 12

receive radiotherapy and endocrine therapy, be treated in later calendar years, and had fewer close or positive margins. These findings suggest that oncologists were more likely to order an MRI in women at higher risk and may explain the slightly higher incidence of recurrence in patients who had an MRI, said Dr. Pilewskie.

In an analysis adjusted for patient characteristics and risk factors associated with breast cancer recurrence, use of MRI was not associated with lower 5-year rates of locoregional recurrence or contralateral breast cancer (3.5 years in both groups). At 8 years, the rates of locoregional recurrence were 14.6% for those who had an MRIs 10.2% for those who did not. The 8-year rates of contralateral

Role of MRI in Patients With Ductal Carcinoma In Situ ■■ The study results call into question routine use of perioperative MRI in patients with ductal carcinoma in situ (DCIS).

■■ MRI is expensive and is associated with false-positives, and more judicious use of this technology is warranted in patients with DCIS.

Radiation in DCIS continued from page 12

Study Methods and Results The retrospective study was based on data from 10,468 women diagnosed with DCIS before the age of 75 between 1989 and 2004. Surgery alone was performed in about 71% (43% had mastectomy and the remaining women had lumpectomy), and 28% underwent both surgery and radiotherapy. At a median follow-up of 10 years, compared with the general population in the Netherlands, survivors of DCIS had a similar risk of dying from any cause and a 30% lower risk of dying of cardiovascular disease. Women treated with surgery alone and women treated with surgery and radiotherapy had a similar risk of developing cardiovascular disease: 9% vs 8%, respective-

E. Shelly Hwang, MD on DCIS continued from page 14

sults conflict with those published earlier this year by Darby and colleagues, who found a significantly increased risk for major coronary events from chest wall radiation, which was dose-dependent. This raises the issue of whether the current study may have been underpowered to show a difference between groups.” Other concerns include additional short-term toxicities as well as serious but rare late effects (eg, secondary cancers). Dr. Hwang added, “These [other]

ly. The risk of cardiovascular disease was similar in those who received leftsided radiotherapy (includes a portion of the heart in the radiation field) or right-sided radiotherapy (the heart is not included in the radiation field); in these subgroups, the incidence of cardiovascular disease was 7% vs 8%, respectively. n

Disclosure: Ms. Boekel reported no potential conflicts of interest.

References 1. Boekel NB, Schaapveld M, Gietema JA, et al: Cardiovascular morbidity and mortality in patients treated for ductal carcinoma in situ of the breast. ASCO Breast Cancer Symposium, September 7-9, 2013, San Francisco, CA. Abstract 58. 2. Esserman L, Thompson IM, Reid B. Overdiagnosis and overtreatment in cancer. JAMA. July 29, 2013 (early release online).

morbidities must be considered when administering radiation as part of treatment for a disease which we know has negligible impact on breast cancer mortality.” At this point, there is no way to determine which DCIS will progress to invasive cancer. “Going forward, we will have to redouble our efforts to identify those [patients with] DCIS at highest risk for progression to invasive cancer and to limit treatment for those [patients with] DCIS at lowest risk of progression,” Dr. Hwang said. Work is progressing on identifying

breast cancer were 3.5% and 5.1%, respectively. Lower rates of locoregional recurrence were significantly associated with radiotherapy, endocrine therapy, and margin status, Dr, Pilewskie said.

No Improvement in Outcomes According to Dr. Pilewskie, previous studies indicate that perioperative MRI does not reduce the need for reexcision in women with DCIS. In her opinion, the evidence to date suggests that routine perioperative MRI does not improve either short- or long-term outcomes for patients with DCIS. Dr. Pilewskie said that future research should focus on areas where MRI has the potential to improve outcomes, for

example, in predicting a change in surgical management following neoadjuvant therapy for invasive breast cancer, or in more cost-effective short-sequence MRI screening techniques. n

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

Reference 1. Pilewskie ML, Olcese C, Eaton A, et al: Association of MRI and locoregional recurrence rates in ductal carcinoma in situ patients treated with or without radiation therapy. 2013 Breast Cancer Symposium, September 7-9, 2013, San Francisco, CA. Abstract 57.

EXPERT POINT OF VIEW

teven J. O’Day, MD, Director of Clinical Research at the Beverly Hills Cancer Center and Adjunct Member of the John Wayne Cancer Institute in Los Angeles, said, “This is an important study. It allows us to feel comfortable with our aggressive approach to the management of DCIS.” Dr. O’Day moderated the premeeting presscast where this study was presented.

Study Is Reassuring “Screening picks up both invasive and noninvasive cancers. Some patients with DICS will progress to invasive cancer, but we are not sure which patients those are, so we are very aggressive about surgery and radiation if breast-conserving surgery is achieved,” said Dr. O’Day. “There has been concern about the morbidity and mortality related to radiation. Older studies have shown correlations between radiotherapy and cardiovascular disease toxicity when radiation fields overlapped the heart. Although we need to follow this cohort longer, the study is reassuring that with aggressive treatment there is no overall increase in [risk of] death and in particular, no increased risk of cardiovascular death. In fact, there was a slight decrease, which may be due to healthier lifestyle changes adopted by cancer survivors,” Dr. O’Day said. n Disclosure: Dr. O’Day reported no potential conflicts of interest.

See additional expert comments on page 14

both clinical and molecular markers of poor prognosis. “Although there are limitations to any prognostic panel, these predictors have helped to lay the framework to encourage conversations with patients about the tradeoffs between the benefits and morbidities [as well as costs] of treatment. The morbidity of adjuvant treatments remains the same, whether given for low- or high-risk disease. Thus we must continue to question whether the use of radiation can be adequately justified by long-term health benefits in low-risk clinical scenarios,” Dr. Hwang said. n

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

References 1. Pilewskie MD, Olcese C, Eaton A, et al: Association of MRI and locoregional recurrence rates in ductal carcinoma in situ patients treated with or without radiation therapy. 2013 Breast Cncer Symposium. Abstract 57. Presented September 7, 2013. 2. Boekel NB, Schaapveld M, Gietma JA, et al: Cardiovascular morbidity and mortality in patients treated for ductal carcinoma in situ of the breast. 2013 Breast Cancer Symposium. Abstract 58. Presented September 7, 2013.

The ASCO Post | OCTOBER 15, 2013

PAGE 16

Breast Cancer Symposium Breast Cancer

Could MRI Be a Better Breast Cancer Screening Tool Than Mammography? By Caroline Helwick

erman investigators reported at the 2013 Breast Cancer Symposium in San Francisco that an abridged magnetic resonance imaging (MRI) protocol can accurately detect cancers among women whose mammographic screenings were negative.1 MRI, therefore, may reveal the type of tumor that mammography typically misses—and can do so in a time-efficient fashion, thus making MRI feasible for breast cancer screening, said Christiane K. Kuhl, MD, of RWTH Aachen University in Aachen, Germany. “We already know that we find more cancers with MRI screening than with mammographic screening, including more invasive cancers and more ductal carcinoma in situ (DCIS),” she said. These cancers may be more “prog-

nostically relevant” than those detected by mammography, which can be “irrelevant,” she suggested. “The aim of new, nonmammographic screening strategies is not necessarily to detect more cancers but to improve the detection of cancers that are prognostically relevant.”

As long as so many women die of breast cancer, the search for improved screening strategies must continue. True screening breast MRI may be such a strategy. —Christiane K. Kuhl, MD

Types of Cancers Detected Dr. Kuhl suggested that mammography has a “technology-inherent bias” for preferentially detecting slowgrowing cancers. Detection is based on the identification of architectural distortions, spiculations, and calcifications, ie, pathophysiologic processes that reflect regressive changes such as hypoxia, necrosis, and fibrosis and that confer length-time bias, she said.

EXPERT POINT OF VIEW

onica Morrow, MD, the Anne Burnett Windfohr Chair of Clinical Oncology and Chief of the Breast Service, Department of Surgery, at Memorial Sloan-Kettering Cancer Center, New York, congratulated Christiane K. Kuhl, MD, and colleagues for “an innovative approach to making screening magnetic resonance imaging (MRI) more accessible.” But Dr. Morrow cautioned against using lowgrade ductal carcinoma in situ (DCIS) as a surroMonica Morrow, MD gate for breast cancers that are “not important.” She said, “We need to keep in mind that every single prospective randomized trial of DCIS radiotherapy, vs no radiotherapy, showed that the risk of progression to invasive cancer was equal, regardless of the grade of DCIS. I’m not sure that this, in and of itself, is a good surrogate.” Dr. Morrow also suggested that if the two modalities detect different types of cancers, a randomized trial would be necessary to prove MRI superior to mammography, perhaps with an endpoint of breast cancer–specific survival.

Presenter’s Response Dr. Kuhl agreed on the need for additional data if MRI is going to be used for screening. “But this study shows proof of principle,” she maintained. “Can we think of using MRI for mass screening? I think the answer is ‘yes, maybe.’” She further explained, “I don’t think MRI will identify different cancers, but I think MRI is specifically ‘blind’ to cancers and DCIS that don’t have the proteomic tools required for growth and metastasis. Absence of enhancement is not necessarily equivalent to low nuclear grade—there are cases of low-grade DCIS that show strong enhancement on MRI, and there are lowgrade invasive cancers that do kill women. So we do not claim that we can disregard all low-grade DCIS—but it is possible that we can indeed disregard nonenhancing DCIS. You can think of MRI as in vivo proteomic imaging. Enhancement on MRI may be more accurate to classify the prospective biologic behavior of breast lesions than mere structural changes observed on light microscopy. So being blind for nonenhancing DCIS—not low-grade DCIS— may be a virtue rather than a disadvantage.” n Disclosure: Dr. Morrow reported no potential conflicts of interest.

On the other hand, MRI detection of cancer is determined by the tumor’s angiogenic and protease activity, ie, by tissue alterations that directly correlate with carcinogenesis, cell proliferation, and metastatic growth, she maintained. “MRI detection of cancers and DCIS is biased, therefore, toward biologically active, prognostically relevant disease. The MRI phenotype of cancers or DCIS reflects the disease’s ‘proteomic tool box’ for growth and metastasis,” she said.

Abridged MRI Modality Current MRI protocols used for screening are identical to those used for diagnostic purposes and, as such, are time consuming to acquire and to read. Dr. Kuhl and colleagues, therefore, designed an abridged breast MRI protocol that would be more suitable for screening purposes. The MRI consists only of the first post–contrastsubtracted (FAST) images and their maximum intensity projection (MIP). The MIP images allow readers to quickly detect enhancement, while the FAST images provide further categorization of these enhancements, she explained. They evaluated the screening MRI protocol in an observational study of 443 asymptomatic women at intermediate or slightly increased lifetime risk of breast cancer. All subjects had no abnormalities on digital mammography.

Experienced breast magnetic resonance radiologists rated the MIP images as positive or negative depending on the presence or absence of significant enhancement. They read the FAST images to provide Breast Imaging Reporting and Data System (BIRADS) scores and the full diagnostic MRI protocol to compare the abridged modality for diagnostic yield and accuracy.

MIP/FAST Screening In 606 screening rounds, 11 breast cancers were detected, including 4 cases of DCIS and 7 invasive cancers, for a cancer yield of 18.3 per 1,000. All lesions were Tis or T1, N0, and M0; virtually all were grade 2/3, and the median tumor size was 8.4 mm. No interval cancers were diagnosed. The sensitivity and negative predictive value of reading only the MIP image was already 98.9%; after reviewing the FAST images of the abridged protocol, it was 100%—equivalent to the full diagnostic protocol, Dr. Kuhl reported. The MIP/FAST screening also compared favorably with mammographic screening with regard to the time needed to acquire or review images. The abridged protocol required 3 minutes of acquisition time (vs 21 minutes for the full protocol) and about 30 seconds of reading time. The abridged MRI screening modality “allowed a substantial additional continued on page 18

Breast MRI vs Mammography ■■ In 443 patients with breast cancer and negative screening mammograms, additional screening by MRI identified 4 cases of DCIS and 7 invasive cancers.

■■ Screening was accomplished via an abridged MRI protocol that was quickly performed and read.

■■ MRI may identify prognostically “relevant” cancers that mammography misses, but is less likely to see low-grade DCIS.

THIS IS WHAT RECURRENT GBM THERAPY CAN LOOK LIKE TODAY NovoTTFTM Therapy delivers efficacy with improved quality of life and fewer treatment-related toxicities1 •

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•

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•

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Learn more about the NovoTTF-100A System at NovoTTFtherapy.com The NovoTTF-100A System is approved for the treatment of adult patients with recurrent glioblastoma. GBM=Glioblastoma Reference: 1. Instructions for use. NovoTTF-100A System. Novocure; 2012.

For full prescribing information refer to the IFU at NovoTTFtherapy.com

Important Safety Information Indications for Use

ASCOPost.com | OCTOBER 15, 2013

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Breast Cancer Symposium

The NovoTTF™-100A System is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM), following histologically- or radiologically-confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

Pathologic Complete Response as a Test Bed for Novel Therapies: Proceed—With Caution!

Contraindications

Do not use the NovoTTF-100A System if you have an active implanted medical device, a skull defect (such as, missing bone with no replacement), a shunt, or bullet fragments. Examples of active electronic devices include deep brain stimulators, spinal cord stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts. Use of the NovoTTF-100A System together with implanted electronic devices has not been tested and may theoretically lead to malfunctioning of the implanted device. Use of the NovoTTF-100A System together with skull defects, shunts, or bullet fragments has not been tested and may possibly lead to tissue damage or render the NovoTTF-100A System ineffective. Do not use the NovoTTF-100A System if you are known to be sensitive to conductive hydrogels like the gel used on electrocardiogram (ECG) stickers or transcutaneous electrical nerve stimulation (TENS) electrodes. In this case, skin contact with the gel used with the NovoTTF-100A System may commonly cause increased redness and itching, and rarely may even lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions Use the NovoTTF-100A System only after receiving training from qualified personnel, such as your doctor, a nurse, or other medical personnel who have completed a training course given by the device manufacturer (Novocure). All servicing procedures must be performed by qualified and trained personnel. Do not wet the device or transducer arrays. Do not use any parts that do not come with the NovoTTF-100A System Treatment Kit, or that were not sent to you by the device manufacturer or given to you by your doctor. The NovoTTF-100A System commonly causes skin irritation beneath the transducer arrays and in rare cases can lead to headaches, falls, fatigue, muscle twitching or blisters. Please refer to the Instructions For Use NovoTTF-100A System for complete information regarding the device’s indication, contraindications, risks and benefits.

ASCO President Clifford Hudis, MD, FACP, comments on pathologic complete response as an endpoint for drug approval. By Caroline Helwick athologic complete response as assessed surgically after neoadjuvant treatment is being touted by some researchers as a more efficient means of testing the value of agents that might be useful in the adjuvant setting and as a surrogate endpoint justifying accelerated drug approval. The FDA will soon respond to a favorable vote by the Oncologic Drugs Advisory Committee (ODAC) in support of using pathologic complete response in labeling an agent for neoadjuvant use. The important and urgent overarching goal is to improve the sometimes cumbersome drug approval process. But ASCO President Clifford Hudis, MD, FACP, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College in New York City, believes that using pathologic complete response for drug approval carries potential risks that investigators should consider as more drugs are possibly brought forward on this pathway. At the 2013 Breast Cancer Symposium, Dr. Hudis noted the increasing role that neoadjuvant trials play in the clinical trials portfolio. Results can be obtained less expensively and sooner than with later-stage trials. At the same time, he expressed concern that preoperative trials may sometimes overstate the benefits of novel therapies in terms of long-term endpoints, and could complicate and compromise the conventional, off-study treatment of patients. “Clinicians and clinical investiga-

Breast Cancer Screening continued from page 16

yield of biologically relevant invasive cancers and DCIS in this cohort of women at moderately or slightly increased risk of breast cancer,” Dr. Kuhl concluded. “As long as so many women die of breast cancer, the search for improved screening strategies must continue.

tors need to appreciate the limits of using this approach,” he cautioned. “By aiming for efficiency and trying to change the clinical trials paradigm, some developers may think they see an open door for accelerated approval for drugs. But limited data sets may not be sufficient. Remember that bevacizumab [Avastin] garnered accelerated approval in metastatic breast cancer based on its second randomized trial, and we know how that played out. And bone marrow transplants produced very high pathologic complete response rates, and we know how that played out, too. Activity, as measured by surrogates, can be impressive but may not be consistent nor correlated with long-term benefit. In the most current example of pertuzumab, not only was pCR increased, but this followed a demonstration of improved overall survival in the metastatic setting as well as the completion of a conventional adjuvant trial. ”

Validation of Pathologic Complete Response Limited In the neoadjuvant setting, the hypothesis is that between two potential treatment options, the one yielding the higher pathologic complete response rate will be the one associated with superior long-term outcomes, specifically disease-free survival and overall survival. “The challenge we have in considering this hypothesis is simply that the available validation is limited and the potential for long-term error remains,” said Dr. Hudis. continued on page 19

True screening breast MRI may be such a strategy,” she said. n

Disclosure: Dr. Kuhl has served in a consultant or advisory role for Bayer.

Reference 1. Kuhl CK, Schrading S, Strobel K, et al: Accelerated breast MRI for breast cancer screening. 2013 Breast Cancer Symposium. Abstract 1. Presented September 7, 2013.

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Breast Cancer Symposium Pathologic Complete Response continued from page 18

While it has been established that among similarly treated patients, those achieving pathologic complete responses have a better prognosis than those who do not, pathologic complete response has not been fully validated as a surrogate for long-term outcomes, nor has such an association been observed in all studies and tumor subtypes. For example, in NSABP B27, the addition of docetaxel (Taxotere) to neoadjuvant doxorubicin (Adriamycin)/cyclophosphamide (Cytoxan) nearly doubled the pathologic complete response rate but did not improve disease-free and overall survival.1 Dr. Hudis further suggested that neoadjuvant trials can’t completely substitute for adjuvant trials, as it will be challenging to determine, for a new compound, the optimal duration of therapy for postoperative use and the safety signals that only large numbers of subjects can provide. He notes, that new efforts such as ASCO’s CancerLinQ may enable investigators to rely on off-study use to generate reliable safety signals in the future.

Breast Cancer Subtypes Can Confound the Effects Furthermore, Dr. Hudis pointed out that the molecular heterogeneity of breast cancer creates complexity in the neoadjuvant setting that is not always recognized. For example, different subtypes may have different sensitivities to new agents. Several neoadjuvant studies recently demonstrated that pathologic complete response rates after anti-HER2 therapies vary according to estrogen receptor/progesterone receptor status. In CALGB 40601, reported at 2013 ASCO Annual Meeting, pathologic complete response rates after dual HER2 blockade reached 77% in hormone receptor-negative patients, but were just 42% in hormone receptor-

positive patients.2 And in GeparSixto, also reported at ASCO, the addition of carboplatin (Paraplatin) to paclitaxel (Taxol) and non-pegylated liposomal doxorubicin led to pathologic complete responses in almost 60% of patients with triple-negative breast cancer but failed to increase responses in HER2-positive patients.3 Other important modulators of response may not be recognized until later. Even knowing this, trial results may not be completely confirmatory.

long-term benefit, but a recent metaanalysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) failed to provide answers. The study, which included 12 randomized neoadjuvant trials and nearly 13,000 patients, found that patients achieving a pathologic complete response had a 52% reduction in events (P < .001) and a 64% reduction in the probability of death (P < .001), but the magnitude of pathologic complete response improvement that predicted

The challenge we have in considering this hypothesis [higher pathologic complete response rate will be associated with superior long-term outcomes] is simply that the available validation is limited and the potential for long-term error remains. —Clifford A. Hudis, MD, FACP

In the Neo-ALLTO trial, which evaluated lapatinib (Tykerb), trastuzumab (Herceptin) and the combination, it was less clear that incremental improvements in pathologic complete response varied by hormone receptor status. But importantly, the neoadjuvant results failed to predict the eventual inferiority of single-agent lapatinib in the adjuvant setting, according to early analysis from the ongoing ALLTO study.4 While stratification of the population will help sort these things out, there may be additional factors that could influence pathologic complete response rates for specific targeted agents. “How will we avoid potentially misleading and unrecognized imbalances in the typically smaller neoadjuvant studies testing new agents?” Dr. Hudis asked. Additionally, for an approval based on pathologic complete response it is necessary to know what magnitude of improvement will be associated with

event-free and overall survival benefit could not be established.5 “Is it, for example, a 7% absolute increase or a 14% absolute increase? By the FDA’s own analysis, we don’t see a simple association,” said Dr. Hudis.

Where Do We Stand? “Change in pathologic complete response rate is not yet an established stand-alone surrogate endpoint and we do not have sufficient experience to validate it. We still need a validated endpoint for the regular approval of drugs. The ODAC vote in favor of pertuzumab’s (Perjeta) approval therefore relied heavily on the availability of an unprecedented overall survival improvement in the metastatic setting, as well as the existence of a completed, but unreported adjuvant trial,” Dr. Hudis said. “A similar triad of data and completed studies is unlikely to recur anytime soon. Dr. Hudis made it clear that he

strongly supports studies in the preoperative stetting as well as the development of a pathway for preoperative drug approval. “I run, conduct, design, and strongly support preoperative studies,” he said. “They are a good screen for a drug’s activity, may ultimately indicate improvements in long-term outcomes, and can provide informative imaging and tissue correlates,” he said. “When we have the rapid acquisition of data, as occurred with pertuzumab, accelerated approval may be justified. But this should not be misunderstood as evidence that [pathologic complete response] stands alone as a surrogate.” n Disclosure: Dr. Hudis reported no potential conflicts of interest.

References 1. Rastogi P, Anderson SJ, Bear HD, et al: Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols: B-18 and B-27. J Clin Oncol 26:778-785, 2008. 2. Carey LA, Berry DA, Ollila D, et al: Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatininb for HER2-positive breast cancer. 2012 ASCO Annual Meeting. Abstract 500. Presented June 2, 2013. 3. Von Minckwitz G, Schneeweiss A, Salat C, et al: A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triplenegative and HER2-positive early breast cancer (GeparSixto). 2013 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2012. 4. Baselga, J, Bradbury I, Eidtmann H, et al: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): A randomized, open-label, multicentre, phase 3 trial. The Lancet, 379(9816):633-40. 5. Cortazar P, Zhang L, Untch M, et al: Meta-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S1-11. Presented December 5, 2012.

Direct From ASCO See pages 72–80 in this issue of The ASCO Post for news Direct From ASCO, including a listing of 2014 candidates for the open leadership positions within the Society on page 75. Voting opens Tuesday, October 29, and closes on Tuesday, November 26.

The ASCO Post | OCTOBER 15, 2013

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Breast Cancer Symposium Accountable Care Organizations continued from page 1

need to keep the patient front and center,” he said. The Patient Protection and Affordable Care Act of 2010 laid the groundwork for ACOs, and included the Boston area in its pilot programs. The model already includes Partners Healthcare (Massachusetts General and Brigham and Women’s Hospitals), Beth Israel Deaconess Medical Center, Lahey Healthcare, Steward (a private facility), and Atrius Healthcare (a large physician group). “ACOs are a big part of our world in Boston,” Dr. Shulman said, adding that “ACOs are permeating the medical world [in Boston], but the meaning for cancer care is still uncertain.” The ACO population is no longer restricted to Medicare beneficiaries, but has widened its applicability to the general population. The ACO model is driven by primary care providers who will coordinate and direct care and, to some degree, be involved in treatmentrelated decisions. The goal is to provide quality care and reduce costs. The physician organization will supposedly benefit from costs that incur below the projected line and will be penalized for costs above that line. Physicians will be responsible for measuring and reporting quality metrics, Dr. Shulman said. While the goals of ACOs are admirable, Dr. Shulman expressed concerns about how medical oncology will interface with primary care within this model. “Primary care providers may have something to say about the choice

of a beta-blocker in a cardiac patient, but will they agree or disagree with the oncologist about the choice of an adjuvant chemotherapy regimen?” he said. While they should, and probably will, leave such decisions to the oncologist, they will still maintain power over oncology practices, he suggested. “Primary care providers may refer patients only to those oncologists who can measure and report quality metrics, as well as cost metrics. They may tell you that they will use your practice, or not use it,

therapy for every clinical situation in the years to come,” he noted. “Maybe ASCO’s CancerLinQ™ [Learning Intelligence Network for Quality] will provide a better mechanism to analyze what we do in practice and to measure outcomes and cost.” CancerLinQ™ will collect and analyze cancer care data from patient visits, creating a knowledge base that can be accessed in real-time by clinicians, researchers, and patients. Meanwhile, physicians need to think

Cancer Care in the Era of Accountable Care Organizations ■■ Accountable care organizations are up and running in some areas, such as Boston, Massachusetts.

■■ Primary care providers will drive ACOs, and how oncology will interface within the model remains to be seen.

■■ Primary care providers will likely choose to refer to practices that are

measuring and demonstrating competitive costs and high quality of care.

based on outcomes. Oncology practices will be most attractive to ACOs if they can measure and show competitive cost and good quality,” said Dr. Shulman.

Reducing Variations in Practice Variations in practice patterns commonly occur among physicians and among institutions. This is sometimes related to the lack of good evidence as guidance, but it happens—and results in higher cost—even in the setting of evidence, Dr. Shulman said. “As a nation we are not set up to be able to analyze the outcome of large groups of patients receiving routine care to better inform us of the best

beyond guidelines, which are focused on a particular decision point in care, and more toward pathways, which describe an entire course of treatment and specify “not only what should be done, but also what should not be done,” he said. Pathways must take into account the total cost of care and focus on practices that are truly needed.

data supporting a particular regimen for reasons of efficacy or toxicity, all things being equal physicians should choose the less expensive regimen or test, he advised. “We must include issues of utilization and cost as we plan cancer care, and must do this prospectively rather than patient by patient,” said Dr. Shulman.

Case in Point To illustrate how much oncologists can influence the cost of care, Dr. Shulman described the management options for a hormone receptor-positive, node-positive patient. Using average charges for 10 different management options, he showed that a course of adjuvant therapy could range from about $23,000 (with endocrine therapy and a short course of radiotherapy) to more than $130,000 (endocrine therapy, chemotherapy, radiotherapy, growth factor support, use of Oncotype DX). “You can see that in this very gray area, choices impact cost a great deal,” said Dr. Shulman. “My own feeling is that much that we do day to day has only weak evidence to tell us the best treatment choices. The most interesting things we argue about in tumor boards are areas where the data are weakest. When options are relatively equivalent in efficacy and toxicity, we should take cost into account.” n

Utilization and Cost Considerations

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

In the absence of phase III prospective randomized clinical trial data, said Dr. Shulman, oncologists should avoid “shooting from the hip” and should try to “reason out the best we can, in the theoretical.” And in the absence of

Reference 1. Shulman LN: Accountable care organizations and the future in cancer care. 2013 Breast Cancer Symposium. Presented September 8, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Graham A. Colditz, MD, DrPH, on alcohol and breast cancer risk see page 87

Maha Hussein, MD, FACP, FASCO, on radium-223 in prostate cancer see page 96

Jose Baselga, MD, PhD, on the future of medical oncology see page 110

Barrie R. Cassileth, MS, PhD, on herb-drug interactions in oncology see page 112

Federico A. Sanchez, MD, on the Wisconsin Association of Hematology & Oncology see page 118

Alexander V. Prokhorov, MD, PhD, on E-cigarettes see page 142

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | OCTOBER 15, 2013

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FDA Update

FDA Approves First Generic Capecitabine to Treat Colorectal and Breast Cancers

he U.S. Food and Drug Administration (FDA) has approved the first generic version of capecitabine (Xeloda), an oral chemotherapy

agent used in the treatment of metastatic colorectal cancer and breast cancers. Teva Pharmaceuticals USA has gained FDA approval to market

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] • in 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.

generic capecitabine in 150 and 500 mg strengths. Generic drugs approved by the FDA have the same high quality and

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 16 0 5 0 Chillsa 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 43 2 21 1 Alanine Transaminase, highc 38 1 24 1 Aspartate Transaminase, highc c Alkaline Phosphatase, high 33 <1 24 0 respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd 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 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.

strength as brand-name drugs, and generic drug manufacturing and packaging sites must pass the same continued on page 22

The ASCO Post | OCTOBER 15, 2013

PAGE 22

FDA Update

Generic Capecitabine

Adverse Effects

continued from page 21

In the clinical trials for capecitabine, the most commonly observed adverse reactions included diarrhea; vomiting; nausea; pain, redness, swelling, or sores in the mouth; hand-and-foot syndrome; and fever or infection. It is important that the prescriber know if the patient is also taking an

quality standards as those of brandname drugs. “Generic drugs are important options that allow greater access to health care for all Americans,” said Kathleen Uhl, MD, Acting Director of the Office of Generic Drugs in the FDA’s

Center for Drug Evaluation and Research. “This medication is widely used by people living with cancer, so it is important to have access to affordable treatment options.”

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 (cetuximab) 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 44 11 27 8 Infectionb 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 70 9 2 0 Acneiform Rashc 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:

anticoagulant such as warfarin, as capecitabine can increase the effect of this medicine, possibly leading to serious side effects. Capecitabine has a boxed warning to alert health-care professionals and patients about this risk. Information about the availability of generic capecitabine can be obtained from Teva. n

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 b 1–4 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 b c than that seen in the FOLFIRI arm. Adverse reactions were graded using the NCI CTC, V 2.0. 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 18 3 0 0 Infusion Reactionsc 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.

ASCOPost.com | OCTOBER 15, 2013

PAGE 23

FDA Update

FDA Approves Nab-Paclitaxel for Late-Stage Pancreatic Cancer

he U.S. Food and Drug Administration (FDA) has expanded the approved uses of paclitaxel protein-bound particles for injectable suspension, albumin-bound (nab-paclitaxel, Abraxane) to treat

patients with late-stage pancreatic cancer. “Patients with pancreatic cancer are often diagnosed after the cancer has advanced and cannot be surgically removed,” said Richard

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.

3810101_0207501_UpTheAnti_ROB_v3_M.indd 3

Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “In these situations, and in situations when the cancer has progressed following

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

Rev August 2013 693US13PBS02201

surgery, options like [nab-paclitaxel] can help prolong a patient’s life.” Nab-paclitaxel is a chemotherapy drug that can slow the growth of certain tumors. The agent is intended to be used with gemcitabine in patients with metastatic pancreatic cancer.

The FDA reviewed the new use for nab-paclitaxel under the agency’s priority review program, which provides for an expedited review of drugs. Nab-paclitaxel was also granted orphan product designation for pancreatic cancer because it is intended to treat a rare disease or condition.

Clinical Trial The safety and effectiveness of nab-paclitaxel for pancreatic cancer were established in a clinical trial with 861 participants who were randomly assigned to receive nabpaclitaxel plus gemcitabine or gemcitabine alone. Participants treated with nab-paclitaxel plus gemcitabine lived, on average, 1.8 months longer than those treated with gemcitabine alone. Additionally, participants who received nab-paclitaxel plus gemcitabine experienced a delay in tumor growth that was, on average, 1.8 months later than the participants who only received gemcitabine. 8/22/13 3:54 PM Common side effects observed in nab-paclitaxel plus gemcitabine– treated participants include neutropenia, thrombocytopenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, rash, and dehydration. The most common serious side effects were pyrexia, dehydration, pneumonia, and vomiting. Other clinically important serious side effects included sepsis and pneumonitis. Nab-paclitaxel was approved to treat breast cancer in 2005 and non– small cell lung cancer in 2012. n

FDA Update For more FDA news see pages 30 and 89.

The ASCO Post | OCTOBER 15, 2013

PAGE 24

Best of ASCO® Targeted Therapy

Applying Molecular Profiling to Clinical Practice: Promises and Challenges By Charlotte Bath

“new kind of pathology,” with anatomy and histology being supplemented by molecular etiology, has been emerging over the past decade and promises better response rates among patients with cancer, as genomic alterations continue to be identified and treated with targeted therapies. “The list of genomic alterations in cancer that can be therapeutically targeted is growing rapidly,” according to Shridar Ganesan, MD, PhD, Associate Director of Translational Science at Rutgers Cancer Institute of New Jersey, in a presentation on molecular profiling at the recent Best of ASCO meeting in Chicago. The presentation incorporated information from education sessions presented at the 2013 ASCO Annual Meeting.1-5

Critical Targets Using non–small cell lung cancer as an example, Dr. Ganesan noted that while there are a few histologic subtypes, molecular analysis reveals “a large, surprising hetereogeneity of different molecular driver events that are seen in histologically identical cancers.” These molecular driver events “are probably critical for the development of that cancer and are critical for their continued growth and proliferation, and so they are critical targets that are now being appropriately hit by small molecules,” Dr. Ganesan added. Overall, the kinds of alterations that can be targeted in cancer cells include “classical activating oncogenes like ABL, ALT, RET, and JAK. But now we are also starting to be able to target loss of function in tumor suppressors like BRCA1, BRCA2, and PALB2. Loss of function of those genes leads to an underlying repair defect that can be targeted by certain classes of standard chemother-

apy like the platinum salts as well as new small molecules like the PARP inhibitors,” Dr. Ganesan stated.

Impact of IMPACT Study “Maybe the reason we have not gained as much as we would like from large, randomized trials based on histologically defined cancer subtypes is that common cancers are really caused by a large set of underlying genomic aberrations. Targeted agents and perhaps even standard chemotherapy work only in a subset of cancers that have the appropriate underlying sensitizing mutations,” Dr. Ganesan said. The IMPACT (Initiative for Molecular Profiling in Advanced Cancer Therapy) study showed that response rates can increase when patients receive appropriate molecular therapy. Patients eligible for phase I trials at The University of Texas MD Anderson Cancer Center in Hous-

also had improved failure-free and overall survival. Patients who had no molecular match and were assigned to other trials had a 0% complete response rate and a 14% partial response rate. “This suggests that if you have molecular targeted therapy, you can see a response signal very early, even in phase I data,” Dr. Ganesan noted. These data include a response rate of 77% using imatinib (Gleevec) in patients with chronic myelogenous leukemia and a 57% response rate for crizotinib (Xalkori) in patients with non–small cell lung cancer and the EML4-ALK fusion biomarker.

Challenges Amid Advances Along with an increasing number of molecular therapies, the technology for gene sequencing is rapidly improving. This has led to “the overall schema of personalized medicine we were hoping for,” Dr. Ganesan

This kind of high response rate in early-phase trials for which therapies are targeted to underlying molecular aberrations is now commonplace. —Shridar Ganesan, MD, PhD

ton had tumor specimens analyzed for the presence of genomic alterations and were matched to appropriately targeted phase I trials if available, or to other phase I trials. Of 2,282 patients with adequate tissue available to be analyzed, 52.2% had at least one molecular aberration. About 20% of these patients who were matched to appropriate molecular therapies had no progression for at least 6 months, including 2% with complete response and 17% with partial response by RECIST criteria. Patients with matched therapy

Update on Molecular Profiling in Clinical Practice ■■ Histologic classification is now being supplemented by molecular etiology in classifying types of cancer.

■■ An increasing number of genomic alterations in cancer can now be specifically therapeutically targeted.

■■ Logistic and biologic challenges remain in the implementation of

personalized oncology, but collaborative efforts could overcome many of these challenges.

said. In this schema, “when a person has a cancer diagnosis, not only do you get your standard histologic diagnosis, but the tumor is also sent for multiplexed genomic sequencing, leading ultimately to a readout of what genomic alterations are present or absent in each patient. That would lead to a genomic profile for each patient, which hopefully will allow us to select targeted therapy.” Dr. Ganesan explained. “Although this is very exciting, there are a lot of challenges or obstacles to implementing this kind of personalized oncology, and they include logistical problems as well as biologic challenges,” he noted. “One of the big problems involves tissue collection and testing. There are no established guidelines for what makes an adequate tissue sample for molecular or genomic analysis and what exact platform and type of analysis should be done,” Dr. Ganesan said. “If we are really going to use this technology to dictate

patient care, we need to carefully evaluate the positive and negative predictive value of each test,” he added. “Right now, we don’t know the limitations of many of these assays.”

Collaboration Needed To overcome these problems, Dr. Ganesan suggested collaboration on guidelines, such as the collaborative efforts ASCO participated in to develop guidelines for HER2 testing in breast cancer. “Ultimately, we will have to develop some sort of standardized method for evaluating and validating these assays,” Dr. Ganesan said. “We need to have overall national guidelines.” Another problem concerns determining which gene alterations “are truly actionable,” Dr. Ganesan noted. That determination should be based on the strength of the evidence that a genomic alteration is driving the growth of the cancer, and the size of the effect to be achieved by intervening. “To establish that, we need to have standardized clinical decision support,” Dr. Ganesan said. As an example, he cited a computer search form that would allow the clinician to enter data on the molecular alterations and the tumor site of origin and then get current data on clinical implications and what agents are available to treat the patient.

Access to Drugs “Another big problem, of course, is access to new targeted therapies,” Dr. Ganesan added. One of the proposed solutions is to create a national formulary of targeted agents against common aberrations along with a registry of administered treatment and patient outcomes. A national pharmacy exchange could benefit patients who receive a targeted agent matched to their molecular profile, as well as physicians who receive guidance in treatment recommendations and access to drugs, drug manufacturers who receive data on drug use and outcomes, payers who receive data to inform future coverage decisions, and regulators who receive data on

ASCOPost.com | OCTOBER 15, 2013

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Best of ASCO® extent and outcomes of off-label drug and test use and real-world safety data.

Biologic Challenges There are also biologic challenges to applying molecular profiling in clinical practice, Dr. Ganesan explained. These include variations in how mutations signal in different contexts, intratumor heterogeneity, and rapid emergence of resistance, compensating mutations, and pathway adaptation. Among recommendations for preventing resistance are the following strategies: target drivers of genomic instability and clonal diversity, combine targeted therapy with immunotherapy and/or chemotherapy, conduct frequent tumor biopsies to monitor emergence of new aberrations, and eradicate significant subclones early. As with many aspects of life, timing is also important and treatment should begin “as early as possible before diversity explodes.”

Encourage Tissue Donation In a question-and-answer session following Dr. Ganesan’s presentation, the meeting moderator, Douglas Yee, MD, of the University of Minnesota Masonic Cancer Center in Minneapolis, said that patients should be encouraged to donate tissues to be analyzed for genomic ab-

Douglas Yee, MD

errations as part of “a movement to have better-annotated specimens available for research. In my practice, I think most patients would be will-

ing to contribute,” Dr. Yee noted. In an interview with The ASCO Post, Dr. Yee was asked about the National Institutes of Health’s recent decision to restrict its financing of research on the HeLa genome because of family concerns about privacy if the full genomic sequence of HeLa cells was published. “The HeLa cells issue is from a completely different era and a very egregious case of not informing the patient about what was being done to her, and I think there is no excuse for that,” Dr. Yee said. In the current situation, patients would be fully informed and understand that specimens would be used for research about clinical outcomes. Patients with cancer often ask how they can contribute to cancer control efforts, Dr. Yee noted. “When we talk about how to help, we always talk about advocacy and money and donations, but I think there is another component where patients can help

by making their tissues available for study,” he said. n Disclosure: Drs. Ganesan and Yee reported no potential conflicts of interest.

References 1. Kurzrock R: Applications of profiling to the clinical setting. 2013 ASCO Annual Meeting Education Session. Presented June 3, 2013. 2. Schilsky RL: Removing barriers to personalized cancer care. 2013 ASCO Annual Meeting Education Session. Presented June 1, 2013. 3. Tsimberidou AM: Rewards and challenges of individualized therapy in clinical trials. 2013 ASCO Annual Meeting Education Session. Preseneted June 1, 2013. 4. McShane LM: Designing prospective trials in the era of molecular profiling. 2013 ASCO Annual Meeting Education Session. Presented June 3, 2013. 5. Swanton C: Heterogeneity of tumors and how to approach it. 2013 ASCO Annual Meeting Education Session. Presented June 3, 2013.

Telomere Length May Be a Prognostic Marker for Prostate Cancer

ancer cells are known to have short telomeres, but just how short they are from cancer cell to cancer cell may be a determining factor in a prostate cancer patient’s prognosis, according to a study1 led by scientists at Johns Hopkins. “Doctors are looking for new ways to accurately predict prostate cancer patients’ prognoses, because the current methods that use disease stage, Gleason score, and PSA are not perfect,” said Alan Meeker, PhD, Assistant Professor of Pathology at the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center. “Telomere shortening is common in cancer, but the degree of shortening varies from one cancer cell to another within each patient, and this variability may give us a better idea of how prostate cancers behave.”

tissue samples of each patient. Dr. Meeker and his team used a technique they developed called telomere-specific fluorescent in situ hybridization (TELI-FISH) to measure telomere length in cancer and stromal cells. The technique uses fluorescentlabeled probes specific for particular locations in DNA, and is commonly used to detect or confirm gene or chromosome abnormalities. In the new

telomere length measurements in the cancer and stromal cells with each patient’s survival.

Results “Men who had a combination of more variable telomere length among cancer cells and shorter telomere length in stromal cells were more likely to develop metastatic disease and die sooner from their prostate cancer than

Men who had a combination of more variable telomere length among cancer cells and shorter telomere length in stromal cells were more likely to develop metastatic disease and die sooner from their prostate cancer than other men. —Elizabeth Platz, ScD, MPH

Study Details In the study, scientists looked at tissue samples from 596 men surgically treated for prostate cancer thought to be confined to the prostate and who were participants in a long-term follow-up study on men’s health. Then, they used images of prostate cancer cells and nearby cells called stroma, which include smooth muscle and fibroblast cells, taken from surgery-

study, a fluorescent probe specific for telomere regions was added to the cells, enabling the scientists to identify these specific chromosomal locations under a microscope and measure the level of fluorescence that corresponds to telomere length. After determining telomere length for more than 40,000 cells among the samples, researchers then correlated

other men,” said Elizabeth Platz, ScD, MPH, Professor of Epidemiology at the Johns Hopkins Bloomberg School of Public Health and the Martin D. Abeloff Scholar in Cancer Prevention at the Johns Hopkins Kimmel Cancer Center. In the group of 98 men with more variable telomere length in cancer cells and shorter telomeres in stromal cells, 20 died of their prostate cancer

an average of 8.4 years after diagnosis. Accounting for standard prognostic factors, these men were 14 times more likely to die of their prostate cancer compared with another group of 98 men whose telomeres had less variable length among cancer cells and were longer in stromal cells. In this group, one man died, and that was after 16.5 years. “Our studies strongly suggest that the combination of telomere length in stromal cells and its variability among prostate cancer cells could be a marker for prostate cancer prognosis,” said Dr. Platz. Drs. Meeker and Platz are continuing to study additional groups of patients and are now using an automated fluorescence microscope and computer software to speed the collection of tissue images and extract telomere data. n

Disclosure: Funding for the study was provided by the Department of Defense; the National Institutes of Health’s National Cancer Institute; the National Heart, Lung, and Blood Institute; the Seraph Foundation; and the Prostate Cancer Foundation.

Reference 1. Heaphy CM, Yoon GS, Peskow SB, et al: Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death. Cancer Discovery. June 18, 2013 (early release online).

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.

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.

The ASCO Post | OCTOBER 15, 2013

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FDA Update

FDA Grants Breakthrough Therapy Status to Entinostat for Advanced Breast Cancer

yndax Pharmaceuticals Inc announced that the U.S. Food and Drug Administration (FDA) has designated entinostat as a Break-

through Therapy for the treatment of locally recurrent or metastatic estrogen receptor (ER)-positive breast cancer when added to exemestane

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

in postmenopausal women whose disease has progressed following nonsteroidal aromatase inhibitor therapy. Entinostat is an investiga-

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

tional histone deacetylase (HDAC) inhibitor set to begin phase III testing in combination with exemestane in postmenopausal women with

(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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FDA Update

metastatic ER-positive breast cancer whose disease has progressed on hormonal therapy.

Clinical Trials The Breakthrough Therapy designation for entinostat is based on data from the completed phase II ENCORE 301 study, in which en-

• 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

tinostat was shown to extend both progression-free survival and overall survival when added to exemestane in postmenopausal women with ERpositive metastatic breast cancer whose cancer had progressed after treatment with a nonsteroidal aromatase inhibitor and with a very acceptable tolerability profile. A phase

(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)]

III trial, planned to begin enrolling patients in the first quarter of 2014,

is currently being developed by the ECOG-ACRIN Cancer Research

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.

Group, which would conduct the study under the sponsorship of the National Cancer Institute’s Division of Cancer Treatment and Diagnosis. “The FDA’s decision to designate entinostat a Breakthrough Therapy is important validation of the drug’s therapeutic potential in women with continued on page 32

The ASCO Post | OCTOBER 15, 2013

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FDA Update

Entinostat continued from page 31

advanced breast cancer,” said Arlene M. Morris, Syndax’s Chief Executive Officer. “Currently, women with ER-positive breast cancer [that has] progressed on hormonal therapy have limited therapeutic options. Entinostat’s epigenetic mechanism may re-

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.

verse resistance to hormonal therapy, delaying the need for toxic chemotherapeutic agents and improving survival when given in combination with aromatase inhibitors. This breakthrough designation will allow us to more rapidly bring this new treatment option to patients who may benefit from its availability.”

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 FDA Safety and Innovation Act, signed in July 2012, created the Breakthrough Therapy Designation. According to the FDA, the designation allows the expedited development and review of a drug to treat a serious or life threatening disease or condition intended alone or in combination with one or more other drugs for which

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

preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

About Entinostat Entinostat has been studied in more than 800 cancer patients where objective tumor responses have been observed in both solid and hematologic malignancies. The drug’s established safety and efficacy profile as both a single agent and in combination with a number of commercially available targeted therapies differentiates it from other HDAC inhibitors. Having demonstrated promising clinical results in breast and lung cancer, entinostat is moving toward pivotal clinical testing. It is an oral, novel inhibitor of class I histone deacetylases, key enzymes that alter the structure of chromatin to control gene expression. Designed to selectively target the HDAC isoforms most relevant to the biology of tumors, entinostat can normalize dysregulated gene expression in cancer cells, thereby restoring sensitivity to targeted therapy. Entinostat is the first HDAC inhibitor with positive results in a randomized phase II study in breast cancer and is the only HDAC inhibitor in late-stage development for this indication. n See pages 21-23 and 89 for more FDA Updates.

The ASCO Post

@ASCOPost

ASCOPost.com | OCTOBER 15, 2013

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Best of ASCO® Gastrointestinal Oncology

Important Findings in Metastatic Colorectal Cancer Studies Address Treatment, Management Options By Caroline Helwick

t the Best of ASCO Meeting in Los Angeles, Tony Reid, MD, PhD, Director of the Early Phase Clinical Research Program and Professor of Hematology/Oncology at the University of California, San Diego, reviewed important findings in metastatic colorectal cancer presented at the 2013 ASCO Annual Meeting, and offered his thoughts on their clinical application.

Presurgical Treatment Options The new EPOC study presented evaluated cetuximab (Erbitux) plus chemotherapy, vs chemotherapy alone, for operable metastatic colorectal cancer in patients with KRAS wild-type tumors.1 While response rates were higher with the combination, progression-free survival was significantly worse with cetuximab: 14.1 months vs 20.5 months with chemotherapy alone (HR = 1.49; P = .030). Median overall survival was not reached in the chemotherapy alone arm and was 39.1 months with chemotherapy/cetuximab (HR = 1.40; P = .163). “EPOC showed a detrimental effect of cetuximab when added to chemotherapy. No specific subset accounted for this finding. We also learned that response rate does not predict progression-free or overall survival,” Dr. Reid said. “The results of the EPOC trial indicate a disconnect between response rate and overall survival but do not support the use of cetuximab presurgically in operable patients with KRAS wild-type tumors.”

First-Line Metastatic Disease The German FIRE 3 study compared the addition of bevacizumab (Avastin) vs cetuximab, given with FOLFIRI (leucovorin, fluorouracil [5‑FU], irinotecan), in the first-line treatment of KRAS wild-type metastatic disease.1 Among the 592 patients, the intent-to treat analysis showed no significant differences between the two treatment arms in terms of response rates, however, among patients assessable for response, ie, those who received at least three cycles (n = 526), response rates were higher with cetuximab (72% vs 63%; P = .017). Progression-free survival was approximately 10 months in either arm

(P = .547), however, “intriguingly,” overall survival was better with cetuximab: 28.7 vs 25.0 months with bevacizumab (HR = 0.77; P = .017). Despite this, he called the regimens “essentially equivalent.” “FIRE 3 showed that bevacizumab and cetuximab have similar progression-free survival rates when added to FOLFIRI,” Dr. Reid said. “Regarding overall survival, the duration of exposure to first-line treatment was about 5 months in either arm, but the curves did not separate until about 18 months. While the overall survival was better among patients randomized to

FIRI/bevacizumab (HR = 0.73; P = .0012). The progression-free survival rate at 2 years was 20.3% vs 11.4%, respectively. Median overall survival in the intent-to-treat population was 31.0 vs 25.8 months (HR = 0.83; P = .125), with a strong trend favoring FOLFOXIRI in the stratified analysis (HR = 0.79; P = .054). Response rates were also higher with FOLFOXIRI (65% vs 53%; P = .006). There was no notable difference in toxicity, suggesting that “FOLFOXIRI can be given relatively safely, especially with dose reductions,” Dr. Reid suggested.

Intensive upfront therapy improves progression-free and possibly overall survival in the first-line setting. These findings could potentially change my practice. I have favored sequential therapy because it is less toxic, but this study [TRIBE 3] is persuading me to perhaps use the triplet [FOLFOXIRI/ bevacizumab] up front. —Tony Reid, MD, PhD

the arm that received cetuximab as part of the first-line treatment, the delay in separation of the curves did not occur until 13 months after the first-line therapy was discontinued. This prolonged delay suggests that the difference in survival was due to what happened in the second-line setting, where there was greater use of bevacizumab after cetuximab.” TRIBE asked which of two regimens—FOLFIRI (the control arm) vs FOLFOXFIRI (leucovorin, 5-FU, irinotecan, oxaliplatin)—might be the best backbone for bevacizumab in unresectable patients. 3 The study concluded that FOLFOXIRI may be superior in terms of progression-free and overall survival. Surgical resections rates (negative margins) were also numerically greater. FOLFOXIRI/bevacizumab carried more side effects but no greater incidence of serious adverse events. Median progression-free survival was 12.2 months with FOLFOXIRI/ bevacizumab vs 9.7 months with FOL-

In subset analyses, the benefit of FOLFOXIRI was especially strong for BRAF-mutated tumors (HR = 0.55) compared to wild-type (HR = 0.83). Benefit was seen in both KRAS-mutated (HR = 0.84) and wild-type tumors (HR = 0.83). “For the patient with poor genetics, FOLFOXIRI/bevacizumab may be a beneficial regimen,” he suggested. Drawing conclusions from the TRIBE study, Dr. Reid said, “Intensive upfront therapy improves progressionfree and possibly overall survival in the first-line setting. These findings could potentially change my practice. I have favored sequential therapy because it is less toxic, but this study is persuading me to use the triplet up front for appropriate patients.”

Maintenance Therapy A recent meta-analysis of 10 studies evaluated the use of various maintenance therapy approaches and, taken together, these studies showed

no detrimental effect to maintenance regimens. Two studies presented at ASCO 2013, and reviewed at the Best of ASCO meeting, evaluated maintenance therapy. CAIRO 2 compared capecitabine plus bevacizumab vs observation after induction treatment while the DREAM trial evaluated bevacizumab with or without erlotinib (Tarceva), according to KRAS status. The phase III CAIRO3 study, by the Dutch Colorectal Cancer Group, randomized 558 metastatic patients with stable disease after six cycles of CAPOX (capecitabine/oxaliplatin) plus bevacizumab to continued capecitabine/bevacizumab as maintenance, vs observation.4 At the time of second progression, patients were reintroduced to CAPOX/bevacizumab (or other treatment) and were evaluated again for time to second progression. Time to first progression was significantly prolonged by maintenance therapy: 8.5 months vs 4.1 months with observation (unadjusted HR = 0.41; P < .001). Time to second progression was also significantly longer in the maintenance arm: 19.8 months vs 15.0 months, respectively (adjusted HR = 0.63; P < .001). Overall survival was 21.7 months and 18.2 months, respectively, which was not statistically significant in the stratified analysis (HR = 0.87; P = .156) but reached significance in the adjusted analysis (adjusted HR = 0.80; P = .035). “Maintenance was significantly better. Patients benefited from being kept on treatment. Did this translate into an overall survival advantage? Yes, but with qualifications. In the intent-to-treat analysis the difference was not statistically significant, but in the adjusted analysis it was,” he said “The findings favor treating patients with capecitabine/bevacizumab as maintenance rather than no therapy; however, the difference in overall survival advantage was only significant when adjusted for the time from diagnosis to randomization and for the stage of disease.” continued on page 38

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.

600-10-0008-13b

08/13

Printed in USA

Introducing Xofigo

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.

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.

NEW

radium Ra 223 dichloride INJECTION

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

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

6.1 Trials Clinical Trials Experience 6.1 Clinical Experience 1 INDICATIONS 1 INDICATIONS AND USAGE AND USAGE Becausetrials clinical trials are conducted under widelyconditions, varying conditions, adverserates reaction rates Because clinical are conducted under widely varying adverse reaction Xofigo™ isXofigo™ indicated is for indicated the treatment for the treatment of patientsofwith patients castration-resistant with castration-resistant prostate cancer, prostate observed cancer, in observed in the clinical trialscannot of a drug directly compared in the clinical the clinical trials of a drug be cannot directlybe compared to rates in to therates clinical trials of trials of symptomatic symptomatic bone metastases bone metastases and no known and no visceral known metastatic visceral metastatic disease. disease. another drugnot andreflect may not the ratesinobserved another drug and may the reflect rates observed practice.in practice. In the randomized In the randomized clinical trialclinical in patients trial inwith patients metastatic with metastatic castration-resistant castration-resistant prostate cancer prostate withcancer with 2 DOSAGE 2 AND DOSAGE ADMINISTRATION AND ADMINISTRATION bone metastases, bone metastases, 600 patients 600received patientsintravenous received intravenous injections of injections 50 kBq/kg of 50 (1.35 kBq/kg microcurie/kg) (1.35 microcurie/kg) 2.3 Instructions 2.3 Instructions for Use/Handling for Use/Handling of Xofigo and of Xofigo best standard and bestofstandard care andof301 carepatients and 301received patientsplacebo receivedand placebo best standard and bestofstandard care of care General warning General warning once everyonce 4 weeks everyfor 4 weeks up to 6for injections. up to 6 injections. Prior to randomization, Prior to randomization, 58% and 57% 58% of and patients 57% ofhad patients had Xofigo (anXofigo alpha (an particle-emitting alpha particle-emitting pharmaceutical) pharmaceutical) should be should received, be used received, and used administered and administered received docetaxel received in docetaxel the Xofigo in the andXofigo placebo and arms, placebo respectively. arms, respectively. The medianThe duration medianofduration treatment of treatment only by authorized only by authorized persons inpersons designated in designated clinical settings. clinicalThe settings. receipt, The storage, receipt,use, storage, transfer use,and transfer was and 20 weeks was (6 20cycles) weeks for (6 cycles) Xofigo for andXofigo 18 weeks and (5 18cycles) weeks for (5 cycles) placebo. for placebo. disposal Xofigo disposal are Xofigo subjectare to the subject regulations to the regulations and/or appropriate and/or appropriate licenses oflicenses the competent of the competent official The official most common The mostadverse common reactions adverse(≥ reactions 10%) in(≥patients 10%) inreceiving patientsXofigo receiving were Xofigo nausea, were diarrhea, nausea, diarrhea, organization. organization. vomiting, and vomiting, peripheral and peripheral edema (Table edema 3). Grade (Table33). and Grade 4 adverse 3 and events 4 adverse were events reported wereamong reported 57% among 57% Xofigo should Xofigo be should handledbebyhandled the user by inthea user manner in awhich manner satisfies whichboth satisfies radiation both safety radiation andsafety and of Xofigo-treated of Xofigo-treated patients and patients 63% of andplacebo-treated 63% of placebo-treated patients. The patients. most The common most hematologic common hematologic pharmaceutical pharmaceutical quality requirements. quality requirements. Appropriate Appropriate aseptic precautions aseptic precautions should be should taken. be taken. laboratory laboratory abnormalities abnormalities in Xofigo-treated in Xofigo-treated patients (≥patients 10%) were (≥ 10%) anemia, werelymphocytopenia, anemia, lymphocytopenia, leukopenia,leukopenia, thrombocytopenia, thrombocytopenia, and neutropenia and neutropenia (Table 4). (Table 4). Radiation protection Radiation protection Treatment discontinuations discontinuations due to adverse due toevents adverse occurred events in occurred 17% ofinpatients 17% ofwho patients received who received The administration The administration of Xofigo isofassociated Xofigo is associated with potential withrisks potential to other risks persons to other(e.g., persons medical (e.g., staff, medical staff, Treatment 21% of andpatients 21% ofwho patients received whoplacebo. receivedThe placebo. most The common most hematologic common hematologic laboratorylaboratory caregivers caregivers and patient’s andhousehold patient’s household members)members) from radiation fromorradiation contamination or contamination from spillsfrom of bodily spills ofXofigo bodilyandXofigo abnormalities leading to leading discontinuation to discontinuation for Xofigofor were Xofigo anemia were(2%) anemia and (2%) thrombocytopenia and thrombocytopenia fluids suchfluids as urine, suchfeces, as urine, or vomit. feces,Therefore, or vomit. Therefore, radiation protection radiation protection precautions precautions must be taken mustinbe taken in abnormalities (2%). (2%). accordanceaccordance with national with and national local regulations. and local regulations. Table 3 shows Tableadverse 3 showsreactions adverse occurring reactions occurring in ≥ 2% ofinpatients ≥ 2% ofand patients for which and for the which incidence the for incidence for For drug handling For drug handling Xofigo exceeds Xofigo the exceeds incidence the for incidence placebo. for placebo. Follow the Follow normalthe working normalprocedures working procedures for the handling for theofhandling radiopharmaceuticals of radiopharmaceuticals and use universal and use universal Table 3: Adverse Table 3:Reactions Adverse Reactions in the Randomized in the Randomized Trial Trial precautions precautions for handling for and handling administration and administration such as gloves such as andgloves barrierand gowns barrier when gowns handling when handling blood and blood bodilyand fluids bodily to avoid fluidscontamination. to avoid contamination. In case of In contact case of with contact skin or with eyes, skinthe oraffected eyes, the affected System/Organ System/Organ Class Class Xofigo (n=600) Xofigo (n=600) Placebo (n=301) Placebo (n=301) area shouldarea be flushed should be immediately flushed immediately with water.with In the water. eventInofthe spillage event of of spillage Xofigo, the of Xofigo, local radiation the local radiation Preferred Term Preferred Term Grades 1-4Grades Grades 1-4 3-4Grades Grades 3-4 1-4Grades Grades 1-4 3-4Grades 3-4 safety officer safety should officer be contacted should be immediately contacted immediately to initiate the to initiate necessary the necessary measurements measurements and required and required % % % % % % % % proceduresprocedures to decontaminate to decontaminate the area. Athecomplexing area. A complexing agent suchagent as 0.01 suchMasethylene-diamine0.01 M ethylene-diamineBlood and Blood lymphatic and lymphatic system disorders system disorders tetraacetic tetraacetic acid (EDTA) acid solution (EDTA)issolution recommended is recommended to remove to contamination. remove contamination. Pancytopenia Pancytopenia 2 2 1 1 0 0 0 0 For patientFor carepatient care Whenever Whenever possible, patients possible,should patients useshould a toiletuse anda toilet the toilet and should the toilet be should flushedbeseveral flushed times severalGastrointestinal times Gastrointestinal disorders disorders after each after use. When each use. handling Whenbodily handling fluids, bodily simply fluids, wearing simplygloves wearing andgloves hand washing and handwill washing protectwill Nausea protect Nausea 36 36 2 2 35 35 2 2 caregivers.caregivers. Clothing soiled Clothing withsoiled Xofigowith or patient Xofigo fecal or patient matter fecal or urine matter should or urine be should washedbe promptly washed promptly Diarrhea Diarrhea 25 25 2 2 15 15 2 2 and separately and separately from otherfrom clothing. other clothing. Vomiting Vomiting 19 19 2 2 14 14 2 2 Radium-223 Radium-223 is primarilyisan primarily alpha emitter, an alpha with emitter, a 95.3% with fraction a 95.3% of fraction energy emitted of energy as emitted alpha-particles. as alpha-particles. The fraction The emitted fraction as emitted beta-particles as beta-particles is 3.6%, and is 3.6%, the fraction and the emitted fraction as emitted gamma-radiation as gamma-radiation is 1.1%. isGeneral 1.1%. disorders General and disorders administration and administration site conditions site conditions The external Theradiation externalexposure radiation associated exposure associated with handling withofhandling patient doses of patient is expected doses istoexpected be low, to be low, Peripheral Peripheral edema edema 13 13 2 2 10 10 1 1 because the because typical the treatment typical activity treatment willactivity be below will8,000 be below kBq 8,000 (216 microcurie). kBq (216 microcurie). In keeping In with keeping the with the Renal and Renal urinary and disorders urinary disorders As Low AsAs Reasonably Low As Reasonably AchievableAchievable (ALARA) principle (ALARA)for principle minimization for minimization of radiationofexposure, radiation exposure, it is it is recommended recommended to minimizetothe minimize time spent the time in radiation spent inareas, radiation to maximize areas, to the maximize distance thetodistance radiationto radiation Renal failure Renal andfailure impairment and impairment 3 3 1 1 1 1 1 1 sources, and sources, to useand adequate to useshielding. adequate Any shielding. unused Any product unused orproduct materials orused materials in connection used in connection with with LaboratoryLaboratory Abnormalities Abnormalities the preparation the preparation or administration or administration are to be treated are to be as treated radioactive as radioactive waste and waste shouldand be should disposed beofdisposed of Table 4 shows Tablehematologic 4 shows hematologic laboratory laboratory abnormalities abnormalities occurring in occurring > 10% ofinpatients > 10% ofand patients for which and for which in accordance in accordance with local regulations. with local regulations. the incidence the for incidence Xofigo for exceeds Xofigothe exceeds incidence the for incidence placebo. for placebo. The gamma Theradiation gammaassociated radiation associated with the decay with the of radium-223 decay of radium-223 and its daughters and its daughters allows for allows the for the Table 4: Hematologic Table 4: Hematologic LaboratoryLaboratory Abnormalities Abnormalities radioactivity radioactivity measurement measurement of Xofigo and of Xofigo the detection and theofdetection contamination of contamination with standard withinstruments. standard instruments. Hematologic Hematologic Xofigo (n=600) Xofigo (n=600) Placebo (n=301) Placebo (n=301) 4 CONTRAINDICATIONS 4 CONTRAINDICATIONS LaboratoryLaboratory Xofigo is contraindicated Xofigo is contraindicated in pregnancy. in pregnancy. Grades 1-4GradesGrades 1-4 3-4Grades Grades 3-4 1-4GradesGrades 1-4 3-4Grades 3-4 % % % % % % % % Xofigo canXofigo cause can fetalcause harm fetal whenharm administered when administered to a pregnant to awoman pregnant based woman on its based mechanism on its mechanism of Abnormalities of Abnormalities action. Xofigo action. is not Xofigo indicated is notfor indicated use in for women. use inXofigo women. is contraindicated Xofigo is contraindicated in women in who women are orwhoAnemia are or Anemia 93 93 6 6 88 88 6 6 may become maypregnant. become Ifpregnant. this drugIf isthis used drug during is used pregnancy, during pregnancy, or if the patient or if the becomes patient pregnant becomes pregnant Lymphocytopenia Lymphocytopenia 72 72 20 20 53 53 7 7 while taking while thistaking drug, apprise this drug, theapprise patientthe of the patient potential of thehazard potential to the hazard fetusto[see the fetus Use in[see Specific Use in Specific Leukopenia Leukopenia 35 35 3 3 10 10 <1 <1 Populations Populations (8.1)]. (8.1)]. Thrombocytopenia Thrombocytopenia 31 31 3 3 22 22 <1 <1 5 WARNINGS 5 WARNINGS AND PRECAUTIONS AND PRECAUTIONS Neutropenia Neutropenia 18 18 2 2 5 5 <1 <1 5.1 Bone5.1 Marrow BoneSuppression Marrow Suppression Laboratory values were values obtained wereatobtained baselineatand baseline prior to and each prior 4-week to each cycle. 4-week cycle. In the randomized In the randomized trial, 2% oftrial, patients 2% ofonpatients the Xofigo on the armXofigo experienced arm experienced bone marrow bonefailure marrow or failure or Laboratory ongoing pancytopenia ongoing pancytopenia compared compared to no patients to no treated patients withtreated placebo. withThere placebo. wereThere two deaths were two duedeaths to Asdue an to adverse As an reaction, adversegrade reaction, 3-4 thrombocytopenia grade 3-4 thrombocytopenia was reported wasinreported 6% of patients in 6% of onpatients Xofigo and on Xofigo and bone marrow bone failure marrow andfailure for 7 ofand 13for patients 7 of 13 treated patients with treated Xofigo, with bone Xofigo, marrow bone failure marrow wasfailure ongoing was ongoing in 2% of patients in 2% ofonpatients placebo. onAmong placebo. patients Amongwho patients received whoXofigo, received theXofigo, laboratory the laboratory abnormality abnormality at the timeatofthe death. timeAmong of death. theAmong 13 patients the 13who patients experienced who experienced bone marrow bonefailure, marrow 54% failure, required 54% required grade 3-4 thrombocytopenia grade 3-4 thrombocytopenia occurred inoccurred 1% of docetaxel in 1% of naïve docetaxel patients naïve and patients in 4% and of patients in 4% of who patients who blood transfusions. blood transfusions. Four percent Four (4%) percent of patients (4%) ofonpatients the Xofigo on the armXofigo and 2% armonand the2% placebo on thearm placebo had arm received hadprior received docetaxel. prior docetaxel. Grade 3-4 neutropenia Grade 3-4 neutropenia occurred inoccurred 1% of docetaxel in 1% ofnaïve docetaxel patients naïve and patients and permanently permanently discontinued discontinued therapy due therapy to bone due marrow to bone suppression. marrow suppression. in 3% of patients in 3% ofwho patients have received who haveprior received docetaxel. prior docetaxel. In the randomized In the randomized trial, deathstrial, related deaths to vascular related to hemorrhage vascular hemorrhage in association in association with myelosuppression with myelosuppression Fluid Status Fluid Status were observed wereinobserved 1% of Xofigo-treated in 1% of Xofigo-treated patients compared patients compared to 0.3% ofto patients 0.3% of treated patients withtreated placebo. with placebo. Dehydration Dehydration occurred inoccurred 3% of patients in 3% of onpatients Xofigo and on Xofigo 1% of and patients 1% of onpatients placebo.onXofigo placebo. increases Xofigo increases The incidence The of incidence infection-related of infection-related deaths (2%), deaths serious (2%), infections serious infections (10%), and(10%), febrileand neutropenia febrile neutropenia adverse reactions adversesuch reactions as diarrhea, such asnausea, diarrhea, and nausea, vomiting andwhich vomiting maywhich resultmay in dehydration. result in dehydration. Monitor Monitor (<1%) were (<1%) similar were forsimilar patients fortreated patientswith treated Xofigo with andXofigo placebo. and Myelosuppression; placebo. Myelosuppression; notably patients’ notably oral patients’ intakeoral andintake fluid status and fluid carefully statusand carefully promptly and treat promptly patients treatwho patients display who signs display or signs or thrombocytopenia, thrombocytopenia, neutropenia, neutropenia, pancytopenia, pancytopenia, and leukopenia; and leukopenia; has been has reported been inreported patientsin patients symptomssymptoms of dehydration of dehydration or hypovolemia. or hypovolemia. treated with treated Xofigo. with In Xofigo. the randomized In the randomized trial, complete trial,blood complete counts blood (CBCs) counts were (CBCs) obtained wereevery obtained 4 every 4 Injection Site Injection Reactions Site Reactions weeks prior weeks to each prior dose to each and the dose nadir andCBCs the nadir and CBCs times and of recovery times ofwere recovery not well werecharacterized. not well characterized. Erythema, Erythema, pain, and edema pain, and at the edema injection at thesite injection were reported site wereinreported 1% of patients in 1% ofonpatients Xofigo.on Xofigo. In a separate In asingle-dose separate single-dose phase 1 study phase of 1Xofigo, study of neutrophil Xofigo, neutrophil and plateletand count platelet nadirs count occurred nadirs occurred 2 to 3 weeks 2 toafter 3 weeks Xofigo after administration Xofigo administration at doses that at doses were up thattowere 1 to up 5 times to 1 to the5 recommended times the recommended SecondarySecondary Malignant Malignant NeoplasmsNeoplasms dose, and dose, most patients and mostrecovered patients recovered approximately approximately 6 to 8 weeks 6 toafter 8 weeks administration after administration [see Adverse [see Adverse Xofigo contributes Xofigo contributes to a patient’s to aoverall patient’s long-term overall long-term cumulativecumulative radiation exposure. radiation exposure. Long-termLong-term Reactions Reactions (6)]. (6)]. cumulativecumulative radiation exposure radiation may exposure be associated may be associated with an increased with an risk increased of cancer riskand of cancer hereditary and hereditary Hematologic Hematologic evaluationevaluation of patientsofmust patients be performed must be performed at baselineatand baseline prior and to every priordose to every of dose of Due defects. defects. to itsDue mechanism to its mechanism of action of andaction neoplastic and neoplastic changes, including changes, including osteosarcomas, osteosarcomas, Xofigo. Before Xofigo. theBefore first administration the first administration of Xofigo, of theXofigo, absolute theneutrophil absolute neutrophil count (ANC) count should (ANC) be should be following in rats in rats following administration administration of radium-223 of radium-223 dichloride,dichloride, Xofigo may Xofigo increase may the increase risk ofthe risk of 9 9 ≥ 1.5 x 10≥9/L, 1.5the x 10 platelet /L, the count platelet ≥ 100 count x 10≥9/L 100 and x 10 hemoglobin /L and hemoglobin ≥ 10 g/dL.≥Before 10 g/dL. subsequent Before subsequent osteosarcoma osteosarcoma or other secondary or other secondary malignant malignant neoplasmsneoplasms [see Nonclinical [see Nonclinical ToxicologyToxicology (13.1)]. (13.1)]. 9 9 9 9 administrations administrations of Xofigo, of theXofigo, ANC should the ANC be should ≥ 1 x 10 be/L≥ and 1 x 10 the/L platelet and the count platelet ≥ 50count x 10 ≥/L.50If x 10 /L. If the However, However, overallthe incidence overall incidence of new malignancies of new malignancies in the randomized in the randomized trial was lower trial was on the lower on the there is nothere recovery is notorecovery these values to these within values 6 towithin 8 weeks 6 toafter 8 weeks the last after administration the last administration of Xofigo, of Xofigo Xofigo,armXofigo compared arm compared to placeboto(<1% placebo vs. 2%; (<1%respectively), vs. 2%; respectively), but the expected but the latency expected period latency period despite receiving despitesupportive receiving supportive care, further care, treatment further with treatment Xofigowith should Xofigo be should discontinued. be discontinued. Patients Patients for the development for the development of secondary of secondary malignancies malignancies exceeds the exceeds duration theofduration follow up of follow for patients up for patients with evidence withofevidence compromised of compromised bone marrow bonereserve marrow should reserve be should monitored be monitored closely andclosely provided and provided on the trial.on the trial. with supportive with supportive care measures care measures when clinically when indicated. clinically indicated. Discontinue Discontinue Xofigo in Xofigo patientsinwho patients who Subsequent Subsequent Treatment Treatment with Cytotoxic with Chemotherapy Cytotoxic Chemotherapy experienceexperience life-threatening life-threatening complications complications despite supportive despite supportive care for bone caremarrow for bonefailure. marrow failure. The safety and The efficacy safety and of concomitant efficacy of concomitant chemotherapy chemotherapy with Xofigowith haveXofigo not been haveestablished. not been established. Outside In Outside the randomized In the randomized clinical trial, clinical 16% trial, patients 16%inpatients the Xofigo in the group Xofigo and group 18% patients and 18%inpatients the placebo in the placebo of a clinicaloftrial, a clinical concomitant trial, concomitant use with chemotherapy use with chemotherapy is not recommended is not recommended due to the due potential to thefor potential groupforreceived groupcytotoxic received chemotherapy cytotoxic chemotherapy after completion after completion of study treatments. of study treatments. Adequate safety Adequate safety additive myelosuppression. additive myelosuppression. If chemotherapy, If chemotherapy, other systemic otherradioisotopes systemic radioisotopes or hemibody or hemibody external external monitoringmonitoring and laboratory and laboratory testing wastesting not performed was not performed to assess how to assess patients howtreated patients with treated Xofigowith Xofigo radiotherapy radiotherapy are administered are administered during the during treatment the period, treatment Xofigo period, should Xofigo be should discontinued. be discontinued.will toleratewill subsequent tolerate subsequent cytotoxic chemotherapy. cytotoxic chemotherapy.

10 OVERDOSAGE 10 OVERDOSAGE 7 DRUG 7 INTERACTIONS DRUG INTERACTIONS There haveThere been have no reports been no of reports inadvertent of inadvertent overdosingoverdosing of XoďŹ go during of XoďŹ go clinical during studies. clinical studies. No formal No clinical formal drug clinical interaction drug interaction studies have studies been have performed. been performed. There is no There speciďŹ c is noantidote. speciďŹ cInantidote. the event In of theanevent inadvertent of an inadvertent overdose of overdose XoďŹ go, of utilize XoďŹ go, general utilize general 3UBGROUPÂŹ3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ ANALYSESÂŹTHATÂŹ INDICATEDÂŹ THEÂŹ CONCURRENTÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹORÂŹCHANNELÂŹ CALCIUMÂŹ CHANNELÂŹ supportivesupportive measures,measures, including including monitoringmonitoring for potential for hematological potential hematological and gastrointestinal and gastrointestinal blockers did blockers not affect did the notsafety affect and the safety efďŹ cacy and of efďŹ cacy XoďŹ go inofthe XoďŹ go randomized in the randomized clinical trial. clinical trial. toxicity, and toxicity, consider and using consider medical usingcountermeasures medical countermeasures such as aluminum such as aluminum hydroxide,hydroxide, barium barium 8 USE 8IN SPECIFIC USE IN POPULATIONS SPECIFIC POPULATIONS 1 sulfate, calcium sulfate, carbonate, calcium carbonate, calcium gluconate, calcium gluconate, calcium phosphate, calcium phosphate, or sodium or alginate. sodium alginate.1 8.1 Pregnancy 8.1 Pregnancy Category XCategory [see Contraindications X [see Contraindications (4)] (4)] 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ XoďŹ go canXoďŹ go cause can fetalcause harm fetal whenharm administered when administered to a pregnant to a woman pregnant based woman on its based mechanism on its mechanism 1 clinical trial 1 clinical and notrial dose-limiting and no dose-limiting toxicities were toxicities observed. were observed. of action. While of action. thereWhile are no there human are no or animal human data or animal on thedata useon of the XoďŹ go useinofpregnancy XoďŹ go in pregnancy and XoďŹ goand XoďŹ go 13 NONCLINICAL TOXICOLOGY TOXICOLOGY is not indicated is not for indicated use in for women, use inmaternal women,use maternal of a radioactive use of a radioactive therapeutictherapeutic agent could agent affect could13affectNONCLINICAL 13.1 Carcinogenesis, 13.1 Carcinogenesis, Mutagenesis, Mutagenesis, Impairment Impairment of Fertilityof Fertility development development of a fetus.ofXoďŹ go a fetus. is contraindicated XoďŹ go is contraindicated in women inwho women are orwho mayare become or maypregnant become pregnant while receiving whilethe receiving drug. Ifthe thisdrug. drugIfisthis used drug during is used pregnancy, during pregnancy, or if the patient or if the becomes patientpregnant becomes pregnant Animal studies Animal have studies not been have conducted not been conducted to evaluatetothe evaluate carcinogenic the carcinogenic potential ofpotential radium-223 of radium-223 while taking while thistaking drug, apprise this drug, theapprise patientthe of the patient potential of thehazard potential to the hazard fetustoand thethe fetus potential and therisk potential risk dichloride. dichloride. However, in However, repeat-dose in repeat-dose toxicity studies toxicityin studies rats, osteosarcomas, in rats, osteosarcomas, a known effect a known of effect of for pregnancy for pregnancy loss. Advise loss. females Adviseoffemales reproductive of reproductive potential topotential avoid becoming to avoid becoming pregnant during pregnant bone-seeking during bone-seeking radionuclides, radionuclides, were observed were at observed clinicallyatrelevant clinicallydoses relevant 7 todoses 12 months 7 to 12after months the after the treatment with treatment XoďŹ go. with XoďŹ go. start of treatment. start of treatment. The presence Theofpresence other neoplastic of other neoplastic changes, including changes,lymphoma including lymphoma and mammary and mammary gland carcinoma, gland carcinoma, was also reported was alsoinreported 12- to 15-month in 12- to 15-month repeat-dose repeat-dose toxicity studies toxicity in rats. studies in rats. 8.3 Nursing 8.3 Mothers Nursing Mothers Genetic toxicology Genetic toxicology studies have studies not been have conducted not been conducted with radium-223 with radium-223 dichloride.dichloride. However, the However, the XoďŹ go is not XoďŹ go indicated is not for indicated use infor women. use inItwomen. is not known It is not whether knownradium-223 whether radium-223 dichloride dichloride is is mechanismmechanism of action ofofradium-223 action of radium-223 dichloride dichloride involves induction involves of induction double-strand of double-strand DNA breaks, DNA breaks, excreted inexcreted human milk. in human Because milk.many Because drugs many are excreted drugs areinexcreted human milk, in human and because milk, andofbecause potentialof potential which is a which knowniseffect a known of radiation. effect of radiation. for seriousfor adverse seriousreactions adverse inreactions nursing in infants nursing from infants XoďŹ go, from a decision XoďŹ go, ashould decision be should made whether be made whether Animal Animal have studies not been haveconducted not been conducted to evaluatetothe evaluate effectsthe of radium-223 effects of radium-223 dichloride dichloride on male on male to discontinue to discontinue nursing, ornursing, discontinue or discontinue the drug taking the drug intotaking account intotheaccount importance the importance of the drugoftothe drug to studies or female fertility or female or reproductive fertility or reproductive function. XoďŹ go function. mayXoďŹ go impairmay fertility impair andfertility reproductive and reproductive function infunction in the mother.the mother. humans based humans on its based mechanism on its mechanism of action. of action. 8.4 Pediatric 8.4 Use Pediatric Use 17 PATIENT 17 COUNSELING PATIENT COUNSELING INFORMATION INFORMATION The safety The and safety efďŹ cacy and of efďŹ cacy XoďŹ go inofpediatric XoďŹ go inpatients pediatrichave patients not been haveestablished. not been established. 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Based (12.3)]. on Based on completioncompletion of XoďŹ go treatment. of XoďŹ go treatment. subgroup analyses subgroupinanalyses the randomized in the randomized clinical trial, clinical dose trial, adjustment dose adjustment is not needed is not in patients needed inwith patients with mild hepatic mild impairment. hepatic impairment. No dose adjustments No dose adjustments can be recommended can be recommended for patientsforwith patients moderate with moderate or severe hepatic or severe impairment hepatic impairment due to lackdue of clinical to lack data. of clinical data.

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Bayer HealthCare Bayer HealthCare Pharmaceuticals Pharmaceuticals Inc. Inc. 8.8 Males 8.8of Reproductive Males of Reproductive Potential Potential Wayne, NJWayne, 07470 NJ 07470 Contraception Contraception Manufactured in Norway in Norway Because ofBecause potentialofeffects potential on effects spermatogenesis on spermatogenesis associatedassociated with radiation, with advise radiation, menadvise who are men who are Manufactured sexually active sexually to use active condoms to use and condoms their female and their partners femaleofpartners reproductive of reproductive potential topotential use a highly to use aXoďŹ go highly is aXoďŹ go trademark is a trademark of Bayer Aktiengesellschaft. of Bayer Aktiengesellschaft. effective contraceptive effective contraceptive method during method andduring for 6 months and for after 6 months completing after completing treatment with treatment XoďŹ go. with XoďŹ go. ÂŠ 2013, Bayer ÂŠ 2013, HealthCare Bayer HealthCare Pharmaceuticals Pharmaceuticals Inc. Inc. All rights reserved. All rights reserved. Infertility Infertility Revised: 05/2013 Revised: 05/2013 There are no There dataare onno thedata effects on the of XoďŹ go effectson of human XoďŹ go on fertility. human There fertility. is a potential There is arisk potential that radiation risk that radiation by XoďŹ go could by XoďŹ go impair could human impair fertility human [see fertility Nonclinical [see Nonclinical ToxicologyToxicology (13.1)]. (13.1)]. "3 "3

The ASCO Post | OCTOBER 15, 2013

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Best of ASCO® Colorectal Cancer Studies continued from page 33

Nonchemotherapy Doublet The DREAM Trial (OPTIMOX III), involving 452 metastatic patients, showed that the addition of erlotinib to bevacizumab—a nonchemotherapy doublet—following induction therapy significantly increases progression-free survival over maintenance with bevacizumab alone, and resulted in a median overall survival time of 25 months.5 It also showed that, in contrast to treatment with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), benefit from erlotinib is not governed by KRAS tumor status. Interestingly, the benefit of the combination was mainly observed in patients with KRAS-mutated tumors. The study randomized patients with one of the two maintenance arms after induction therapy with a bevacizumab-based regimen. Patients received single-agent bevacizumab 7.5 mg/kg every 3 weeks or bevacizumab plus erlotininb 150 mg/d. Median progression-free survival from the time of maintenance initiation was 5.9 months with the combination

vs 4.8 months with the single agent (HR = 0.76; P = .0096). Interestingly, the treatments conveyed similar benefits regardless of KRAS status, however, patients with KRAS-mutated tumors had longer progression-free survival than wildtype patients (nearly 10 months, vs 6 months), “which is contrary to what we would expect,” he said. The combination was slightly more toxic, especially for skin toxicity (grade 3/4 in 20%) and diarrhea (grade 3/4 in 9%). Dr. Reid commented that the doublet allows patients to continue treatment “off chemotherapy” and “hopefully to tolerate second-line therapy

better,” but the comparator of bevacizumab alone is not typical of clinical practice.” He suggested, “A more appropriate arm might have been bevacizumab plus 5-FU or capecitabine. However, the findings support the notion that maintenance therapy with this nonchemotherapy doublet could be of benefit.” n

Disclosure: Dr. Reid is a consultant for Genentech, Bristol-Myers Squibb, and Novartis.

References 1. Primrose JN, Falk S, Finch-Jones M et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type

Key Findings From Metastatic Colorectal Cancer Trials ■■ EPOCH Trial: In operable patients, cetuximab should not be added to presurgical chemotherapy.

■■ FIRE 3 Trial: In KRAS wild-type patients, bevacizumab and cetuximab added to FOLFIRI convey similar benefit in progression-free survival. Bevacizumab given beyond progression may be effective.

■■ TRIBE Trial: The optimal first-line chemotherapy backbone for

bevacizumab may be FOLFOXIRI, which was superior to FOLFIRI in progression-free and overall survival.

■■ CAIRO 2 Trial: For maintenance therapy, capecitabine plus bevacizumab

is superior to observation, and bevacizumab plus cetuximab is superior to bevacizumab alone.

patients with operable metastases from colorectal cancer: The new EPOC study. 2013 ASCO Annual Meeting. Abstract 3504. Presented June 1, 2013. 2. Heinemann V, von Weikersthal LF, Decker T et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013. 3. Falcone A, Cremolini C, Masi G et al. FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer patients: results of the phase III TRIBE trial by GONO group. 2013 ASCO Annual Meeting. Abstract 3505. Presented June 1, 2013. 4. Koopman M, Simkens LHJ, Tije AJT et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer: The phase III CAIRO3 study of the Dutch Colorectal Cancer Group. 2013 ASCO Annual Meeting. Abstract 3502. Presented June 1, 2013. 5. Tournigand C, Chibaudel B, Samson B et al. Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer according to KRAS: Results of the GERCOR DREAM phase III trial. 2013 ASCO Annual Meeting. Abstract 3515. Presented June 4, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Derek Raghavan, MD, PhD, on Value in Cancer Care see page 1

George Sledge, MD, and Monica Morrow, MD, on Breast Cancer Management see page 3

Christiane K. Kuhl, MD, on MRI in Breast Cancer Screening see page 16

Tony Reid, MD, PhD, on Metastatic Colorectal Cancer see page 33

Gary Lyman, MD, on Comparative Effectiveness Research see page 69

Brian Rini, MD, on Metastatic Renal Cell Carcinoma see page 82

Bruce Chabner, MD, on Cancer Care in Botswana see page 90

Chris Parker, MD, on Radium-223 in Metastatic Prostate Cancer see page 94

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | OCTOBER 15, 2013

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Best of ASCO® Gynecologic Oncology

Challenging and Changing the Standard of Care for Cervical and Ovarian Cancers By Charlotte Bath

“I

t was a very exciting session this year, particularly for cervical cancers,” said Paul Haluska MD, PhD, of the Mayo Clinic, Rochester, Minnesota, in speaking of the 2013 ASCO Annual Meeting’s gynecologic oncology session and the abstracts highlighted recently at Best of ASCO in Chicago. In one study in recurrent cervical cancer, the addition of bevacizumab (Avastin) to chemotherapy has changed the standard of care,1 and, in another study, the results reportedly have “global implications” that could help avoid 22,000 cervical cancer deaths per year in India and over 72,000 deaths from cervical cancer annually in resource-poor countries.2 Dr. Haluska also discussed a number of studies in ovarian cancer from the Annual Meeting and presented subsequently at Best of ASCO.3-6

Improved Outcomes in Advanced Cervical Cancer Adding bevacizumab (Avastin) to chemotherapy improved outcomes for women with persistent, metastatic, or recurrent cervical cancer treated in a randomized phase III study, and for those with recurrent disease, the improvements were great enough to warrant a change in the standard of care, according to Dr. Haluska. The 452 patients participating in the four-armed Gynecologic Oncology Group (GOG 240) clinical trial were randomly assigned to treatment with a chemotherapy-alone regimen or to chemotherapy plus bevacizumab at 15 mg/kg. The two chemotherapy

regimens tested included (1) cisplatin at 50 mg/m2 plus paclitaxel at 135 to 175 mg/m2 and (2) topotecan at 0.75 mg/m2 on days 1 to 3, plus paclitaxel at 175 mg/m2 on day 1. “The rationale for the non–platinum-containing regimen is that many patients have previously been treated with a platinum,” Dr. Halus-

improvement in overall survival,” Dr. Haluska said. Median overall survival was 17.0 months for those in the bevacizumab/chemotherapy arms vs 13.3 months for those receiving chemotherapy only. “If we look at the progression-free survival, this was also statistically significant and improved by addition of bevacizumab, from 5.9 to

We have learned a lot about the role of PARP inhibitors and who may be the best patients in ovarian cancer to receive these therapies. —Paul Haluska MD, PhD

whether it will be approved for use in this setting is not presently clear.

Global Implications of Cervical Cancer Screening Study Referring to a study showing that cervical cancer mortality was reduced by 31% among women in India screened with biennial visual inspection with acetic acid or vinegar, Dr. Haluska commented, “While this may have little impact on U.S. care, the global implications are enormous.” An estimated 22,000 lives per year could be saved in India alone and the worldwide benefit could reach 250,000 lives saved per year. “Importantly, the results were not due to overdiagnosis,” Dr. Haluska said, but “clearly the identification of premalignant lesions.”

Maintenance Therapy for Ovarian Cancer ka explained, since chemoradiation with platinum is the standard of care for front-line treatment of locally advanced cervical cancer. “So the question is, after patients have received a platinum, is a non–platinum-containing regimen better? We know that there is activity with topotecan in combination with paclitaxel, which is the justification for these additional arms.” Little progress has been made over the past 30 years in treating advanced cervical cancer. This coupled with additional data led investigators to conduct this study. They reported no significant differences in survival between the two chemotherapy arms, but the addition of bevacizumab to a chemotherapy regimen “led to a statistically significant and substantial

Paul Haluska, MD, on Standards of Care in Cervical and Ovarian Cancers ■■ For patients with locally advanced cervical cancer, chemoradiation is still the standard of care.

■■ For patients with recurrent or persistent cervical cancer, paclitaxel/cisplatin plus bevacizumab represents a new standard of care.

■■ BRCA-mutated epithelial ovarian cancers are very sensitive to PARP

inhibition. Olaparib, a PARP inhibitor, may exert its greatest benefit in the population of patients with BRCA-mutated ovarian cancer.

■■ For patients with newly diagnosed ovarian cancer, upfront surgical debulking followed by chemotherapy is still the standard of care.

8.2 months,” said Dr. Haluska. Adverse events were similar to those seen in other patients receiving bevacizumab, including hypertension, neutropenia, thromboembolisms, and gastrointestinal perforations.

Standards of Care Vary by Disease Setting Dr. Haluska acknowledged that chemoradiation remains the standard of care for locally advanced disease. Further, the study suggested that patients with metastatic disease did not benefit as much by the addition of bevacizumab to chemotherapy as patients who had previously been treated for locally advanced disease. In the setting of recurrent disease, however, Dr. Haluska said bevacizu mab/chemotherapy should be the standard of care. “I think the results speak for themselves,” Dr. Haluska said, and “the addition of bevacizumab to chemotherapy yielded statistically significant improvement in progression-free and overall survival rates [in patients with recurrent disease] with no significant effect on quality of life.” Adverse events with the addition of bevacizumab were expected and mostly manageable, according to study investigators. Dr. Haluska added that bevacizumab as of yet “has no formal labeled indication” for cervical cancer and

Maintenance therapy for patients with ovarian cancer was tested in two trials, one with the multi-kinase inhibitor pazopanib (Votrient) and the other with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Among 940 patients who had not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers, those randomized to maintenance therapy with pazopanib for 24 months had a median progression-free survival of 17.9 months vs 12.3 months for those receiving placebo. This difference of 5.6 months was statistically significant, Dr. Haluska reported. “However, overall survival at the first analysis was not statistically significant,” he noted. “So one has to be concerned that in the end, we will not see an overall survival benefit with pazopanib despite the improvement in progression-free survival.” Pazopanib therapy was “fairly toxic,” Dr. Haluska said, and “this led to a substantial reduction in the dosing of patients after the first cycle.” Side effects included hypertension, neutropenia, some liver toxicities, hand/foot syndrome, and headache. While patients could have received chemotherapy prior to the trial, those who had received any anti-VEGF therapy, including bevacizumab, were excluded from this trial. “I think that was continued on page 40

The ASCO Post | OCTOBER 15, 2013

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Best of ASCO® Cervical and Ovarian Cancers continued from page 39

a mistake, as patients who may have gone into remission with a VEGF-targeted therapy may have been the best patients to receive this therapy. Perhaps they would have the most to gain from pazopanib. Yet we don’t know how well they would have performed with pazopanib because they were not included in the study.” Dr. Haluska observed that there were parallels between this study with pazopanib and the use of paclitaxel as maintenance therapy. The paclitaxel studies had shown about a 7-month improvement in progression-free survival, but there was no overall survival improvement, and there was toxicity, particularly the possibility of fairly severe neuropathy in about 25% of patients. “My sense is that most physicians in practice are not using paclitaxel as maintenance chemotherapy after remission,” Dr. Haluska said, and “given this data, it is unlikely that pazopanib will be accepted or approved as a maintenance therapy, particularly without any overall survival benefit.”

Relapsed Ovarian Cancer “We have learned a lot about the role of PARP inhibitors and who may be the best patients in ovarian cancer to receive these therapies,” Dr. Haluska noted. In particular, tumors with homologous recombination repair deficiency “may be most sensitive to PARP inhibition because of their inefficiency at repairing single-strand DNA breaks, leading to cell death. And BRCA1 and BRCA2 mutant tumors are probably the reference gene mutation for demonstrating this,” Dr. Haluska continued. “BRCA-mutated epithelial cancers are very sensitive to PARP inhibition, although these only represent about 10% to 15% of epithelial ovarian cancers.” Other data, however, indicate the percentage of high-grade serous ovarian cancers sensitive to PARP inhibition could be as high as 50%, according to Dr. Haluska. A previously reported study among women with platinum-sensitive relapsed serous ovarian cancer found that maintenance therapy with olaparib led to significant improvement in progression-free survival. In addition, a preplanned analysis suggested that progression-free survival might be greater, and there might be an overall survival benefit as well, in patients with a known germline BRCA mutation. BRCA mu-

tation was not a requirement for the study and at baseline only about 36% of patients had a known BRCA mutation, “but given this data on the role of BRCA mutations and response to PARP inhibitors, the investigators went back and identified, as best they could, the number of patients that had a germline BRCA mutation and a tumor mutation

BRCA,” Dr. Haluska explained. “They identified a large number of mutations in the tumor as well as germline mutations,” he said. Out of a total of 265 patients in the original study, 136 had a mutation either in the tumor or at the germline level for BRCA. Among these patients, “there was a fairly impressive improve-

ment in progression-free survival” for those who had received olaparib, 11.2 months vs 4.3 months for those receiving placebo. The hazard ratio was .35 for all patients, but this improved to .18 for patients with mutations in BRCA either in the tumor or at the germline level. “This was highly statistically significant,” Dr. Haluska said.

Tumor lines of defense merit closer examination

References: 1. Batist G, Wu JH, Spatz A, et al. Resistance to cancer treatment: the role of somatic genetic events and the challenges for targeted therapies. Front Pharmacol. 2011;2:59. doi:10.3389/fphar.2011.00059. 2. Verheul HMW, Pinedo HM. Clinical implications of drug resistance. In: Pinedo HM, Giaccone G, eds. Drug Resistance in the Treatment of Cancer. Cambridge, United Kingdom: Cambridge University Press; 1998:199-231. In: Sikora K, ed. Cancer: Clinical Science in Practice. 3. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615-627. 4. Morin PJ. Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat. 2003;6(4):169-172. 5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. 6. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26(9):1324-1337. 7. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature. 2004;432(7015):307-315. 8. Evan G, Littlewood T. A matter of life and cell death. Science. 1998;281(5381):1317-1322. 9. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest. 2008;118(6):1979-1990. 10. Zoubeidi A, Gleave M. Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol. 2012;44(10):1646-1656. 11. So A, Hadaschik B, Sowery R, Gleave M. The role of stress proteins in prostate cancer. Curr Genomics. 2007;8(4):252-261. 12. Jäättelä M, Wissing D. Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection. J Exp Med. 1993;177(1):231-236. 13. Wilson MR, Easterbrook-Smith SB. Clusterin is a secreted mammalian chaperone. Trends Biochem Sci. 2000;25(3):95-98. 14. Gleave M, Miyake H, Zangemeister-Wittke U, Jansen B. Antisense therapy: current status in prostate cancer and other malignancies. Cancer Metastasis Rev. 2002;21(1):79-92. 15. Kaufmann SH, Vaux DL. Alterations in the apoptotic machinery and their potential role in anticancer drug resistance. Oncogene. 2003;22(47):7414-7430. 16. Zoubeidi A, Ettinger S, Beraldi E, et al. Clusterin facilitates COMMD1 and I-κB degradation to enhance NF-κB activity in prostate cancer cells. Mol Cancer Res. 2010;8(1):119-130. 17. Sensibar JA, Sutkowski DM, Raffo A, et al. Prevention of cell death induced by tumor necrosis factor α in LNCaP cells by overexpression of sulfated glycoprotein-2 (clusterin). Cancer Res. 1995;55(11):2431-2437. 18. Hassan MK, Watari H, Han Y, et al. Clusterin is a potential molecular predictor for ovarian cancer patient’s survival: targeting clusterin improves response to paclitaxel. J Exp Clin Cancer Res. 2011;30:113. 19. July LV, Beraldi E, So A, et al. Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther. 2004;3(3):223-232. 20. Miyake H, Nelson C, Rennie PS, Gleave ME. Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer Res. 2000;60(1):170-176.

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Best of ASCO® Overall survival in the total patient population was 29.8 months for those receiving olaparib vs 27.8 months for those receiving placebo, with a hazard ratio of 0.88. In the subset of patients with BRCA mutations, “the hazard ratio was a bit better—0.74, or 34.9 vs 31.9 months—but still was not statistically significant as far as overall survival,” Dr. Haluska said.

“Importantly, there is no difference in quality of life in patients receiving olaparib. It is a very tolerable agent,” Dr. Haluska said. “There were no major problems with delivering this therapy in this population. But its benefit may be greatest in the BRCA-mutated population, and we anxiously await the overall survival data to be updated.”

Chemotherapy Schedule in Advanced Ovarian Cancer The MITO 7 trial5 compared conventional chemotherapy with paclitaxel and carboplatin vs a weekly regimen for 822 women with advanced ovarian cancer. Both study arms performed well and there were no statistically significant differences

Cytoprotective proteins and the evasion of apoptosis

Clusterin may promote cancer resistance in multiple ways

Resistance is a fundamental challenge in all forms of cancer and at all stages of disease.1 Its primary clinical manifestation is tumor progression.2 Resistance may result from changes in the tumor microenvironment, genetic factors, or cellular mechanics.3,4 In almost 50% of cases, intrinsic resistance is present before treatment begins, and resistance will be acquired in a large number of the remaining cases.2

Research suggests that stress-induced clusterin contributes to cancer’s ability to resist apoptosis by:

Avoiding apoptosis is a fundamental biologic capability acquired by cancer to enable its growth, survival, and resistance.5-9 Mechanisms such as upregulation of cytoprotective proteins, including HSP27, HSP70, and HSP90, have evolved to protect cells against environmental stress.3,10-12 Clusterin, possibly the first identified secreted chaperone protein, is one such molecule.13 While secretory clusterin is involved in many normal biologic processes, its overexpression has been implicated in a wide variety of cancers.10,14 It is thought that clusterin contributes to both cancer cell survival and resistance by disrupting important cell death pathways, thus protecting the cancer cell from apoptosis.5-10,15-21

• Inhibiting proapoptotic signaling through interaction with surface proteins (eg, receptors) on stressed cells10,22,23 • Inhibiting the proapoptotic protein Bax to prevent its activation of the intrinsic pathway through the mitochondria24 • Promoting cell survival by enhancing activity of NF-κB transcriptional activity16 • Inhibiting endoplasmic reticulum stress and the aggregation of proteins to maintain protein homeostasis and prevent apoptosis10,22,25-27 In studies, clusterin expression has also been notably associated with poor prognosis, advanced stage of cancer, higher tumor grade, and invasion and metastasis.18,20,28-35

Join us on the journey at exploremerit.com Teva Oncology is committed to exploring the latest insights into tumor dynamics and resistance.

21. Hoeller C, Pratscher B, Thallinger C, et al. Clusterin regulates drug-resistance in melanoma cells. J Invest Dermatol. 2005;124(6):1300-1307. 22. Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res. 2010;16(4):1088-1093. 23. Carver JA, Rekas A, Thorn DC, Wilson MR. Small heat-shock proteins and clusterin: intra- and extracellular molecular chaperones with a common mechanism of action and function? IUBMB Life. 2003;55(12):661-668. 24. Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005;7(9):909-915. 25. Poon S, Easterbrook-Smith SB, Rybchyn MS, Carver JA, Wilson MR. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000;39(51):15953-15960. 26. Nizard P, Tetley S, Le Dréan Y, et al. Stress-induced retrotranslocation of clusterin/ApoJ into the cytosol. Traffic. 2007;8(5):554-565. 27. Li N, Zoubeidi A, Beraldi E, Gleave ME. GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer [published online ahead of print June 11, 2012]. Oncogene. doi:10.1038/onc.2012.212. 28. Miyake H, Gleave M, Kamidono S, Hara I. Overexpression of clusterin in transitional cell carcinoma of the bladder is related to disease progression and recurrence. Urology. 2002;59(1):150-154. 29. Redondo M, Villar E, Torres-Muñoz J, Tellez T, Morell M, Petito CK. Overexpression of clusterin in human breast carcinoma. Am J Pathol. 2000;157(2):393-399. 30. Hazzaa SM, Elashry OM, Afifi IK. Clusterin as a diagnostic and prognostic marker for transitional cell carcinoma of the bladder. Pathol Oncol Res. 2010;16(1):101-109. 31. Ekici S, Eroglu A, Dogan Ekici AI, Türkeri L. Clusterin immunoreactivity as a predictive factor for progression of non-muscle-invasive bladder carcinoma. Urol Int. 2011;86(1):31-35. 32. Pucci S, Bonanno E, Pichiorri F, Angeloni C, Spagnoli LG. Modulation of different clusterin isoforms in human colon tumorigenesis. Oncogene. 2004;23(13):2298-2304. 33. Shannan B, Seifert M, Leskov K, et al. Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 2006;13(1):12-19. 34. Yang GF, Li XM, Xie D. Overexpression of clusterin in ovarian cancer is correlated with impaired survival. Int J Gynecol Cancer. 2009;19(8):1342-1346. 35. Steinberg J, Oyasu R, Lang S, et al. Intracellular levels of SGP-2 (Clusterin) correlate with tumor grade in prostate cancer. Clin Cancer Res. 1997;3(10):1707-1711. ©2013 Teva Pharmaceutical Industries Ltd. All rights reserved. ONC-40235 August 2013.

in progression-free or overall survival, Dr. Haluska said. “There were differences, however, in the number of people that could complete the six cycles of chemotherapy, favoring the every-3-weeks regimen, though the quality of life in the weekly group was better,” he added. There were more toxicities, specifically neuropathy, hair loss, vomiting, and neutropenia in the every-3-weeks regimen. The quality of life for those patients was “pretty much coincident with the delivery of chemotherapy on an every-3-weekly basis” and the decrease in the quality of life “was statistically significantly different,” he said. “There was a lot of discussion at ASCO about this study, as well as subsequently, and I think it is important to consider the MITO 7 results in the context of the standards of care established in the Japanese GOG study,” he said. “There is a great difference between weekly and dose-dense. This study, MITO 7, was a weekly treatment; it was not a dose-dense treatment, so the lack of an improvement compared to conventional chemotherapy doesn’t dampen my enthusiasm for dose-dense chemotherapy.” Dose-dense therapy, such as established in the Japanese GOG study, “is still a standard of care,” he said. “This study was not to confirm those results. We will have further data from the GOG 252 and ICON 8, which will help us verify that the dose-dense strategy benefit that was seen on the Japanese GOG study was not because of some unrealized pharmacogenomics changes or differences in the Japanese population vs the rest of the world,” Dr. Haluska stated. “The weekly regimen is a reasonable alternative for patients wanting to focus on quality of life,” Dr. Haluska said. The patient should be counseled, however, “that the outcomes might not be [equivalent to standard dosing of chemotherapy]. I wouldn’t advocate this for routine use, but it could be a discussion that you have with your patients.”

Neoadjuvant Chemotherapy for Ovarian Cancer The CHORUS trial compared neoadjuvant chemotherapy followed by surgery to upfront surgery followed by chemotherapy among 550 women with newly diagnosed advanced ovarian cancer and found no real differences in progression-free or overall survival.6 continued on page 42

The ASCO Post | OCTOBER 15, 2013

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Journal Spotlight Survivorship

Study Shows Increased Risk of Mental Disorders in Childhood Cancer Survivors and Potential Increased Risk in Young Siblings By Matthew Stenger

urvivors of childhood cancer are at risk for long-term adverse physical and mental effects, but little is known about the effects of illness in siblings of these patients. In a study reported in The Lancet Oncology, Lasse Wegener Lund, MD, of the Danish Cancer Society Research Centre and Paediatrics and Adolescent Medicine, Juliane Marie Centre, in Copenhagen, and colleagues found that cancer survivors were at long-term risk of mental disorders and that increased risk may also be present in siblings who were young at the time of diagnosis of the patient’s illness.1

Study Details The study involved assessment of hospital contacts for mental disorders in a population-based cohort of 7,085 Danish children treated for cancer between 1975 and 2010 and in 13,105 of their siblings using data from the Danish Psychiatric Central Research Registry. For the survivor cohort, families with two or more children with cancer were excluded

Cervical and Ovarian Cancers continued from page 41

“But what was striking about this study was the poor performance of the arms in this study,” Dr. Haluska said, “compared to some of the more contemporary adjuvant chemotherapy trials.” While median overall survival in these trials was in the 50- to 60-month range, in the CHORUS trial, median overall survival was in the 20- to 30-month range. The underperformance in the neoadjuvant chemotherapy vs adjuvant chemotherapy trials “is really compelling,” Dr. Haluska said. To determine underlying reasons for these differences, Dr. Haluska reviewed some key predictors of outcome. There were “impressive” differences in performance status, he noted. The number of patients with performance status 0 “was fairly low in the CHORUS study” compared to other contemporary studies and “may

from the analysis, due to anticipated high levels of psychosocial stress. The sibling and survivor cohorts were compared with two population-based cohorts that did not include childhood cancer survivors or siblings of survivors. For each child treated for cancer, 20 control com-

patient contacts from 1995 to 2011 were included in the analysis. All diagnoses of mental disorders were categorized into two main groups: psychotic disorders, consisting of the subcategories of organic psychosis, schizophrenia and other psychoses, and bipolar depression; and

Childhood cancer survivors should be followed up for mental late effects, especially those diagnosed in young age. Further, clinicians should also be aware that siblings who were young at the time of cancer diagnosis might be at increased risk for mental health disorders. —Lasse Wegener Lund, MD, and colleagues

parators born on the same day and without cancer at the date of diagnosis of the survivor were identified (n = 144,700), as were siblings of these comparators (n = 260,400). First hospital inpatient contacts for mental disorders from 1975 to 1994 and both inpatient and out-

nonpsychotic disorders, including other affective disorders (mainly unipolar depression), anxiety, personality disorder, and two groups defined as neurodevelopmental and other nonpsychotic organic disorders and emotional and behavioral disorders. For the cancer survivors, age at

explain the poor underperformance of the arms in this study.” The percentage of optimal debulking was “reasonable” in the CHORUS study and “somewhat comparable, although probably less than most of the studies done with adjuvant chemotherapy,” Dr. Haluska said. There was a wide range in the ability to optimally debulk patients according to the country, with some countries having poor rates of optimal debulking “and that may have affected the outcome,” he added. “I think it is unlikely that these results really can be generalized to patients who have a good performance status and are good surgical candidates,” Dr. Haluska stated. “In my opinion, upfront surgical debulking followed by chemotherapy is still the standard of care until we can have a trial that has performance of the arms that are comparable to the adjuvant chemotherapy trials.” n

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

Editor’s note: Additional details of these trials were reported in previous issues of The ASCO Post. References 1. Tewari KS, Sill M, Long HJ, et al: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. ASCO Annual Meeting. Abstract 3. Presented June 2, 2013. 2. Shastri SS, Mittra I, Mishra G, et al: Effect of visual inspection with acetic acid screening by primary health workers on cervical cancer mortality. ASCO Annual Meeting. Abstract 2. Presented June 2, 2013. 3. Du Bois A, Floquet A, Kim JW, et al: Randomized, double-blind placebo, phase III trial of pazopanib vs placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer:

time of diagnosis was 0 to 4 years in 31%, 5 to 9 years in 18%, 10 to 14 years in 19%, and 15 to 19 years in 32%. The most common diagnoses were CNS tumors (25%), leukemia (24%), and lymphoma (13%).

Overall Risk Follow-up was conducted for up to 37 years, with a median of 8.8 years for survivors and 17.3 years for comparators. On multivariate analysis adjusting for calendar period (1975–1980 as reference) and hospital contact for mental disorder in a parent or sibling 5 years before cancer diagnosis, male survivors had a 40% increased risk (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.24–1.58) and female survivors had a 20% increased risk (HR = 1.20, 95% CI = 1.05–1.37) for hospital contact for any psychiatric disorder compared with populationbased comparators. For both sexes combined, the hazard ratio was 1.38 (95% CI = 1.26–1.51). In a sensitivity analysis of only inpatient contacts, the hazard ratio was 1.51 (95% CI = 1.24–1.84) for male survivors and 1.36 (95% CI = 1.08–1.72) for fecontinued on page 44

Results of an international Intergroup trial (AGO-OVAR16). ASCO Annual Meeting. Abstract LBA5503. Presented June 2, 2013. 4. Ledermann JA, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation. 2013 ASCO Annual Meeting. Abstract 5505. Presented June 1, 2013. 5. Pignata S, Scambia G, Lauria R, et al: A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin plus paclitaxel in patients with advanced ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO)7—European Network of Gynaecological Trial Groups (ENGOT-ov-10) and Gynaecologic Cancer Intergroup (GCIG) trial. 2013 ASCO Annual Meeting. Abstract LBA5501. Presented June 1, 2013. 6. Kehoe S, Hook J, Nankivell M, et al: Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial. 2013 ASCO Annual Meeting. Abstract 5500. Presented June 1, 2013.

The ASCO Post | OCTOBER 15, 2013

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Journal Spotlight

Mental Effects in Childhood Cancer Survivors continued from page 42

male survivors. Increased risks were found in survivors of central nervous system (CNS) tumors, hematologic malignancies, and solid tumors. No increased risk of hospital contact was found for brothers (HR = 0.99, 95% CI = 0.91–1.08) or sisters (HR = 1.01, 95% CI = 0.93–1.10) of survivors overall or in specific psychiatric subtypes.

Risk of Particular Disorders Male survivors were at significantly increased risk of all psychotic disorders (HR = 1.39, 95% CI = 1.07–1.81), all nonpsychotic disorders (HR = 1.45, 95% CI = 1.28– 1.64), unipolar depression (HR = 1.55, 95% CI = 1.19–2.01), neurode-

velopmental and other nonpsychotic organic disorders (HR = 1.77, 95% CI = 1.44–2.17), and emotional and behavioral disorders (HR = 1.50, 95% CI = 1.27–1.76). There were too few cases (≤ 30) of organic psychosis, bipolar depression, and anxiety in male survivors to be included in the multivariate analysis; risk for organic psychosis was significantly increased on univariate analysis. Female survivors were at significantly increased risk of all nonpsychotic disorders (HR = 1.18, 95% CI = 1.03–1.36), neurodevelopmental and other nonpsychotic organic disorders (HR = 2.29, 95% CI = 1.69–3.09), and emotional and behavioral disorders (HR = 1.21, 95% CI = 1.02–1.45). There were too few cases of organic psychosis, schizophrenia and other psychoses, and

Mental Effects in Childhood Cancer Survivors and Their Siblings ■■ Survivors of childhood cancer were at significantly increased risk of hospital contact for mental disorders compared with the general population.

■■ Among survivors, risk increased with younger age at diagnosis. ■■ Although siblings had no overall increased risk, siblings who were young at the time of their sibling’s cancer diagnosis appeared to be at increased risk.

bipolar depression to be included in multivariate analysis; risk of organic psychosis was significantly increased on univariate analysis.

Effect of Age at Diagnosis Among survivors, risk was significantly increased among males in all age groups (HRs = 1.31–1.71); risk was greater among those aged 0 to 9 years (HRs = 1.66–1.71) compared with those aged 10 to 19 years (HRs = 1.31–1.44), although risk

did not differ significantly across age groups (P = .31). Among female survivors, risk was higher with younger age (P = .043 across age groups), with risk significantly increased in those diagnosed at 0 to 4 years (HR = 1.67) and nonsignificantly increased at ages 5 to 14 (HRs = 1.27–1.28). There were no significant trends in risk by number of years since cancer diagnosis in males (P = .84) or females (P = .56) continued on page 45

Psychosocial Health in Long-Term Survivors of Childhood Cancer By Kevin R. Krull, PhD

he study by Lund and colleagues discussed in this issue of The ASCO Post reinforces concerns about psychosocial health in long-term survivors of childhood cancer. Taking advantage of national registries, these investigators demonstrated that, when compared to the general population, survivors are at increased risk not only for emotional and behavioral disorders, but also for more pervasive and persistent neurodevelopmental and psychotic disorders. Siblings were also at increased risk for emotional disorders compared to the general population, particularly if they were born after the cancer was diagnosed.

Emotional and Behavioral Outcomes Understandably, survivors of CNS tumors demonstrated higher risk for neurodevelopmental disorder and psychosis, suggesting a probable organic basis for these conditions. Survivors of hematologic cancers, CNS tumors, and solid tumors each demonstrated higher risk for emotional and behavioral disorders. Given the differential neurotoxic treatments associated with these cancer diagnoses, the relatively similar hazard ratios may suggest a more general impact from stress Kevin R. Krull, PhD, is in the Department of Epidemiology and Cancer Control and the Department of Psychology, St. Jude Children’s Research Hospital, in Memphis, Tennessee.

associated with the cancer experience. As such, these emotional and behavioral outcomes may be preventable. Although the increased risk for mental health problems in long-term survivors is well demonstrated in this study, the number of problems identified is likely a significant underestimation of the true frequency of pathology. The frequency of contact for depression reported in this

seek services from specialized treatment facilities or may go untreated.

Treatment-Specific Risks Notably missing from this study is information on specific treatment exposures. Long-term follow-up guidelines have been developed based on studies demonstrating treatment-specific risk for physical and mental health outcomes.3

The study by Lund and colleagues clearly demonstrates the need for monitoring mental health in longterm survivors of childhood cancer. —Kevin R. Krull, PhD

study range from 2.2% in survivors to 1.7% in siblings, both significantly lower than those reported by the World Health Organization or the National Institute of Mental Health in the United States, which report lifetime risk in the general population ranging from 3.3% to 21.4%.1,2 Similarly, frequency of anxiety in the current study is reported at 1.2% for survivors and 0.9% for siblings, though range from 4.8% to 31.0% in the general population surveys. These discrepancies may suggest that many survivors and siblings who experience mental health problems do not

Such data were not available in the population registries employed by the investigators, though such information is vital for planning survivor-specific monitoring or interventions. Treatments differ within diagnoses and change over time, with the common variable often being type and cumulative dose of exposure. CNS tumors, for example, may be treated with surgery only or with high doses of cranial radiation therapy. It has repeatedly been demonstrated that dose and location of cranial radiation therapy is the driving force in increased risk for specific neurobehavioral

and emotional health problems.4,5 Despite these shortcomings, the study by Lund and colleagues clearly demonstrates the need for monitoring mental health in long-term survivors of childhood cancer. Early identification and treatment of such conditions may improve long-term quality of life and support survivors as they continue to be productive members of our society. n

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

References 1. Kessler RC, Angermeyer M, Anthony JC, et al: Lifetime prevalence and age-ofonset distributions of mental disorders in the World Health Organization’s World Mental Health Survey Initiative. World Psychiatry 6:168-176, 2007. 2. National Institute of Mental Health: Mental Health Information, National Institutes of Health, 2013. 3. Landier W, Bhatia S, Eshelman DA, et al: Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22:4979-4990, 2004. 4. Armstrong GT, Jain N, Liu W, et al: Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies. Neuro Oncol 12:1173-1186, 2010. 5. Brinkman TM, Zhu L, Zeltzer LK, et al: Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Br J Cancer 109:1373-1381, 2013.

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World Conference International Lungon Cancer Lung Congress Cancer Thoracic Oncology

Ancient Chinese Military Tactics Might Help Win the War on Lung Cancer By Caroline Helwick

t the 14th International Lung Cancer Congress, held recently in Huntington Beach, California, Tony S.K. Mok, MD, Professor of Clinical Oncology at the Chinese University of Hong Kong, was the honored recipient of the Bonnie J. Addario Lung Cancer Foundation Award. The award

utes 10% of the country’s gross domestic product, and the country’s smoking rate is 1,711 cigarettes per person annually. For a population of 1.3 billion, this amounts to a “huge amount of tobacco consumed,” and accounts for billions in company profits, he noted. “The global war on lung cancer was

We are fighting this war on an individual scale and also among each other. Is it possible we can combine forces as a group? This would save money, effort, and patient resources. —Tony S.K. Mok, MD

was presented by Ms. Addario, a 9-year lung cancer survivor and nationally recognized business leader, and her husband, Tony. Dr. Mok delivered the Addario Lecture at the meeting. “Pain, suffering, and mortality are obvious to those of us treating lung cancer,” Dr. Mok said. “The impact of this ‘war on lung cancer’ on us is great. How do we deal with it?”

Tobacco Timeline The war began in 1492, when tobacco was discovered in the New World. It gained steam in 1902, when the cigarette rolling machine was popularized, and became entrenched in 1950, when the Marlboro Man became a household image. Since then, smoking rates have decreased in Western countries, but this is counteracted globally by increasing rates in the East, especially Asia, where half of all tobacco consumption occurs. In China, one tobacco company alone contrib-

Mental Effects in Childhood Cancer Survivors continued from page 44

Among siblings, the effect of age at the time of their sibling’s diagnosis was significant for both brothers (P = .0045) and sisters (P < .0001), with risk in both brothers and sisters being greater when they were 0 to 9 years of age at the time of diagnosis (HRs = 1.12–1.24, significant for brothers who were aged 5 to 9 years) than when they were older (HRs = 0.79–

initiated by humans and is fueled by a desire for financial gain,” Dr. Mok observed.

‘How We Fight This War’ The Art of War is an ancient Chinese military treatise attributed to Sun Tzu, a military general, strategist, and tactician. Key principles espoused in the book can be instructional for the global war on lung cancer, according to Dr. Mok, who shared pivotal quotes. “If you know the enemy and know yourself, you need not fear the result of a hundred battles.” The question, he said, is whether we really know the enemy, lung cancer. “What we do know is how the cancer occurs, its appearance, where it is located, its clinical behavior, treatment outcomes, and now its genomic abnormalities,” he said. “But do we really know? Knowledge changes how we deal with it.” 0.97); both brothers (HR = 0.79) and sisters (HR = 0.83) had risk significantly below that of the general population when they were aged > 15 years at the time of diagnosis. The greatest risk was among sisters born after their sibling’s diagnosis (HR = 1.59, 95% CI = 1.30–1.95). Young age at diagnosis was associated with increased risk for behavioral and emotional disorders in both brothers (P < .0001 for trend) and sisters (P = .0018) and for schizophrenia

With increasing understanding of the complex molecular profile of the tumor, “subgroups of subgroups” are becoming recognized. “Our general knowledge about lung cancer may or may not be applicable to all patients. It’s important to know what we don’t know. Then we can start looking for an answer.” For example, it remains unclear why mutation patterns differ between Eastern and Western populations. In squamous cell carcinoma, the TP53 mutation is prominent, but a means of targeting it has eluded researchers. Primary resistance occurs irrespective of tyrosine kinase inhibition of the driver oncogene, but why? Why is there heterogeneity between the primary and nodal or distant lesions? “We must have ways to tackle what we don’t know,” he said. But the “greatest fear,” he continued, “is that we don’t know what we don’t know. It will take a global effort to know our enemy better.” “In war, the way is to avoid what is strong and to strike at what is weak.” “This is common sense, but when, if ever, does lung cancer become weak?” Dr. Mok questioned. This is an area that needs dedicated research, to be able to exploit the tumor both in the early and later stages. Currently, the approach is to treat local disease and hope for a response, then wait until the disease progresses before re-treating, but it is possible that “hitting” the tumor while it is already under attack might be a good idea, he said. “Supreme excellence consists of breaking the enemy’s resistance without fighting.” If a tumor’s resistance to treatment could be overcome, the war would be won, he said. The problem is that only the tumor—not the clinician—under(P = .0034), unipolar depression (P < .0001), and anxiety (P = .011) in sisters. The risk for hospital contact for a mental disorder increased with longer time since sibling’s cancer diagnosis in sisters (P = .0023) but not in brothers (P = .28). The investigators concluded, “Childhood cancer survivors should be followed up for mental late effects, especially those diagnosed in young age. Further, clinicians should also be aware that siblings who were

stands this resistance. “This is how lung cancer fights us: by innate immune resistance,” he said. “Our immune system tries to fight it, but the cancer evades us.” With the novel anti–programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies, treatment is getting “smarter”; however, PD-1/PD-L1 is only one means by which cancer deceives the complex immune system, Dr. Mok noted. “We need to learn a lot more in order to use the immune system to fight cancer.” “Strategy without tactics is the slowest route to victory. Tactics without strategy is the noise before defeat.” Most optimal treatment strategies prove to be short-lived, therefore, researchers must continually refine their moves, Dr. Mok emphasized. “Our current tactic is to identify a molecular target and conduct randomized trials to prove a target agent is better than standard therapy. This has made a difference to our patients and changed our treatment paradigm. However, this tactic may not be sufficient for us to win the war on lung cancer. For such, we must reexamine our strategy,” he said. Identifying new mutations and pairing patients with relevant drugs is a good start, but even that tactic is flawed, he said.

Strategy on Research Funding The current approach is to aim for novel discoveries, primarily through academic-based research. This leads to the development of a drug and a biomarker, which is evaluated in a clinical trial whose objective is registration of the drug. If successful, the drug becomes available and is further studied for different indications. continued on page 46

young at the time of cancer diagnosis might be at increased risk for mental health disorders.” n

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

Reference 1. Lund LW, Winther JF, Dalton SO, et al: Hospital contact for mental disorders in survivors of childhood cancer and their siblings in Denmark: A population-based cohort study. Lancet Oncol 14:971-980, 2013.

The ASCO Post | OCTOBER 15, 2013

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World Conference International Lungon Cancer Lung Congress Cancer War on Lung Cancer continued from page 45

“This general strategy is reasonable, but there is a problem, and that is how we place our ‘soldier’ in this war. The soldier is the money,” Dr. Mok suggested. The vast majority of research funding is directed toward clinical research,

the goal being to fulfill the criteria set by the Food and Drug Administration and to achieve registration of the drug. “What if we put that amount of money into novel discovery efforts? Think of how much more we could learn about the enemy,” he maintained. If the drug approval process eliminated the need for large phase III trials

to evaluate drugs for uncommon targets, and if the process were carried out on a global scale, rather than country by country, that would also be more efficient and cost-saving, he pointed out.

‘Me Too’ Strategy Finally, Dr. Mok called for streamlining the drug pipeline. For example,

In Ph+ CML

A BCR-ABL assay that reads between the lanes GenoTRACE® reveals what you don’t want to miss Standardized to the International Scale (IS) Ability to truly assess major molecular response (MMR) High sensitivity to 4.5 logs (below baseline) to assess whether undetectable disease has been achieved1 Only routine, highly sensitive molecular monitoring standardized to the International Scale (IS) gives you the confidence to make clinical decisions.2

National Comprehensive Cancer Network® (NCCN®) recommends INTERNATIONAL SCALE RQ-PCR with 4.5-log sensitivity every 3 months1

Ph+ CML, Philadelphia chromosome–positive chronic myeloid leukemia; RQ-PCR, real-time quantitative polymerase chain reaction. References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia Version 4.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed July 19, 2013. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Jabbour EJ, Quintás-Cardama A. Molecular monitoring 101: helping your patients with chronic myeloid leukemia to understand the meaning of molecular response. Leuk Lymphoma. 2012;53(8):1452-1460.

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there are currently 12 MET inhibitors on the “short list” in development. “Do we need that many?” he asked. “Because of the ‘me too’ strategy, one company makes a nice discovery and everyone wants a piece of that market.” “We are fighting this war on an individual scale and also among each other. Is it possible we can combine forces as a group? This would save money, effort, and patient resources,” he said. Collaboration may be ideal, but it is not without its obstacles. “We have to be humble to do this, to eliminate products. Everyone looks at their baby as beautiful, and we all agree, ‘Yes, your baby is beautiful,’ as a matter of courtesy. But if we had an external tribunal that looks at the pipeline as a whole, maybe its advice would be, ‘Your baby doesn’t look that good, after all.’ This is difficult, but we need to change our ‘me too’ strategy and do this!” he insisted.

‘Me Better’ Strategy The “me better” strategy should also be reconsidered, he continued. For example, studies of maintenance therapy with both pemetrexed (Alimta) and bevacizumab (Avastin) found median survival to be around 12 months. To determine which of these might actually be superior, the PRONOUNCE trial was conducted. “No surprise, they were exactly the same,” he noted. “Millions of dollars were spent in order to know that the benefit of these drugs is the same.” “Small differences won’t help cancer patients, only big differences. When we invest in finding small differences, we lose out on our soldier and our money,” he said. “Unfortunately, I have done many of these studies, spending too much money to learn too little and provide limited benefit to the patient.” He said he would welcome a philosophical shift in which companies aim to maximize patient benefit, rather than profits. In closing, Dr. Mok remembered Martin Luther King. “He had a dream, and today Barack Obama is President.… I hope to wake up from my own dream some day and say, ‘Take that, lung cancer! We won!’” n Disclosure: Dr. Mok receives honoraria from AstraZeneca, Eli Lilly, Eisai, F. HoffmanLaRoche, Merck Serono, Bristol-Myers Squibb, BeiGene, Pfizer, Boehringer Ingelheim, AVEO, Taiho, and GlaxoSmithKline Biologicals; he is a speaker for AstraZeneca, Eli Lilly, Boehringer Ingelheim, F. Hoffmann-La Roche, and Merck Serono; and he receives research funding from AstraZeneca.

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World Conference International Lungon Cancer Lung Congress Cancer Thoracic Oncology

Stereotactic Body Radiation Therapy Offers Near-Complete Tumor Control for Medically Inoperable Early-Stage NSCLC By Caroline Helwick

atients with stage I non–small cell lung cancer (NSCLC) who are medically inoperable have an excellent chance at full local tumor control and long-term survival with stereotactic body radiation therapy. Hak Choy, MD, Professor and Chairman of the Department of Radiation Oncology at The University of Texas Southwestern Medical School in Dallas, has spearheaded trials of this modality, and he described the rationale and recent data at the 14th International Lung Cancer Congress in Huntington Beach, California.

mizing the doses to the normal tissue around the tumor. This distinguishes a good radiation treatment plan from a poor one,” he said. “The delivery of small doses to a larger volume of normal tissue is preferable to delivering higher doses to a smaller amount of normal tissue,” he said. “When stereotactic body radiotherapy is carefully planned and

Image-guided stereotactic body radiotherapy is highly effective but also potentially dangerous…. It’s not about the beams, the machine, or the motion control. It’s also about the high conformal dose.

Surgery Still the Best Option, but… The early-stage NSCLC population includes standard-risk patients who can undergo surgical resection, patients who are deemed at high risk, and medically inoperable patients. Outcome for these groups is determined as much by age and morbidities as by treatment modality. The alternative to standard surgery is conventional radiation therapy, but reported outcomes with this treatment have varied widely. Overall survival has been report to be 16% to 57%, cancer-specific survival rates have ranged from 19% to 70%, and local failure rates have fallen between 19% and 70%. High-risk surgical candidates and medically inoperable patients should be considered for stereotactic body radiotherapy in centers where this newer modality is available, according to Dr. Choy.

Image-Guided Technique “Image-guided stereotactic body radiotherapy is potentially highly effective but also potentially dangerous,” Dr. Choy noted. “It’s not about the beams, the machine, or the motion control. It’s also about the high conformal dose.” But in highly trained hands, stereotactic body radiotherapy is safe and can be delivered efficiently in a manner that spares normal tissues surrounding the tumor. “The delivery of conformal high doses to the tumor is straightforward, especially with the use of many beams or arc therapy. What is hard is doing this while mini-

progression was 79.6% and overall survival was 47.1%. The biologic effective dose was the most significant factor influencing these outcomes, which improved to 92.5% and 62.2%, respectively.1 The other major stereotactic body radiotherapy dataset reported to date, of 505 stage I/IIB patients from the Elekta Lung Research Group,

—Hak Choy, MD

properly delivered, there is far less risk compared to conventional radiotherapy, of producing tissue damage,” he said. “Stereotactic body radiotherapy also offers the advantages of being noninvasive, allowing the course to be completed within a week or two, requiring minimal recovery time, and causing less delay to or interruption of systemic therapy. The use of image guidance and technologic advances in motion control, dosimetry, and accuracy makes stereotactic body radiotherapy the preferred radiotherapy modality,” he said.

Evidence of Efficacy Evidence of clinical efficacy for stereotactic body radiotherapy has primarily come from large retrospective, multi-institutional groups of stage I medically inoperable or elderly patients, generally showing a local control rate of about 80%. A recent study involving 582 patients from radiotherapy centers in Germany confirmed its safety and efficacy, despite considerable interinstitutional variability and time trends in stereotactic body radiotherapy practice. Radiotherapy dose was identified as a major factor influencing local tumor control and overall survival. After a mean follow-up of 21 months, 3-year freedom from local

showed an even higher rate of local control, which was correlated with a median biologically equivalent prescription dose of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival rates were encouraging. Two-year rates of local control, regional control, and distant metastasis were 94%, 89%, and 20%, respectively, and cause-specific and overall survival were 87% and 60% (78% in operable patients, 58% in inoperable), respectively.2

Prospective Data In a study by the Nordic Study Group, 57 patients receiving a total of between 45 Gy and 66 Gy in three fractions had a 3-year local control rate of 92%, overall survival rate of 59.5%, and lung cancer–specific survival rate of 88.4%.3 The Japan Clinical Oncology Group ( JCOG) 0403 study found medically inoperable patients to have a 59.9% rate of 3-year survival and an 88% rate of local control.4 The Radiation Therapy Oncology Group (RTOG) 0236 study, the first North American cooperative group trial of stereotactic body radiotherapy, is producing even more impressive outcomes.5 “We waited for 3 years for the data to mature before publishing the results, and our local control rate is near 100%,” Dr. Choy reported.

The study enrolled 59 patients with medically inoperable stage I disease, for whom the prescription dose was 54 Gy total in three fractions. At a median follow-up of 34 months, only one patient had a primary tumor failure, yielding a 3-year primary tumor local control rate of 97.6%. Three patients had recurrence within the involved lobe, and two patients experienced regional failures, for a local-regional control rate of 87.2%. Rates for disease-free and overall survival at 3 years were 48.3% and 55.8%, respectively, and median overall survival was 48.1 months. “This trial set the standard for North America and Europe,” said Dr. Choy, who is the senior investigator of RTOG 0236. “The strong and consistent efficacy shown in these trials has led to a near-doubling in the use of radiotherapy for elderly patients over the past dozen or so years. Whereas historically more than one-third of patients were followed by observation alone, only about one-quarter of patients remain untreated, and survival rates are rising for patients not able to have surgery, he said.

SEER Analysis An analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare database of 10,923 patients with stage I NSCLC treated between 2001 and 2007 evaluated survival outcomes associated with five strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic body radiotherapy, and observation.6 After a median followup time of 3.2 years, stereotactic body radiotherapy was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio [HR] = 0.48), and after 6 months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after stereotactic body radiotherapy was similar to that after lobectomy (HR = 0.71), whereas conventional radiation and observation were associated with poor outcomes. The authors concontinued on page 50

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.

Learn L earn more more a att XtandiHCP.com XtandiHCP.c com

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; OCTOBER 15, 2013

PAGE 50

World Conference International Lungon Cancer Lung Congress Cancer Early-Stage NSCLC continued from page 47

cluded that lobectomy led to the best long-term outcomes in fit elderly patients with early-stage NSCLC, but stereotactic body radiotherapy offers efficacy comparable to that of surgery in select populations. The established indications for ste-

reotactic body radiotherapy are for early-stage (node-negative) NSCLC that is medically inoperable. Less established or emerging indications are for the treatment of limited multifocal NSCLC, oligometastases, reirradiation after local

recurrence, and for stereotactic boost for locally advanced disease. n

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

References 1. Guckenberger M, et al: J Thorac Onc 8:1050-1058, 2013. 2. Grills IS, et al: J Thorac Oncol

7:1383-1393, 2012. 3. Baumann P, et al: J Clin Oncol 27:3290-3296, 2009. 4. Nagata Y, et al: Int J Radiat Oncol Biol Phys 78(3 suppl):S27-S28, 2010. 5. Timmerman R, et al: JAMA 303:1070-1076, 2010. 6. Shirvani SM, et al: Int J Radiat Oncol Biol Phys 84:1060-1070, 2012.

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

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

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

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

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; OCTOBER 15, 2013

PAGE 51

News Issues in Oncology

ASCO Releases Statement on the Impact of the Government Shutdown on Cancer Care By Jo Cavallo

ll nonessential government services were suspended at midnight on October 1, 2013, after Congress failed to reach a budget compromise to keep

the government funded before the start of the new fiscal year beginning on October 1, 2013. ASCO issued a statement in response to the government

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy

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

shutdown and as The ASCO Post went to press was closely monitoring the situation and its impact on cancer care. In a statement, ASCO President

Live: 7"w Ă&#x2014; 10"h

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

Clifford A. Hudis, MD, FACP, said: â&#x20AC;&#x153;The country woke up this morning to the first government shutdown in 17 years. This is a sad state of affairs and we must insist that, moving forward, our elected leaders do better to ensure that millions of Americans with cancer can continue to rely on their government for essential cancer care, life-saving research, and the advancement of safe and effective drugs into practice. â&#x20AC;&#x153;The short-term impact on clinical and laboratory research was felt first thing today when investigators were notified that the federal agencies that are critical to ongoing and planned clinical research would not be available until further notice. However, it is theÂ long-term disruption to government services that could be even more devastating to research innovation and the overall health of the nation for decades to come. We call on Congress and the Administration to work together to pass a budget that will continue our countryâ&#x20AC;&#x2122;s commitment to individuals with cancer. Millions of lives, scientific progress, and our worldwide leadership depend on their action.â&#x20AC;?

Additional Resources ASCO is keeping members abreast of any new information on the government shutdown on ASCO in Action. (Visit http://www.asco.org/ advocacy.) n

Government Shutdown â&#x2013; â&#x2013; All nonessential government

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services were suspended on October 1, after Congress failed to reach a budget compromise to keep the government funded before the start of the new fiscal year.

â&#x2013; â&#x2013; ASCO is closely monitoring

the impact of the government shutdown on cancer care and cancer research, and will keep its members updated on its ASCO in Action website.

â&#x2013; â&#x2013; ASCO calls on Congress and the

Administration to pass a budget that will continue the countryâ&#x20AC;&#x2122;s commitment to patients with cancer.

The ASCO Post | OCTOBER 15, 2013

PAGE 52

Journal Spotlight Smoking Cessation

More Active Physician Intervention Needed to Keep Patients From Smoking By Charlotte Bath

ore active support and interventions by physicians are required to get patients who still smoke to stop, according to two articles published online by the Journal of Oncol-

ogy Practice ( JOP),1,2 and to prevent school-aged children and adolescents from starting to use tobacco, according to a U.S. Preventive Services Task Force (USPSTF) recommendation statement published in the Annals of Internal Medicine.3

appear to be robust in that they mirror the results found in other surveys of oncologists.” The authors noted a similar study of thoracic oncologists from the International Association for the Study of Lung Cancer published earlier this year that produced remarkably similar patterns of tobacco assessment and cessation support.4 Because those responding may have a higher interest in tobacco assessment and cessation, the reported results might be “overly optimistic,” and “the true practice patterns of oncologists may in fact be worse than reported,” the investigators noted. The potential benefits of ongoing efforts to improve efficacy of tobacco cessation among patients will not be realized, the researchers concluded, unless clinicians provide either direct support to patients or referrals to dedicated tobacco cessation programs providing structured support.

Smoking Cessation Support

Missed Opportunities

ASCO recommends that clinicians assess tobacco use and provide cessation support. Moreover, Graham W. Warren, MD, PhD, of the Medical University of South Carolina, Charleston, and coauthors noted that 86% of those responding to a survey sent to ASCO members agreed that smoking cessation support should be a standard part of clinical cancer care.1 Yet only 39% reported that they provided smoking cessation support to patients. Nearly 90% of respondents said that they routinely asked patients about tobacco use at their initial visit, and more than 80% reported advising patients to stop using tobacco. During follow-up visits, the percentage who always or usually asked about tobacco and who reinforced the importance of stopping tobacco use hovered at around 70%. Most of those responding to the survey (81%) were medical oncologists, and 79% reported spending at least half their time seeing patients. Nearly 73% had never smoked, and 3% were current smokers. “The response rate to the online survey (6.5%) precludes us from making generalizations about the entire ASCO membership,” the authors acknowledged, but added, “the findings

A retrospective medical record review of 948 patients diagnosed with bronchogenic carcinoma at a community medical center between 2008

Graham W. Warren, MD, PhD

Jessica R. Hildebrand, MD

They found neither a significant correlation between the number of encounters and the likelihood of counseling, nor any significant differences based on age, race, or sex. “However, there was a significant decrease in counseling with higher stages of cancer. Notably, patients with stage I disease were 1.7 times more likely to be counseled than those with stage IV disease (P = .017),” the researchers reported. “Despite the benefits of smoking cessation, there may be a prevailing belief among physicians that treating tobacco dependence is futile in patients who already have cancer,” the authors commented. “Physicians may fail to address this issue in prac-

Oncologists and subspecialists may believe that the [smoking cessation] discussion should occur with primary care physicians. However, it has been argued that oncologists are uniquely positioned to affect smoking rates and should take an active role in smoking cessation. —Jessica R. Hildebrand, MD, and Sangeeta Sastry, MD

and 2010 found that 438 were current smokers at diagnosis, and only 36.1% had been counseled on smoking cessation. “To quit smoking successfully, patients need assistance from their physicians. In our study, patients encountered between two and five physicians from various specialties in the 6 months surrounding their diagnosis, representing numerous missed opportunities to counsel,” commented Jessica R. Hildebrand, MD, of New Hanover Regional Medical Center, Wilmington, North Carolina, and Sangeeta Sastry, MD, of The University of North Carolina, Chapel Hill.2

tice because of competing concerns during their encounters, uncertainty about how to implement brief interventions, or a lack of familiarity with tobacco assessment and effective treatments. Oncologists and subspecialists may also believe that the discussion should occur with primary care physicians. However, it has been argued that oncologists are uniquely positioned to affect smoking rates and should take an active role in smoking cessation.”

Primary Care Interventions That said, primary care physicians should provide interventions

to prevent initiation of tobacco use in school-aged children and adolescents, according to an updated recommendation statement from the USPSTF.3 “The USPSTF found adequate evidence that behavioral counseling interventions, such as face-to-face or phone interaction with a health care provider, print materials, and computer applications, can reduce the risk for smoking initiation in school-aged children and adolescents,” according to the statement. A previous statement in 2003 concluded that “the evidence was insufficient to recommend for or against routine screening for tobacco use or interventions to prevent and treat tobacco use and dependence in children or adolescents.” The updated statement noted that each day in the United States, more than 3,800 children and adolescents smoke their first cigarette, and an estimated 1,000 begin smoking on a daily basis. “Although most serious health effects from smoking occur in adulthood,” the task force wrote, “children and adolescents can have negative respiratory effects, including impaired lung growth; early onset of lung function decline; and respiratory- and asthma-related symptoms, such as coughing and wheezing.” n

Disclosure: For full disclosures reported by the authors of the JOP studies discussed in this article, visit jop.ascopubs.org.

References 1. Warren GW, Marshall JR, Cummings KM, et al: Addressing tobacco use in patients with cancer: A survey of American Society of Clinical Oncology members. J Oncol Pract. July 29, 2013 (early release online). 2. Hildebrand JR, Sastry S: “Stop smoking!” Do we say it enough? J Oncol Pract. July 29, 2013 (early release online). 3. Moyer VA, on behalf of the U.S. Preventive Services Task Force: Primary care interventions to prevent tobacco use in children and adolescents: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. August 26, 2013 (early release online). 4. Warren GW, Marshall JR, Cummings KM, et al, on behalf of the IASLC Tobacco Control and Smoking Cessation Committee: Practice patterns and perceptions of thoracic oncology providers on tobacco use and cessation in cancer patients. J Thorac Oncol 8:543–548, 2013.

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The ASCO Post | OCTOBER 15, 2013

PAGE 58

Expert’s Corner NCI-Designated Comprehensive Cancer Center

New President and CEO of Fox Chase Cancer Center Reflects on Challenges and Opportunities Ahead A Conversation With Richard I. Fisher, MD By Ronald Piana

Richard I. Fisher, MD

n October 8, 1904, a group of Philadelphia physicians and businessmen who were concerned about the escalating incidence of cancer in the city signed a charter that established the American Oncologic Hospital, one of the nation’s first hospitals solely devoted to cancer care. Seven decades later—2 years after President Richard Nixon signed the National Cancer Act—the American

Oncologic Hospital united with the Institute for Cancer Research to form Fox Chase Cancer Center. In many ways, the history of Fox Chase Cancer Center is a snapshot of the history of American oncology, encompassing landmark discoveries and challenging times alike. Fox Chase’s history is also one of exemplary leadership, having a long list of internationally recognized physicians serving as presidents and CEOs. The ASCO Post spoke with Fox Chase’s recently appointed President and CEO, Richard I. Fisher, MD, an internationally recognized oncologist/hematologist. Dr. Fisher shared his vision for Fox Chase’s future and how he plans to deal with the challenges of today’s tumultuous economic and political environment.

Career Path Please tell the readers a bit about the career path that brought you to Fox Chase.

After finishing my training at Harvard College Medical School and Massachusetts General Hospital, my oncology career actually began at the

Chicago and helped develop what became the Cardinal Bernardin Cancer Center at Loyola University. Following that, I went to the University of Roch-

Oncology, with its unique blend of cutting-edge science and humanity, gives the best of both worlds for those who choose it as their career. —Richard I. Fisher, MD

National Cancer Institute (NCI), where I was a clinical associate and then a senior attending physician. It was at NCI that I developed my interest in malignant lymphoma. I subsequently participated in many of the early trials in that area. I was fortunate to have worked with Drs. Robert C. Young and Vincent T. DeVita, Jr, as well as many other esteemed leaders in medical oncology. After leaving the NCI, I went to

ester School of Medicine as Director of the James P. Wilmot Cancer Center. I was there until last year, when I was given the opportunity to come to Philadelphia and serve as Physician-inChief and Executive Vice President of Fox Chase. Within a couple of months, I was promoted to President and CEO.

Glorious History What does being the head of Fox Chase mean to you?

Highlights From Fox Chase Cancer Center ■■ 1945: Hugh J. Creech, PhD, begins his 31-year career at the Institute. Dr.

Creech would become widely recognized for pioneering work in developing chemotherapy agents.

■■ 1959: Peter C. Nowell, MD, University of Pennsylvania School of Medicine,

and his research fellow David A. Hungerford, Fox Chase Cancer Center [who subsequently earned his PhD], detect an abnormality on chromosome 22— the translocation now known as the Philadelphia chromosome—in cells taken from chronic myelogenous leukemia patients, proving cancer is a genetic disorder of somatic cells.

■■ 1960: Beatrice Mintz, PhD, joins the Institute. She would go on to produce the first genetically modified mice.

■■ 1967: Baruch S. Blumberg, MD, PhD, and his team identify the hepatitis B

virus—a major cause of primary liver cancer. Blumberg would go on to receive the Nobel Prize in Medicine in 1976.

■■ 1974: Two years after the National Cancer Act begins the “War on Cancer,”

American Oncologic Hospital and the Institute for Cancer Research unite to form Fox Chase Cancer Center.

■■ Late 1970s: Irwin A. Rose, PhD, Avram Hershko, MD, PhD, and Aaron

Ciechanover, MD, PhD, discover how proteins are broken down and recycled, establishing a new paradigm in biology. They received the Nobel Prize in chemistry in 2004.

■■ 1988: Robert C. Young, MD, internationally known for his work in ovarian cancer, becomes President of Fox Chase.

Fox Chase Cancer Center, Philadelphia, Pennsylvania

■■ 1995: Fox Chase becomes one of the founding members of the National

Comprehensive Cancer Center Network, an alliance of the nation’s leading academic cancer centers dedicated to ensuring the highest-quality, most cost-effective cancer care based on state-of-the-art treatment guidelines and outcomes research.

■■ 2001: Fox Chase becomes the first cancer center in the world to use magnetic resonance imaging to design more precise radiation treatment plans for cancer patients, setting a new standard for therapy.

■■ 2013: Richard I. Fisher, MD, appointed President and CEO of Fox Chase Cancer Center

■■ 1992: The National Institutes of Health names Fox Chase one of four

institutions chosen to analyze all genetic data for the Human Genome Project.

Adapted from Moments in Time: A History of Fox Chase Cancer Center. Available at www.fccc. edu. Courtesy of Fox Chase Cancer Center.

ASCOPost.com | OCTOBER 15, 2013

PAGE 59

Expert’s Corner

Fox Chase is one of the four original freestanding cancer centers in the nation. It was also one of the earliest institutions selected as an NCI-designated comprehensive cancer center. It has a glorious history in American oncology, with a long list of accomplishments and leaders, including two Nobel Laureates, who have contributed to the advances in cancer care we see today. Moreover, for many years Fox Chase was run by one of my early mentors, Dr. Robert C. Young, which makes it even more special for me to assume the institute’s leadership. The institution’s place in American oncology combined with its potential to help advance cancer care in a number of ways makes it a special opportunity for me.

are in the process of recruiting new leadership for the program. We eventually plan to have one of the country’s premier blood cancer programs thriving here at Fox Chase.

Choosing Oncology If you were addressing a group of promising medical students, what

motivations would you give them for choosing a career in the difficult field of oncology? First and foremost, oncology offers a rare opportunity for bright young medical students to make a difference at the individual patient level and for society as a whole. The science of oncology is moving forward rapidly,

improving patient outcomes at a pace never seen before. Equally important, oncologists develop intimate, longterm relationships with patients and their families. So oncology, with its unique blend of cutting-edge science and humanity, gives the best of both worlds for those who choose it as their career. n

Economic Challenges Is Fox Chase well positioned to meet the challenges of today’s difficult economic environment? During these challenging times, Fox Chase has had its trials and tribulations. However, since we’ve become a wholly owned subsidiary of the Temple University Health System, Fox Chase has the opportunity to thrive in a stable academic health system, which mitigates a portion of the fiscal uncertainty associated with freestanding cancer centers in today’s tough economic climate. That said, I do believe it’s going to be difficult for most of the freestanding cancer centers to remain independent in this new world of health care. So I think Fox Chase is being observed by other centers to see how we adjust to the challenges ahead.

Research Priorities Given your strong background in clinical research, have you identified any priorities for Fox Chase moving forward? Fox Chase has traditionally been focused on solid tumor investigations. For instance, ovarian cancer research has been one of the institution’s premier programs, based largely on the work of leaders in the field such as Robert Young and Robert Ozols. Along with its research in other solid tumors, Fox Chase has done some work in hematologic malignancies but certainly not enough. We plan to develop a major hematologic malignancy initiative at the institution, which will incorporate the Temple bone marrow transplant program. To that end, we

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The ASCO Post | OCTOBER 15, 2013

PAGE 60

Journal Spotlight

10-Year Breast Cancer Survival Similar Regardless of BRCA1 Mutation Status By Matthew Stenger

n a study reported in Journal of Clinical Oncology, Tomasz Huzarski, MD, PhD, of Pomeranian Medical University, Szczecin, Poland, and colleagues from the Polish Hereditary Breast Cancer Consortium assessed survival among women with early-onset breast cancer with and without BRCA1 mutation and identified prognostic factors among those with BRCA1-positive disease. They found that 10-year overall survival was similar in BRCA1-positive and BRCA1-negative disease. Positive lymph node status was a predictor of increased mortality and oophorectomy a predictor of reduced mortality in women with BRCA1-positive disease.

Study Details In the study, 3,345 women aged ≤ 50 years with stage I to III invasive breast cancer from 17 affiliated centers in Poland were tested for three founder mutations in BRCA1 (5382insC, C61G, and 4153delA). Dates of diagnosis were between 1996 and 2006. Diagnosis had to

be pathologically confirmed by core or fine-needle aspiration biopsy. Patients with a previous diagnosis of contralateral breast cancer or another cancer were

tive), progesterone receptor (PR) status (positive vs negative or missing), HER2 status (positive vs negative or missing), tamoxifen use (yes vs no), and chemo-

The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy. —Tomasz Huzarski, MD, PhD, and colleagues

excluded from the analysis. Information on tumor characteristics and treatments received was retrieved from medical records, and dates of death were obtained from the vital statistics registry. Survival analysis was conducted using a Cox proportional hazards model, with covariates including BRCA1 status, tumor size (four categories), nodal status (negative vs positive), estrogen receptor (ER) status (positive vs nega-

therapy. Oophorectomy (yes vs no) was a time-dependent covariate. Mutation carriers were diagnosed at an earlier age (42 vs 44 years, P < .001) and were less likely to have ER-positive (16% vs 62%, P < .001), PR-positive (20% vs 70%, P < .001), and HER2positive (6.5% vs 21%, P < .001) disease, more likely to have triple-negative disease (69% vs 13%, P < .001), and more likely to have had oopherectomy

(50% vs 14%), with most (108 of 115 mutation carriers) having the procedure after breast cancer diagnosis.

Survival Analysis Mean follow-up was 7.4 years. The 10year overall survival rate was 80.9% for mutation carriers vs 82.2% for noncarriers (hazard ratio [HR] on univariate analysis = 1.14, P = .42). After adjustment for other prognostic features, the hazard ratio for mutation carriers became significant (1.81, P = .002). Among the subgroup of 485 women with triple-negative cancer, overall survival for mutation carriers was not inferior to that of noncarriers. Ten-year overall survival was 84.1% among BRCA1 carriers with small (> 2 cm) tumors, 89.9% for node-negative patients, and 68.6% for node-positive patients. Among carriers with tumors ≤ 1 cm, 27.5% were node-positive, and 10-year overall survival was 81.8% in these patients. Patients with cancers that were either node-positive or > 5 cm continued on page 62

Germline Mutations and Breast Cancer Prognosis: Does the Cause Matter? By Mark Robson, MD

ince the discovery of BRCA1 and BRCA2, investigators have sought to determine whether the presence of a germline mutation independently influences the outcome of a breast

eg, with breast magnetic resonance imaging (MRI)—or risk-reducing mastectomy. As important as the question is, there are a number of obstacles to arriving at a definitive answer.

Prognostic Significance of Mutations

Mark Robson, MD

cancer diagnosed in a woman with an inherited mutation. The question is highly relevant to an unaffected woman with a mutation, as knowledge of poor prognosis in mutation-associated cancer could influence her decision whether to pursue enhanced breast cancer surveillance— Mark Robson, MD, is with the Clinical Genetics and Breast Cancer Medicine Services, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

BRCA1/2 mutations are uncommon, so study sample sizes tend to be small, magnifying the potential effect of confounding influences. Women do not routinely undergo genetic testing at the time of diagnosis, so there is always the potential for ascertainment bias if the decision to offer genetic testing is influenced by clinical factors that also influence outcome. Examples of such factors could include a young age at diagnosis or the presence of triple-negative breast cancer. Delays in testing until sometime after diagnosis may also confound the interpretation of studies evaluating the prognostic significance of mutations, as women surviving to be tested may not be entirely representative of the entire population of women with mutation-associated cancer. Treatment in retrospective studies of outcome is usually not uniform, which may influence the

association between germline status and survival in unpredictable ways. Lastly, the outcomes of carriers in retrospective studies may not necessarily be reflective of outcomes in women who are undergoing aggressive MRI-based surveillance. Over the years, a number of investigators have sought to overcome these challenges. Many of these studies (but not all) have relied upon the presence of founder mutations in specific populations to expand the sample size of women with mutations. Early studies employed retrospective cohort designs, identifying mutation carriers through testing of archived material from women of Ashkenazi ancestry. These small but relatively unbiased studies suggested that BRCA1 mutations are associated with worse outcomes, largely in women who did not receive adjuvant chemotherapy. However, a larger study of incident breast cancer in Israel identified 110 Ashkenazi carriers over a period of 2 years and found no significant effect of germline BRCA status on outcome. Case ascertainment was incomplete, unfortunately, and treatment was not controlled, raising the

possibility of a confounded result. In 2012, investigators reported the survival experience of mutation carriers in the Breast Cancer Family Registry, an international population-based cohort ascertainment enriched for women with a family history of breast cancer. In this study of 165 women with mutations, germline status had no impact on survival after adjustment for clinical prognostic factors such as stage.

Confirmation of Previous Studies The study by Huzarski and colleagues reviewed in this issue of The ASCO Post confirms and expands upon the results of the previous studies. This study explores the impact of BRCA1 mutations on prognosis in Poland, where most mutation carriers have one of a limited number of founder mutations. Although this was not, strictly speaking, an unselected ascertainment (as women had to be offered and accept testing), the number of women tested was large and the number of BRCA1 carriers identified (n = 233) was substantially greater continued on page 62

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PAGE 62

Journal Spotlight

BRCA1 Mutation Status continued from page 60

constituted a high-risk group; 44% of the mutation carriers were in this group and had 10-year overall survival of 68.2%.

Predictive Factors Among all patients, factors significantly predictive of survival on multivariate analysis in addition to BRCA1-positive status were PR-positive status (HR = 0.63, P < .001), HER2-positive status (HR = 1.68, P < .001), tumor size ≥ 5 cm (HR = 2.28, P < .001), node-positive disease (HR = 3.04, P < .001), and oopherectomy (HR = 0.58, P = .03). Among mutation carriers, multivariate analysis showed that positive lymph node status was a predictor of poorer survival (HR = 4.1, P < .001) and oopherectomy was a predictor of improved survival (HR = 0.30, P = .01). Oophorectomy was associated with a smaller, nonsignificant benefit in noncarriers (HR = 0.83, P = .52). The hazard ratio associated with

Germline Mutations continued from page 60

than in any previous study. In keeping with the results of previous studies, the survival of BRCA1 carriers was not significantly worse than the outcome of noncarriers in univariate analysis, despite the well-recognized association of mutations with triple-negative disease. Cancers in women with mutations were not more advanced than in noncarriers, and the 10-year survival of BRCA1 carriers with T1N0 tumors was 89.9%. Interestingly, the survival of women with smaller cancers (< 1 cm) was no better than that of women with 1.1- to 2-cm primaries, although the numbers of cases in each group were relatively small and the power to detect a difference limited. These overall results should be reassuring to women with mutations, but there are some caveats. Most of the carriers received chemotherapy, which may

oophorectomy among mutation carriers was similar when patients with oophorectomy before diagnosis were excluded from analysis. Factors not significantly associated with overall survival for mutation carriers on multivariate analysis included year of birth, age at diagnosis, ER, PR, and HER2 status, tumor size, and receipt of chemotherapy.

Effect of Chemotherapy The hazard ratio for survival with use of chemotherapy in mutation carriers was 0.79 (P = .66) on univariate analysis and 0.42 (P = .18) on multivariate analysis. Only 18 women who were carriers of a BRCA1 mutation received no chemotherapy. Among noncarriers, the hazard ratio associated with chemotherapy use was 1.56 (95% confidence interval [CI] = 0.88–2.78). The interaction between chemotherapy use and survival by mutation status was significant (P = .01). Among mutahave mitigated an adverse effect of mutation status. Also, in multivariate analysis, the presence of a mutation was associated with a significantly worse overall survival (hazard ratio = 1.81, 95% confidence interval = 1.26–2.61) if it was forced into the proportional hazards model despite being nonsignificant in the univariate analysis. The authors were not able to determine whether the deaths were clearly associated with the index breast cancer or with metachronous breast or ovarian cancers, which were not uncommon in women who did not undergo oophorectomy. The significant impact of oophorectomy on survival in women with mutations suggests a substantial force of mortality from metachronous cancers, as the procedure would be expected to reduce the risk of these events without having a significant effect on the outcomes of a primary hormone receptornegative breast cancer.

Impact of BRCA Mutation Status on Survival ■■ Ten-year survival was similar among BRCA1 mutation carriers (80.9%) and

noncarriers (82.2%) with early-onset breast cancer, although BRCA1-positive status was associated with significantly increased risk of mortality on multivariate analysis.

■■ On multivariate analysis, positive node status was significantly predictive of

poorer survival and oopherectomy was significantly predictive of improved survival in mutation carriers.

■■ Factors not significantly associated with overall survival for mutation

carriers on multivariate analysis included year of birth, age at diagnosis, ER, PR, and HER2 status, tumor size, and receipt of chemotherapy.

tion carriers treated with adjuvant chemotherapy, the hazard ratio associated with CMF (cyclophosphamide, methotrexate, and fluorouracil) vs an anthracycline-based regimen was 0.67 (95% CI = 0.31–1.45) on univariate analysis and 0.81 (P = .62) on multivariate analysis. The investigators concluded, “The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a

Next Steps Taken together, the studies of prognosis in BRCA mutation-associated breast cancer are quite consistent. With the exception of the Breast Cancer Family Registry report, no study has indicated an effect of BRCA2 mutations on survival. Breast cancer-related survival also appears to be similar in BRCA1 mutation carriers and non-carriers, despite the association between BRCA1 mutations and the more dangerous triple-negative subtype. A working hypothesis is that the aggressive use of adjuvant chemotherapy in young women, especially with receptor-negative disease, may be ameliorating the negative prognostic impact of the breast cancer subtype. This hypothesis is difficult to prove with the available study designs, and a randomized biomarkerdriven study to address the question is neither feasible nor ethical. Second malignancies, especially ovar-

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BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy.” n Disclosure: The study authors reported no

potential conflicts of interest.

Reference 1. Huzarski T, Byrski T, Gronwald J, et al: Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol. August 12, 2013 (early release online).

ian cancer, pose a significant threat to women with mutations, and appropriate use of risk-reducing salpingo-oophorectomy consistently improves survival both by reducing the risk of ovarian and fallopian tube cancers and probably by reducing the risk of contralateral breast cancers in women who choose not to undergo risk-reducing mastectomies. Although these conclusions are somewhat reassuring, a 10% mortality rate in young women with small, node-negative tumors remains unacceptably high. One hopes that this rate can be reduced by improvements in systemic adjuvant therapies, possibly including the use of platinum-based regimens or inhibitors of poly (ADP-ribose) polymerase. Studies to assess the impact of these approaches are in development and are urgently needed. n Disclosure: Dr. Robson reported no potential conflicts of interest.

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ASCOPost.com | OCTOBER 15, 2013

PAGE 63

Screening Breast Cancer

American Society of Radiologic Technologists Mammography Checklist

he American Society of Radiologic Technologists has provided a preparation checklist to assist women in preparing for their annual mammograms. Tips include: ■■ Schedule your mammogram just

after your menstrual period, when your breasts are less tender. ■■ Wear a two-piece outfit on the day of your mammogram, so you will have to remove only your top. ■■ Don’t apply deodorant, talcum

powder or lotion under the arms or near the breasts prior to examination. These products can show up on the x-ray image and may make it difficult to interpret. ■■ Bring the name, address and

phone number of your primary care physician. For more information about mammography procedures and other medical imaging exams, your patients can visit https://www.asrt.org/patients. n

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The ASCO Post | OCTOBER 15, 2013

PAGE 64

News Hematology

Myeloma Foundation Launches Open Access Gateways to Accelerate Drug Development By Jo Cavallo

PharmaGraphics

able blood cancer. According to the MMRF, the 5-year survival rate for the cancer is approximately 41%, one of the lowest of all cancers. In 2013, more than 20,000 adults in the United States will be diagnosed with multiple myeloma and nearly 11,000 people will die from the disease.

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Multiple Myeloma Research Foundation Open Access Gateways

■■ The Multiple Myeloma Research Foundation announced two open access gateways, one for researchers and one for patients, to accelerate development of precision medicines for multiple myeloma. ■■ The MMRF Researcher Gateway will upload genomic data as it becomes available and make it accessible to all researchers ■■ The MMRF CoMMunity Gateway will aggregate subtypes of myeloma patients and help them find treatments and clinical trials specific to their needs. n

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fect their disease progression and individual response to treatment. For example, bone marrow tissue samples will be taken before treatment starts and genomically sequenced. New tissue samples will be taken and genomically sequenced again following remission and each time the patient relapses. Fifty centers in the United States and Europe are enrolling patients and have committed to openly share data via the Researcher Gateway portal. To date, 300 patients are enrolled in the study and the MMRF expects the remaining 700 patients to be enrolled by the end of next year. DATE

GNH_HER_Q36341B_JA_D01.indd

JOB#: 36341B CLIENT: Genentech DESC: OS Journal Ad Update PG: Lake, Kathleen/TaranS AD: K Wilkinson PM: N Echandi TRIM: 20.5” x 13.25” BLEED: 22.5” x 15.625” SAFETY: 19” x 12.75” FONTS: Myriad Pro (Bold, Regular, Condensed, Light, Semibold), Helvetica Neue LT Std (45 Light) IMAGES: 36341_B_JA_Chainmail_p1_fn.tif (CMYK; 300 ppi; 100%), Perjeta_US_®_SHS_4C.eps (26.5%) INKS: Cyan, Magenta, Yellow, Black DOC PATH: GNH_HER_Q36341B_JA_D01:Volumes...JA_D01:GNH_HER_Q36341B_JA_D01.indd NOTES: None

he Multiple Myeloma Research Foundation (MMRF) has announced two open access gateways, the MMRF Researcher Gateway, which will upload genomic data as it becomes available and make it accessible to all researchers, and the MMRF CoMMunity Gateway, which will aggregate subtypes of myeloma patients and help them find treatments and clinical trials specific to their needs. The announcement was made before 200 doctors, researchers, scientists, and philanthropists at the Alexandria Center for Life Science in New York.

ED PROD

Galley: 1

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Statement of Ownership, Management and Circulation (Requester Publication) 1) Publication Title: The ASCO Post. 2) Publication Number: 2154-3283. 3) Filing Date: 9/26/13. 4) Issue Frequency: Semi-monthly, except monthly in January, April, August and October. 5) Number of Issues Published Annually: 20. 6) Annual Subscription Price (if any) $259. 7) Complete Mailing Address of Known Office of Publication: Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. Contact Person: John Gentile. Telephone: 631-935-7655. 8) Complete Mailing Address of Headquarters or General Business Office of Publisher: Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 9) Full Names and Complete Mailing Addresses of Publisher, Editor, and Managing Director: Publisher : John A Gentile Jr, Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. Editor: James O. Armitage MD, Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. Managing Editor: Cara Glynn, Harborside Press LLC, 37 Main St, Cold Spring Harbor, Suffolk, NY 11724-1423. 10. Owner: Full Name: Harborside Press LLC, John A Gentile Jr (Principal), Anthony Cutrone (Principal), Conor Lynch (Principal). Complete Mailing Address: 37 Main St, Cold Spring Harbor, NY 11724-1423. 11) Known Bondholders, Mortgagees, and Other Security Holders Owning or Holding 1 Percent or More of Total Amount of Bonds, Mortgages, or Other Securities: None. 12) Tax Cosmos Status:Communications N/A. 1 Q1 Q2 M Y K 13) Publication Title:C The ASCO Post. 14) IssuejaDate for Circulation Data Below: September 15, 2013. 25353a 07.9.13 133 2 15) Extent and Nature of Circulation - Average No. Copies Each Issue During Preceding 12 Months. a) Total Number of Copies (Net press run): 28,136. b)Legitimate Paid and/or Requested Distribution (By Mail and Outside the Mail) (1) Outside County Paid/Requested Mail Subscriptions stated on PS Form 3541: 15,756. (2) In-County Paid/Requested Mail Subscriptions stated on PS Form 3541: N/A. (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and other Paid or Requested Distribution Outside USPS®: N/A. (4) Requested Copies Distributed by Other Mail Classes Through the USPS (e.g. First-Class Mail®): 16. c) Total Paid and/or Requested Circulation (sum of 15b (1), (2,), (3), and (4): 15,772. d) Nonrequested Distribution (By Mail and Outside the Mail) (1) Outside County Nonrequested Copies Stated on PS Form 3541: 12,168. (2) In-County Nonrequested Copies Stated on PS Form 3541: N/A. (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail: N/A. (4) Nonrequested Copies Distributed Outside the Mail: 105. e) Total Nonrequested Distribution (Sum of 15d (1), (2), (3) and (4)) 12,273. f) Total Distribution (Sum of 15c and e): 28,045. g) Copies not Distributed: 91. h) Total (Sum of 15f and g) 28,136. i) Percent Paid and/or Requested Circulation: 56% 15) Extent and Nature of Circulation - No. Copies of Single Issue Published Nearest to Filing Date. a) Total Number of Copies (Net press run): 28,224. b)Legitimate Paid and/or Requested Distribution (By Mail and Outside the Mail) (1) Outside County Paid/Requested Mail Subscriptions stated on PS Form 3541: 15,097. (2) In-County Paid/Requested Mail Subscriptions stated on PS Form 3541: N/A. (3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and other Paid or Requested Distribution Outside USPS®: N/A. (4) Requested Copies Distributed by Other Mail Classes Through the USPS (e.g. First-Class Mail®): 19. c) Total Paid and/or Requested Circulation (sum of 15b (1), (2,), (3), and (4): 15,116. d) Nonrequested Distribution (By Mail and Outside the Mail) (1) Outside County Nonrequested Copies Stated on PS Form 3541: 12,860. (2) In-County Nonrequested Copies Stated on PS Form 3541: N/A. (3) Nonrequested Copies Distributed Through the USPS by Other Classes of Mail: N/A. (4) Nonrequested Copies Distributed Outside the Mail: 72. e) Total Nonrequested Distribution (Sum of 15d (1), (2), (3) and (4)) 12,932. f) Total Distribution (Sum of 15c and e): 28,048. g) Copies not Distributed: 176. h) Total (Sum of 15f and g) 28,224. i) Percent Paid and/or Requested Circulation: 54% 16) Total circulation does not include electronic copies. 17) Publication of Statement of Ownership for a Requester Publication is required and will be printed in the October 15 2013 issue of this publication. 18) Signature and Title of Editor, Publisher, Business Manager, or Owner: John A Gentile Jr, Publisher. Date: 9/26/13. I certify that all information furnished on this form is true and complete. I understand that anyone who furnishes false or misleading information on this form or who omits material or information requested on the form may be subject to criminal sanctions (including fines and imprisonment) and/or civil sanctions (including civil penalties).

STRENGTHEN HER DEFENSE

FDA-approved HER2* dimerization inhibitor (HDI) for the first-line treatment of HER2+ metastatic breast cancer (MBC)1,2

Indication

PERJETA速 (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin速 (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.

Boxed WARNING: 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.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. *HER2 = human epidermal growth factor receptor.

PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly improve progression-free survival PERJETA-based regimen extended median progression-free survival (PFS) to 18.5 months (from 12.4 months)1 6.1-Month Improvement in Median IRF-assessed PFS1* Placebo + Herceptin + docetaxel

100

PERJETA + Herceptin + docetaxel

HR=0.62† 95% CI [0.51-0.75] P<0.0001

80 70

18.5

PFS (%)

MONTHS

12.4

MONTHS

30 20 10 0

P+H+D Pl+H+D

20 MONTHS

402 406

345 311

267 209

139 93

83 42

32 17

10 7

0 0

Patients at risk

• At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

IRF = independent review facility; CI = confidence interval; HR = hazard ratio. *At the time of the final PFS analysis, OS was not mature and first interim OS analysis results did not meet the prespecified stopping boundary for statistical significance.1 † Stratified by prior treatment status and geographic region.1 The CLEOPATRA trial was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of patients with HER2+ locally recurrent, unresectable or metastatic breast cancer (HER2+ status was defined as IHC 3+ or FISH amplification ratio ≥2.0 as determined at a central laboratory) (N=808); patients were randomized in a 1:1 ratio to either PERJETA + Herceptin + docetaxel (n=402) or placebo + Herceptin + docetaxel (n=406).1

Important Safety Information Boxed WARNING: 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 —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 used during pregnancy or if a patient becomes pregnant while being treated with 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 —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

Additional Important Safety Information Left Ventricular Dysfunction

• In the randomized trial, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel

• 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 LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions, Hypersensitivity Reactions/Anaphylaxis

• PERJETA has been associated with infusion and hypersensitivity reactions • On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. 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 the randomized trial, the overall frequency of hypersensitivity reactions/ anaphylaxis was 10.8% in the PERJETA-treated group and 9.1% in the placebotreated group

Significantly prolong overall survival 34% reduction in risk of death with PERJETA1 Second Interim Overall Survival (OS) Results1 Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR=0.66 95% CI [0.52-0.84] P=0.0008‡

OS (%)

MEDIAN NOT YET REACHED

60 50

37.6

20 10 0

P+H+D PI+H+D

402 406

387 383

371 350

342 324

317 285

25 30 MONTHS 230 143 198 128

• More than 50% of patients in the PERJETA + Herceptin + docetaxel arm were alive at the time of the second interim analysis, thereby indicating that the median OS for this arm has not yet been reached1 • At the time of analysis, there were 113 (28.1%) and 154 (37.9%) deaths in the PERJETA + Herceptin + docetaxel arm and the placebo + Herceptin + docetaxel arm, respectively1

MONTHS

• Median follow-up was 30 months (1 year following the first interim analysis) for both the PERJETAbased regimen and the placebo + Herceptin + docetaxel arms (Kaplan-Meier estimate)1-3

84 67

33 22

9 4

0 0

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

Patients at risk

OS = overall survival. ‡ The HR and P-value for the second interim analysis of OS crossed the predefined efficacy stopping boundary (HR≤0.739, P≤0.0138).1

• Consistent PFS and OS benefit demonstrated across several HER2+ MBC patient subgroups1,3 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])1 • The incidence of Grade 3-4 hypersensitivity reactions/anaphylaxis was 2% in the PERJETA-treated group and 2.5% in the placebo-treated group according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) (version 3). Overall, 4 patients in the PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA • 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

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 • In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression, defined as 3+ IHC by Dako HercepTest™ or FISH amplification ratio ≥2.0 by Dako HER2 FISH PharmDx™ test kit. 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 with demonstrated proficiency in the specific technology being utilized

PER0001010503

Printed in USA.

06/13

Most Common Adverse Reactions • 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) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. References: 1. PERJETA Prescribing Information. Genentech, Inc. April 2013. 2. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119. 3. Swain SM, Kim S-B, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471.

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. 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 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. 4 CONTRAINDICATIONS None. 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 the randomized trial, 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 placebotreated 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. 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) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% 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-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial 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 PERJETA-treated 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 PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, 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% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated 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 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)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. 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 with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally 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-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 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. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. 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 on the PERJETA-treated group. 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 (version 3) 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 the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 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: 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 the randomized trial, 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%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial 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.

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)]. 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.

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 20-fold 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 the randomized trial, 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.

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

ASCOPost.com | OCTOBER 15, 2013

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Expert’s Corner Issues in Oncology

Comparative Effectiveness Research: Its Time Has Arrived A Conversation With Gary Lyman, MD By Ronald Piana

eigning in the nation’s runaway medical costs was an underlying theme of President Obama’s healthcare reform platform. Citing projects like The Dartmouth Atlas of Health Care, which documented large gaps in the quality, costs, and outcomes of health services around the country, the administration’s health-care policy proponents warned of the immediate need for better value in our healthcare system. In 2009, $1.1 billion of the President’s stimulus package was earmarked for comparative effectiveness research. Many in the oncology community initially viewed comparative effectiveness research as an overarching government program that would ultimately ration oncologists’ treatment options in order to save money. Health-care policy experts have made a strong case that comparative effectiveness research is an important instrument for comparing the value of competing strategies so that patients, providers, and policy makers can be offered appropriate recommendations for optimal care. However, while acceptance of comparative effectiveness research is growing, operational as well as political and cultural challenges remain. The simple definition of comparative effectiveness research is: a methodology that attempts to frame the delivery of health care by comparing the benefit and harm of available diagnostic, prognostic, and therapeutic strategies in representative patients to define the most effective, safe, and cost-effective approach. To get a better understanding of comparative effectiveness research and its relationship with oncology services, The ASCO Post recently spoke with Gary Lyman, MD, Professor of Medicine at Duke University and the Duke Cancer Institute, where he is Director of the Comparative Effectiveness and Outcomes Research Program.

Informed Decisions, Rational Choices How does the randomized controlled trials process fit in with comparative effectiveness research? First off, it is important to note that comparative effectiveness research has

been applied across the spectrum of cancer needs from prevention, screening, diagnosis, all the way through supportive care and end-of-life issues. In today’s difficult and rapidly changinghealth-care environment, we need alternative sources of evidence to guide the evaluation and approval of new interventions while also addressing the need to make informed public health decisions. Randomized controlled clinical trials and meta-analyses of such trials are still the gold standard and backbone of comparative effectiveness research and the most definitive way to assess treatment efficacy. However, the challenge with using randomized trials is that we simply don’t have trials that compare the vast

Placing Value Over Cost Linking cost savings with the central mission of comparative effectiveness research has perhaps given the impression to many in the oncology community that they are going to be overly scrutinized about the costs of the care they deliver. Have we cleared up that concern? Although we don’t specifically link cost savings to comparative effectiveness research, identifying interventions that provide the most value to patients is fundamental, and any cost benefits may certainly be a desired outcome. But cost is a relative issue. For instance, selecting the most appropriate targeted agent based on biomarkers associated with response, may increase effectiveness while at

The oncology community is beginning to truly understand that comparative effectiveness research is a tool for obtaining and evaluating the best real-world information available on real-world patients that can ultimately translate into better care. —Gary Lyman, MD

majority of clinical issues. Moreover, randomized controlled trials tend to be restricted in terms of eligibility and design, which limits the generalizability of their findings to the broader cancer population. To further evaluate effectiveness and assess less common or delayed toxicities in the broad cancer population, additional sources of evidence are needed to guide the evaluation and approval of new interventions and better guide clinical decisions in the oncology setting. The goal of comparative effectiveness research is to go beyond the boundaries of randomized trials and gather all the credible evidence on a given clinical question so that clinicians can make more rational choices in treatment selection. Comparative effectiveness research is not a license to do away with clinical trials; it is a way to make the best use of comparative data, and randomized trials will always be a component in that process.

the same time reducing harmful and expensive complications. So, more selective use of exciting yet expensive technologies may also reduce healthcare costs by increasing the value of cancer care. That said, the issue that oncologists have wrestled with when it comes to comparative effectiveness research is one of oversight. In other words, who gathers the evidence and what do they do with it? It becomes a matter of not having downstream knowledgeable clinical oversight in reviewing the evidence that will ultimately be used to formulate decisions about care. Community oncologists want to know how much control policymakers or Congressional committees will have over their clinical care decisions. Those concerns still need to be addressed. Needless to say, there are some members of the oncology community who believe that comparative effectiveness research is a backdoor to rationing care, which it is not.

Most importantly, it is essential that the oncology community and our professional society, ASCO, have a prominent seat at the comparative effectiveness research table defining the endpoints and the rigorous processes needed to interpret the evidence. Oncologists are the ones taking care of cancer patients in the clinic. If we don’t take the lead in this initiative to assess care, then other parties, such as payers or government policymakers will. That will not be a good result, so we need to be at the head of this discussion. When I began speaking about comparative effectiveness research several years ago, there was almost total pushback from oncology audiences. I don’t get that feeling anymore. The oncology community is beginning to truly understand that comparative effectiveness research is a tool for obtaining and evaluating the best real-world information available on real-world patients that can ultimately translate into better care.

Big Data There’s been a lot of interest in the development of rapid learning systems since the release of IOM’s report, The Learning Healthcare System. Does comparative effectiveness research dovetail with this exciting initiative, such as ASCO’s CancerLinQ? For one, the hope around integrating rapid learning health systems and comparative effectiveness research is that these systems will synchronize and adapt to the real-time data mining that can be used as a comparative effectiveness research evidence base. Naturally, this type of large-scale system is dependent on widespread adoption of electronic health records, which is a ways down the road. It’s important to note that although it makes intuitive sense to mine realtime clinical data, it is vital to understand both the strengths and limitations of the tools you use to gather the evidence. Ultimately, the rapid learning system, which is at the heart of ASCO’s CancerLinQ, uses observational data, which needs to be carefully quality controlled and can be biased by known as well as unknown confounding factors. That said, our continued on page 70

The ASCO Post | OCTOBER 15, 2013

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Expert’s Corner

Comparative Effectiveness Research continued from page 69

traditional methods of gathering data from meetings and journals, is almost instantly out of date by the following week. Therefore, the goal of rapid learning systems such as CancerLinQ is to provide a robust data bank of clinically dynamic evidence that we’ll be able to tap into and see how patients, across similar settings, are responding to their treatments. This is but one part of the comparative effective-

ness research framework, and like all rapidly culled observational data, it needs to be used wisely, with a full understanding of both the strengths and limitations.

Risk-to-Reward Equation Will comparative effectiveness research have a demonstrable effect on the

practice of oncology moving forward? I think it already has. The challenge that we still have to grapple with is rapidly escalating health-care costs. We all agree that assessing value of the cancer care we deliver demands balancing effectiveness and safety within a riskto-reward equation when it comes to treating our patients. So the value com-

ponent of the equation is already imbedded into our culture. Our next step forward is placing cost into that value equation. But we need to take the lead in that part of the discussion. And to that end, comparative effectiveness research is a tool we should embrace. n Disclosure: Dr. Lyman is a member of the ASCO Board of Directors.

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The ASCO Post

What if you could help the immune system respond to cancer cells? Editorial Correspondence

PD-L1 expression helps tumor cells evade the immune system

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

programmed death-ligand 1 (PD-L1), which binds to the PD-1 and B7.1 receptors on Tumor expression of

Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654

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

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

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

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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.

ASCOPost.com | OCTOBER 15, 2013

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Awards

Association of Community Cancer Centers Honors Paul F. Engstrom, MD, With Annual Clinical Care Achievement Award

aul F. Engstrom, MD, Acting Chairman of Medical Oncology and Senior Vice President of Extramural Research Programs at Fox

Chase Cancer Center was recently honored by the Association of Community Cancer Centers (ACCC) at the organization’s 30th National

Oncology Conference in Boston. Dr. Enstrom received the Association’s Annual Clinical Care Achievement Award. The Award is given to distin-

Paul F. Engstrom, MD

guished individuals who have made outstanding contributions to community cancer care and to patients with cancer.

A Career Devoted to Prevention and Early Detection 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

TCR

MHC

Tumor cell death

PD-1

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

Dr. Engstrom has devoted his professional and academic career to improving cancer prevention and early detection research and service. He established the first Cancer Prevention and Control Program in an NCI-designated cancer center at Fox Chase in 1979. Twelve years later, he established a highly successful and ongoing training and career development program that has groomed national leaders in cancer prevention and control research. Dr. Engstrom has served as an advisor on cancer prevention and screening boards for the American Cancer Society, Philadelphia Division, National American Cancer Society, American Association of Cancer Institutes, ASCO, and the NCI. Dr. Engstrom is also a founding member of the National Comprehensive Cancer Network Patient Guideline Committee. He is a worldwide spokesperson for the national guidelines to screen, diagnose, manage, and support cancer patients. n

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The ASCO Post | OCTOBER 15, 2013

PAGE 72

Direct from ASCO

Philanthropy Spotlight

Sheldon Davidson, MD: Helping Advance the Field of Oncology Through Philanthropy

heldon Davidson, MD, has been an ASCO member for nearly 30 years, and has been a donor to the Conquer Cancer Foundation since its origins as The ASCO Foundation nearly 15 years ago. As a practicing oncologist, Dr. Davidson’s explanation for why he has chosen to support the Conquer Cancer Foundation is succinct. “If we depended entirely on the government to support us, we would be going nowhere,” he said. “I think as professionals we have an obligation to advance the field as much as we can, to help young practitioners to be able to do research and support themselves while they’re doing it.” The Conquer Cancer Foundation is dedicated to building a world free from the fear of cancer in all its manifestations. However, during the month of October, the work that the Foundation and its supporters do to improve the treatment and outcomes

for patients with breast cancer comes to the forefront. Dr. Davidson cites breast cancer as the most common diagnosis in his Northridge, California, practice. “Although we’ve made significant advances, particularly with HER2positive disease, we still have a lot of room for improvement,” he said.

Research is the answer, and we need to support research. —Sheldon Davidson, MD

Conquering Breast Cancer Through Research In October, Breast Cancer Awareness month presents a unique opportunity for the entire breast cancer community—patients, caregivers, advocates, nonprofit organizations, and members of the cancer care team—to engage in the conversation surrounding the state of breast cancer care. For Dr. Davidson, hope and advocacy are crucial components of that discussion. “I think they have to have an optimistic point of view that advances are being made, that treat-

ment of breast cancer is something that we are well aware of and working on, and that they need to do whatever they can to push the government to help the field of oncology,” he said. Alongside that optimism is a continued commitment to advancing breast cancer care on multiple fronts. “We’ve made significant advances in treatment, but there’s a lot yet that we need to do for patients,” said Dr. Davidson. “For example, in the area of survivorship: How do we take

care of the patients after they’re done with their treatment? How do we follow them for second malignancies or complications of our treatment?” “Research is the answer, and we need to support research,” he said.

Conquer Cancer Foundation Grants and Awards In the past 4 years, the Conquer Cancer Foundation has provided more than $4.3 million in funding for continued on page 73

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

eadership has been cited as a critical success factor for improving access to cancer care in low- and middle-income countries.1 Effective clinical leaders in these countries can be transformative by supporting the development of cancer treatments to meet the needs of their patients, by advocating for national and international anticancer policies, and by develop-

ing and leading national and regional organizations that can advance cancer control in a localized, sustainable way. The Conquer Cancer Foundation of ASCO International Development and Education Award (IDEA) aims to support the development of oncology practice and improve access to cancer care in low- and middleincome countries by promoting the

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

Substantial Results The IDEA program produces substantial results. There are currently 205 IDEA alumni from over 40 countries, many of whom have assumed leadership positions on ASCO committees and in their local societies; received fellowships and other research opportunities; pursued longer-term collaborations with their mentors; helped organize ASCO trainings and other activities in their countries; and, in some instances, created oncology

societies where none previously existed. In addition, on average, each IDEA alumnus shares the information and new skills they learn with more than 80 colleagues in his/her country. The application cycle for IDEA opens October 1. Visit www.conquercancerfoundation.org/IDEA to apply or to make a donation to the Conquer Cancer Foundation. n Reference 1. Knaul F, et al: Closing the cancer divide: A blueprint to expand access in low and middle income countries. Boston, Harvard Global Equity Initiative, 2011. This article was partially excerpted from “ASCO and the Conquer Cancer Foundation: A Global Oncology Community Sharing Knowledge to Improve Patient Care,” published in Cancer Control 2013 on November 5, 2012, by publisher Global Health Dynamics. © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | OCTOBER 15, 2013

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Direct from ASCO

Sheldon Davidson, MD continued from page 72

breast cancer research, supporting not only projects focused on drug development and treatment regimens, but also on survivorship, genetics, sideand late-effect management, healthcare disparities, and the relationship between breast cancer and lifestyle factors like smoking and obesity. Conquer Cancer Foundation Grants and Awards are largely focused on early-career physicianscientists, helping them to launch enduring careers in research. A recent survey of past recipients on the occasion of the Grants and Awards Program’s 30th Anniversary revealed that more than 98% of past recipients of Conquer Cancer Foundation of ASCO Young Investigator and Career Development Awards remain active in oncology research. In the past 5 years, Foundation donors like Dr. Davidson have not only invested in individual breakthrough research projects in breast cancer, but also in establishing a professional pipeline of talented breast cancer researchers that will benefit patients—and advance the field of oncology—for decades to come.

Addressing the Full Spectrum of Cancer Care Breast cancer is just one diagnosis of many faced by the patients ASCO members treat every day, and the Conquer Cancer Foundation continues to work to build a world free from the fear of cancer for all pa-

tients. From the most common cancers to the most rare, from pediatric to geriatric oncology, from prevention, to survivorship, to end-of-life care, Conquer Cancer Foundation donors support a range of multidisciplinary projects encompassing the full continuum of oncology care.

Conquer Cancer Foundation supporters come from all walks of life, each with a unique connection to cancer and the practice of oncology. Many, like Dr. Davidson, are ASCO members, and are particularly committed to advancing the field of oncology through their

ASCO’s Quality Care Symposium

Trebananib (AMG 386) Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

TRINOVA-2: A Phase 3, Randomized, Double-Blind Trial of Pegylated Liposomal Doxorubicin (PLD) Plus Trebananib (AMG 386) or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

TRINOVA-3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Trebananib (AMG 386) With Paclitaxel and Carboplatin as First-Line Treatment of Women With FIGO Stage III-IV Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Primary Endpoint: • Progression-free survival (PFS)

Key Secondary Endpoint: • Overall survival (OS)

Key Secondary Endpoint: • Overall survival (OS) Combination Therapy Phase* Maintenance Phase (6 cycles) (for additional 18 months)

R A N D O M I Z A T I O N

Trebananib15 mg/kg IV QW + PLD 50 mg/m2 IV Q4W

ENDPOINTS Primary

PFS Key Secondary

Placebo IV QW + PLD 50 mg/m2 IV Q4W

R A N D O M I Z A T I O N

Trebananib IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Trebananib IV QW Monotherapy

ENDPOINTS

Primary

PFS 2:1 randomization

Placebo IV QW + Paclitaxel IV Q3W + Carboplatin IV Q3W

Key Secondary

Placebo IV QW Monotherapy

*Subjects with FIGO stage IIIC or IV disease undergoing planned interval debulking surgery (IDS) will receive 3 cycles of therapy prior to IDS and 3 cycles of therapy following IDS

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Save the Date

philanthropy. As Dr. Davidson puts it: “Everyone has to do their share. Everyone has to stand together, because if we don’t do it no one else is going to do it for us.” n

Trebananib is an investigational agent that has not been approved by regulatory agencies for the use under investigation for this trial.

Key Inclusion Criteria: • Subjects must have had one to three prior chemotherapeutic regimens • Radiographically documented disease progression either on or following the last dose of prior chemotherapeutic regimen • ECOG performance status of 0 or 1

Key Inclusion Criteria: • FIGO Stages III-IV epithelial ovarian, primary peritoneal or fallopian tube cancer with an indication for first-line treatment with paclitaxel and carboplatin • No prior use of any anticancer therapy or experimental therapy for epithelial ovarian, primary peritoneal or fallopian tube cancer • ECOG performance status of 0 or 1

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2009-017946-30 • www.ClinicalTrials.gov (NCT01281254)

For Additional Information: • Amgen Call Center: (866) 57-AMGEN • EudraCT 2011-001112-53 • www.ClinicalTrials.gov (NCT01493505)

The ASCO Post | OCTOBER 15, 2013

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Direct from ASCO

ASCO Survey: Drug Shortages Still a Problem Despite Slight Improvement

s part of its continued effort to monitor and assess the impact of oncology drug shortages, ASCO will be conducting the third round of its biannual survey of members. The results of the first two surveys indicated that serious problems persist in the accessibility of lifeextending oncology drugs, despite legislation that passed in July 2012 in an attempt to address the shortages.

Background on Shortages In 2010 and 2011, the number of chemotherapy drug shortages rose significantly, with more than 20 chemotherapeutic drugs reported

to be in short supply, compared to only four in 2009. The majority of these agents included decades-old, off-patent drugs—such as methotrexate, cytarabine, and fluorouracil—that are used in standard, evidence-based care of adult and pediatric patients with many types of cancer. Reasons cited for the shortages include manufacturing and quality problems, economic factors, and a lack of U.S. Food and Drug Administration (FDA) authority and resources—factors that are under consideration in multiple federal investigations of the issue. In a step to alleviate the crisis,

Discover ASCO’s Advanced Cancer Care Planning Booklet for Patients and Families

Cancer drug shortages are still interfering with oncologists’ mission to provide patients with the right treatments at the right times. —Andrew D. Seidman, MD

the reauthorization of the Prescription Drug User Fee Act (PDUFA) in July 2012 included provisions that ASCO had recommended to address drug shortages. The measure mandates an early-warning sys-

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting By Michael N. Neuss, MD, et al

Subspecialization in Community Oncology: Option or Necessity? By Dean H. Gesme, MD, et al

SCO’s popular Advanced Cancer Care Planning booklet was re-

tients, families, and caregivers find the information they need to guide them through an advanced cancer diagnosis, this booklet is the newest addition to the ASCO Answers family of patient cently updated with a different look education publications. New additions and new content. Designed to help pato the booklet include topics to assist caregivers and suggestions for discussing an advanced cancer diagnosis with various family members, including children. Download the booklet at www .cancer.net/advancedcancer or order packs of 125 for your office or Your source for public policy news waiting room through and information from ASCO the ASCO University Visit our newly designed one-stop source for the latest information on: Policy Information – get the latest news on key legislation and priorities such as Bookstore at www. access to care, clinical trials and drug shortages cancer.net/estore. All Advocacy Tools – take action with ASCO’s ACT Network booklets ship for free, Position Statements – see ASCO’s positions on current issues and ASCO members Stay informed by visiting receive a 20% dishttp://ascoaction.asco.org count. n

ASCO in

Ac ti o n

Follow @ascoaction on Twitter

Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

tem, requiring drug manufacturers to notify the FDA of a discontinuance or interruption in the production of a life-saving drug at least 6 months in advance. In addition, continued on page 80

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

What’s Hot in

JOP

JCO.org Reduction in Chemotherapy Order Errors With Computerized Physician Order Entry by Barry R. Meisenberg, et al

Potential Benefits of Treatment Summaries for Survivors’ Health and Information Needs: Results From a LIVESTRONG Survey by Ruth Rechis, et al

Skin Cancer Surveillance and Malignancies of the Skin in a Community-Dwelling Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia by Aaron S. Mansfield, et al

Financial Distress, Use of Cost-Coping Strategies, and Adherence to Prescription Medication Among Patients With Cancer by Leah L. Zullig, et al

Improving Quality of Cancer Care at Community Hospitals: Impact of the National Cancer Institute Community Cancer Centers Program Pilot by Michael T. Halpern, et al

ASCOPost.com | OCTOBER 15, 2013

PAGE 75

Direct from ASCO

Society Announces Candidates for ASCO Election

ourteen distinguished ASCO members have been selected by the ASCO Nominating Committee as candidates for open leadership positions within the Society for the 2014 ASCO Election. Biographic informa-

tion and interviews with each candidate, as well as instructions for casting a proxy ballot, will be made available at www.asco.org/election when proxy voting opens on Tuesday, October 29. The proxy voting will close on Tuesday,

November 26. The proxy ballots will be delivered to the ASCO President or his designee for official casting at a special meeting to be held on December 3, 2013, at ASCO Headquarters. Election results will be announced

2014 ASCO Candidates PRESIDENT-ELECT CANDIDATES Lynn M. Schuchter, MD, FASCO University of Pennsylvania Julie M. Vose, MD, MBA, FASCO University of Nebraska Medical Center BOARD OF DIRECTORS—COMMUNITY ONCOLOGIST CANDIDATES Linda D. Bosserman, MD, FACP Wilshire Oncology Medical Group Lynn M. Schuchter, MD, FASCO

William N. Harwin, MD Florida Cancer Specialists & Research Institute

Julie M. Vose, MD, MBA, FASCO

BOARD OF DIRECTORS— INTERNATIONAL ONCOLOGIST CANDIDATES David Khayat, MD, PhD, FASCO Pitié-Salpêtrière Hospital, France Purvish M. Parikh, MD, DNB, FICP, PhD, ECMO, CPI, MBA Indian Cancer Care Society, India BOARD OF DIRECTORS—RADIATION ONCOLOGIST CANDIDATES Thomas A. Buchholz, MD, FACR University of Texas MD Anderson Cancer Center

Linda D. Bosserman, MD, FACP

William N. Harwin, MD

David Khayat, MD, PhD, FASCO

Purvish M. Parikh, MD, DNB, FICP, PhD, ECMO, CPI, MBA

Thomas A. Buchholz, MD, FACR

Walter J. Curran, Jr, MD, FACR

Charles D. Blanke, MD, FACP, FRCPC, FASCO

Arti Hurria, MD

Blase N. Polite, MD, MPP

Gregory H. Reaman, MD, FASCO

David R. Spriggs, MD

Emile E. Voest, MD, PhD

Walter J. Curran, Jr, MD, FACR Emory University Winship Cancer Institute BOARD OF DIRECTORS— UNDESIGNATED SPECIALTY CANDIDATES Charles D. Blanke, MD, FACP, FRCPC, FASCO Oregon Health & Science University Knight Cancer Institute Arti Hurria, MD City of Hope NOMINATING COMMITTEE— UNDESIGNATED SPECIALTY CANDIDATES (2 OPEN SEATS) Blase N. Polite, MD, MPP The University of Chicago Center for Clinical Cancer Genetics & Global Health Gregory H. Reaman, MD, FASCO U.S. Food and Drug Administration Center for Drug Evaluation & Research David R. Spriggs, MD Memorial Sloan-Kettering Cancer Center Emile E. Voest, MD, PhD University Medical Center Utrecht, Netherlands.

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 (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

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

0 0

Time (months)

Patients at risk

A+G: 431 G: 430

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

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.

• 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

600

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 ABRAXANE(125 mg/m2)/Gemcitabined Gemcitabine 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%)

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%)

33 (8%)

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

Hypokalemia

52 (12%)

18 (4%)

28 (7%)

Respiratory, thoracic and mediastinal disorders

Cough

72 (17%)

30 (7%)

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%)

Depression

51 (12%)

1 (<1%)

24 (6%)

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 | OCTOBER 15, 2013

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Direct from ASCO

ASCO Survey: Drug Shortages continued from page 74

PDUFA expands the FDA’s authority to collect user fees from generic drug manufacturers as part of the regulatory approval process, which will provide the FDA resources to

speed generic drug application reviews, making the drugs available to patients sooner.

ASCO Survey Results Despite this legislation, which the FDA has stated has helped the agency mitigate some shortages

since its passage, ASCO survey data indicate that, although shortages appear to be improving very slightly, unavoidable drug substitution decisions persist. This is a troubling trend that has both patient care and cost implications. The first two surveys were con-

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. U.S. Patent Numbers: See www.celgene.com. ABR_PANC_HCP_BSv006 9_2013

ducted in October 2012 and April 2013, with 390 and 462 respondents, respectively. Among respondents to the first survey, 55% noticed an improvement between July 2012 and October 2012 in the availability of drugs included in the shortages, and 58% of respondents to the second survey had a similar assessment of the drugs’ availability between October 2012 and April 2013. However, 70% of respondents to the first survey and 59% of respondents to the second survey indicated that they were aware of ongoing drug substitutions resulting from the unavailability of standardly used drugs. In addition, some respondents to both surveys indicated that they were aware of dose alteration and the use of different treatment regimens. And they noted that a limited number of patients were using atypical drug procurement methods. Of note, those responding to the second survey indicated that although the shortage of chemotherapeutic agents seemed to be easing very slightly, significant concern was expressed over the growing shortages of supportive drugs such as opioids, IV fluids, and steroids. Commenting on the findings, ASCO spokesperson Andrew D. Seidman, MD, an oncologist at Memorial Sloan-Kettering Cancer Center in New York, said that cancer drug shortages are still interfering with oncologists’ mission to provide patients with “the right treatments at the right times.” Results of the third survey, which will be sent to ASCO members soon, will likely be released in mid to late November. n © 2013. American Society of Clinical Oncology. All rights reserved.

Report Drug Shortages Health-care professionals and health consumers may notify FDA of drug shortages. Reports may be sent via email to: drugshortages@fda.hhs.gov

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Journal Spotlight Genitourinary Oncology

Progression-Free Survival With Pazopanib Not Inferior to Sunitinib Benefit in Metastatic Renal Cell Carcinoma By Matthew Stenger

azopanib (Votrient) and sunitinib (Sutent) have been shown to provide progression-free survival benefit compared with placebo or interferon in phase III trials in metastatic renal cell carcinoma. In a noninferiority trial reported in The New England Journal of Medicine by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center, and colleagues, pazopanib was noninferior to sunitinib with regard to progression-free survival among patients with metastatic renal cell carcinoma.1 Moreover, the investigators reported that pazopanib was associated with better safety and quality-of-life profiles.

Study Details In this phase III open-label trial, 1,110 patients with clear-cell metastatic renal cell carcinoma from sites in 14 countries in North America, Europe, Australia, and Asia were randomly assigned to receive continuous dosing of pazopanib at 800 mg once daily (n = 557) or sunitinib in 6-week cycles of 50 mg once daily for 4 weeks followed by 2 weeks without treatment (n = 553 patients). The primary endpoint was progression-free survival, with the study being powered to show the noninferiority of pazopanib vs sunitinib. The study protocol was amended to increase the patient sample size to 1,100 patients after it became clear that the original planned enrollment (876 patients) would be insufficient to observe the necessary number of disease progression events. Instead of reopening enrollment in the original trial, targeted enrollment was achieved by prospectively combining the sample in the original trial (927 patients) with the sample in an ongoing trial (183 patients), a substudy of the original trial conducted in China, Taiwan, and

South Korea. The trials were identical in terms of patient selection criteria and design, except that health-related quality of life and medical resource utilization were not assessed in the substudy. The pazopanib and sunitinib groups were well balanced for age (median, 61 and 62 years), region (eg, North America for 35% and 34%, Asia for 34% and 32%), prior nephrectomy (82% and 84%), prior radiation therapy (8% in both), Karnofsky performance status (90–100 in 75% and 76%), lactate dehydrogenase ≤ 1.5 times upper limit of normal (93% and 95%), number of involved organs (≥ 3 in 42% and 44%), most common metastatic sites (eg, lung in 76% and 77%, lymph nodes in 40% and 45%), Memorial Sloan-Ket-

CI = 8.3–11.1 months) in the sunitinib group. The hazard ratio (HR) for pazopanib vs sunitinib was 1.05 (95% CI = 0.90–1.22), which met the predefined criterion for noninferiority. Subgroup analyses indicated that the results were not driven by any particular subgroup. Similar results were observed across ethnic groups and geographic regions. The post hoc hazard ratios for progression-free survival for pazopanib vs sunitinib were 1.06 (95% CI = 0.90–1.24) in the original study and 0.95 (95% CI = 0.60–1.48) in the substudy.

Response Rate and Overall Survival The objective response rate was 31% in the pazopanib group (includ-

Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib…. Our study showed lower monthly use of medical resources with pazopanib than with sunitinib. —Robert J. Motzer, MD, and colleagues

tering Cancer Center risk category (favorable in 27% in both, intermediate in 58% and 59%), and Heng risk category (favorable in 25% in both, intermediate in 54% and 56%).

Progression-Free Survival Median duration of treatment was 8.0 months in the pazopanib group and 7.6 months in the sunitinib group. Median progression-free survival was 8.4 months (95% confidence interval [CI] = 8.3–10.9 months) in the pazopanib group and 9.5 months (95%

Pazopanib vs Sunitinib in Renal Cell Carcinoma ■■ Pazopanib was noninferior to sunitinib in terms of progression-free survival in patients with metastatic renal cell carcinoma.

■■ Most adverse events, particularly those associated with discomfort, such as fatigue, hand-foot syndrome, and mouth sores, occurred more frequently with sunitinib.

■■ Pazopanib was associated with better quality-of-life outcomes, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet.

ing one complete response) vs 25% in the sunitinib group (including three complete responses; P = .03). Median overall survival was 28.4 months (95% CI = 26.2–35.6 months) in the pazopanib group and 29.3 months (95% CI = 25.3–32.5 months) in the sunitinib group (HR = 0.91, P = .28 on stratified log-rank test).

Safety Common adverse events of any grade that occurred in > 10% of patients in either group and that were reported significantly more frequently with sunitinib included hand-foot syndrome, mucosal inflammation, stomatitis, hypothyroidism, dysgeusia, dyspepsia, epistaxis, and fatigue. Those reported significantly more frequently with pazopanib included changes in hair color, weight loss, and alopecia. Sunitinib patients had a significantly higher risk of grade 3 or 4 fatigue (18% vs 11%) and hand-foot syn-

drome (12% vs 6%) and higher risk of hematologic laboratory abnormalities of any grade and of grades 3 and 4, including grade 3 or 4 leukopenia (6% vs 1%), thrombocytopenia (22% vs 4%), neutropenia (20% vs 5%), and anemia (7% vs 2%). Pazopanib patients had significantly higher risk of increased levels of ALT or bilirubin and hypoglycemia of any grade and higher risk of grade 3 or 4 increases in ALT (17% vs 5%), AST (12% vs 3%), and alkaline phosphatase (3% vs 1%). Cardiac dysfunction criteria were met by 13% of pazopanib patients and 11% of sunitinib patients, and the incidence of myocardial infarction or ischemia was 2% and 4%. Drug-related fatal adverse events occurred in 1% of both groups. Dose interruption for at least 7 days occurred in 44% of pazopanib patients and 49% of sunitinib patients, dose reduction occurred in 44% and 51%, and discontinuation of study drug occurred in 24% and 20%, with the higher rate in the pazopanib group being primarily due to liver function test abnormalities (6% vs 1%).

Medical Resource Utilization Pazopanib patients had significantly fewer monthly telephone consultations (P = .04) and emergency department visits (P = .003). In addition, pazopanib recipients had nonsignificantly fewer medical visits unrelated to the study and hospital days per month.

Quality of Life During the first 6 months of treatment, the pazopanib group had significantly better outcomes on 11 of 14 quality-of-life measures, including the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (P < .001); the Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) scales for treatment side effects (P = .03), disease-related physical symptoms (P = .03), and total score (P = .02); the Cancer Therapy Satisfaction Questionnaire scores for feelings about side effects (P < .001) and satisfaction with therapy (P < .001); and the Supplementary Quality of Life Questionnaire scores for worst continued on page 82

The ASCO Post | OCTOBER 15, 2013

PAGE 82

Journal Spotlight

Pazopanib vs Sunitinib in Metastatic Renal Cell Carcinoma: How Do We Choose? By Brian I. Rini, MD

ver the past decade, the field of metastatic renal cell carcinoma therapy has witnessed the development of multiple drugs targeting the vascular endothelial growth factor (VEGF) pathway, based on the underlying biology of renal cell carcinoma that leads to reliance on angiogenic signaling. The initial investigation of these agents compared them to either placebo or interferon, an old standard of care. More recently, comparisons of active VEGFtargeted agents have taken place, providing insight into the relative risks and benefits of each agent. In general, VEGF-targeted agents are able to more effectively control disease for longer periods of time than historic therapy, but since they are noncurative, they involve ongoing therapy with ongoing toxicity.

COMPARZ Findings In this light, recent data from the COMPARZ trial provide a comparison of the benefit and tolerability of Dr. Rini is Associate Professor of Medicine at Lerner College of Medicine and Cleveland Clinic Taussig Cancer Institute.

Pazopanib in RCC continued from page 81

mouth or throat soreness (P < .001), worst hand soreness (P = .002), worst foot soreness (P = .001), limitations due to mouth or throat soreness (P < .001), and limitations due to foot soreness (P = .01). Effect sizes were of a magnitude conventionally

sunitinib (Sutent) and pazopanib (Votrient). The results provide reassurance to practitioners that both agents are effective in the initial treatment of metastatic renal cell carcinoma. Progression-free survival was similar and in line with previous studies, with

pazopanib. Several quality-of-life indicators favored pazopanib, reflecting these toxicity profile differences. Also notably, the incidence of drug interruption/dose reduction was similar, but more patients treated with pazopanib discontinued because of

It is most important to develop expertise in optimally administering a given drug that best balances the benefit/risk profile for an individual patient, accounting for comorbidities and how specific toxicities will affect the individual. —Brian I. Rini, MD

overall survival reaching nearly 2.5 years, likely reflecting the multitude of active agents that renal cell carcinoma patients now receive in sequence. Noteworthy was the different toxicity profile of the two agents, with more fatigue, mucositis, and handfoot syndrome seen with sunitinib, and more liver function abnormalities, weight loss and alopecia with

toxicity. This latter point highlights the difficulty in assessing the comparative safety and tolerability of two agents. That is, examination of toxicity incidence, quality-of-life scores, or the need to modify/discontinue a drug due to toxicity may lead to different interpretations, and no single measure accurately captures comparative safety/tolerability.

considered small to medium (0.20– 0.50) for seven of these differences, small (< 0.20) for 3, and medium to large (0.50–0.80) for the difference in mouth and throat soreness. The investigators concluded: “Pazopanib and sunitinib have similar efficacy, but the safety and quality-oflife profiles favor pazopanib…. Our

study showed lower monthly use of medical resources with pazopanib than with sunitinib. These end points, plus health-related quality of life and the safety profile, assume special importance in comparative-effectiveness research when clinically similar (noninferior) treatments are being considered.” n

Developing Expertise In the end, it is most important to develop expertise in optimally administering a given drug that best balances the benefit/risk profile for an individual patient, accounting for comorbidities and how specific toxicities will affect the individual. Further, developing a comfort level about when to modify dose or schedule and when to change to another therapy is critical for maximizing clinical outcome and tolerability. The benefit of VEGF-targeted therapy with a single agent or sequence of agents has likely been maximized in metastatic renal cell carcinoma, with additional refinements being focused on increasing tolerability through schedule adjustments, drug holidays, and improvements in supportive care. Biomarkers to guide drug selection remain elusive but are still highly sought after. Clinical trials remain a priority to test novel agents and build upon the advances achieved with VEGFtargeted therapy. n Disclosure: Dr. Rini has received research funding and is a consultant for GlaxoSmithKline and Pfizer.

Disclosure: The study was funded by GlaxoSmithKline Pharmaceuticals. For full disclosures of the study authors, visit www. nejm.org.

Reference 1. Motzer RJ, Hutson TE, Cella D, et al: Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369:722-731, 2013.

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The ASCO Post | OCTOBER 15, 2013

PAGE 84

Journal Spotlight Breast Cancer

Accelerated Partial-Breast Irradiation Using 3D Conformal Radiation Therapy Causes More Adverse Events Compared With Whole-Breast Irradiation By Matthew Stenger

he RAPID trial compared accelerated partial-breast irradiation using three-dimensional (3D) conformal external-beam radiation therapy vs whole-breast irradiation in women with invasive or in situ breast cancer ≤ 3 cm. As reported by Ivo A. Olivotto, MD, FRCPC, of the British Columbia Cancer Agency, and colleagues in the Journal of Clinical Oncology, interim cosmetic results from the trial show that adverse cosmesis at 3 years was significantly increased among patients treated with accelerated partial-breast irradiation compared with whole-breast irradiation as assessed by trained nurses, patients, or physicians.1 Although grade 3 or 4 toxicities were infrequent in both groups, grade 1 or 2 toxicities were more frequent with partial-breast irradiation.

ments and on physician panel assessment using digital photographs. After a planned interim cosmetic analysis, the Data, Safety, and Monitoring Committee recommended release of results. There have been too few ipsilateral breast tumor recurrence events to trigger a primary efficacy analysis. Patients in the whole-breast irradiation and accelerated partial-breast irradiation groups were well matched for age (≥ 50 years in 88% of both), cancer type (invasive in 81% and 82%), tumor size (≥ 1.5 cm in 38% and 39%), estrogen receptor status (positive in 88% and 91%), tumor grade (I in 40% and 42% and II in 41% and 40%), presence of lymphatic or vascular invasion (6% in both), receipt of chemotherapy (16% and 15% of patients with invasive cancers), and endocrine therapy

Clinicians and patients are cautioned against the use of [this approach] outside the context of a controlled trial. —Ivo A. Olivotto, MD, FRCPC, and colleagues

Study Details In this multicenter trial, 2,135 women aged greater than 40 years with invasive or in situ breast cancer ≥ 3 cm were randomly assigned after breast-conserving surgery to 3D conformal radiotherapy–based accelerated partial-breast irradiation (38.5 Gy in 10 fractions twice daily; n = 1,070) or whole-breast irradiation (42.5 Gy in 16 or 50 Gy in 25 daily fractions with or without boost irradiation; n = 1,065). The primary outcome was ipsilateral breast tumor recurrence. Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score on trained nurse and patient assess-

(67% and 69%). At baseline, for the whole-breast vs partial-breast irradiation groups, 17% vs 19% of patients on nurse assessment and 22% vs 24% on patient assessment had adverse cosmesis (no significant differences between groups).

Cosmesis Outcomes Median follow-up was 36 months. The whole-breast irradiation dose was 42.5 Gy in 16 fractions for 82% of whole-breast irradiation patients, and 21% of whole-breast irradiation patients received boost irradiation. At 3 years, adverse cosmesis was increased among those treated with partial-breast irradiation compared with

Accelerated Partial-Breast Irradiation vs Whole-Breast Irradiation ■■ At 3 years, adverse cosmesis was increased among those treated with accelerated partial-breast irradiation compared with whole-breast irradiation as separately assessed by trained nurses, patients, and physicians.

■■ Accelerated partial-breast irradiation was associated with significantly greater rates of grade 1 or 2 late toxicities.

■■ The investigators caution clinicians and patients against the use of 3D

conformal external-beam radiation therapy–based accelerated partialbreast irradiation outside the context of a controlled trial.

whole-breast irradiation as assessed by trained nurses (29% vs 17%, P < .001), by patients (26% vs 18%, P = .0022), and by physicians (35% vs 17%, P < .001). At 5 years, adverse cosmesis was also increased with accelerated partialbreast irradiation on nurse assessment (32% vs 13%, P < .001) and patient assessment (32% vs 22%, P = .034). There was no physician assessment at 5 years. An analysis of nurse-assessed cosmesis at 3 years according to fractionation and boost radiation among whole-breast irradiation patients showed adverse cosmesis for 16% of patients receiving 42.5 Gy in 16 fractions vs 17% of those receiving 50 Gy in 25 fractions (P = .77) and in 17% of patients without a boost vs 16% of those who received a boost (P = .88).

Toxicities Grade 3 toxicities were rare in both the partial-breast irradiation and whole-breast irradiation groups (1% vs 0%) and there were no grade 4 toxicities. Grade 3 toxicities in the accelerated partial-breast irradiation group consisted of telangiectasia, induration or fibrosis, breast pain, and fatty necrosis, with each observed in < 1% of patients. Overall, grade 1 or 2 toxicities were significantly more frequent among patients in the partial-breast irradiation group (P < .001). Telangiectasia (grade 1 or 2 in 17% vs 7%) and breast induration (50% vs 28%) were sig-

nificantly more common with partialbreast irradiation (P < .001). Grade 1 breast pain was common (25% after whole-breast irradiation, 30% after partial-breast irradiation) and grade 2 to 3 breast pain was uncommon (0.5% and 1%). Fat necrosis was uncommon but was significantly more likely after partial-breast irradiation than wholebreast irradiation (3% vs 0.9%, P = .01). The magnitude of differences in toxicity between treatment groups at 5 years was similar to that at 3 years. The authors noted that a number of ongoing trials will contribute additional level I evidence regarding the safety and efficacy of different approaches to accelerated partial-breast irradiation. They concluded: “3D [conformal external-beam radiation therapy–based accelerated partial-breast irradiation] increased rates of adverse cosmesis and late radiation toxicity compared with standard whole-breast irradiation. Clinicians and patients are cautioned against the use of [this approach] outside the context of a controlled trial.” n Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Olivotto IA, Whelan TJ, Parpia S, et al: Interim cosmetic and toxicity results from RAPID: A randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy. J Clin Oncol. July 8, 2013 (early release online).

ASCOPost.com | OCTOBER 15, 2013

PAGE 85

Awards

Jean B. Owen, PhD, Named 2013 ASTRO Honorary Member at Annual Meeting

he American Society for Radiation Oncology (ASTRO) selected health-care researcher Jean B. Owen, PhD, as the 2013 Honorary Member, the highest honor ASTRO bestows on distinguished cancer researchers, scientists, and leaders in disciplines other than radiation oncology, radiobiology, and radiation physics. Dr. Owen was inducted as the 2013 ASTRO Honorary Member during ASTRO’s 55th Annual Meeting. “Dr. Owen’s extensive work in establishing and analyzing benchmarks for optimal care in radiation oncology has been instrumental to the high quality of care our specialty provides cancer patients,” said Michael L. Steinberg, MD, FASTRO, Chairman of ASTRO’s Board of Directors. “Her continuous collaboration with physician investigators, including many ASTRO members, is a testament to her commitment to ASTRO, to radiation oncology and, most importantly, to our patients.”

ate an environment of critical selfassessment within radiation oncology and to build a foundation of quality assessment data that is now embedded within the culture of the

specialty.” She added “I am proud to officially become a member of this outstanding organization that I have long felt very much a part of.” Dr. Owen is currently a health

care consultant and is pursuing a Graduate Certificate in Research Ethics at the Medical College of Wisconsin’s Graduate School of Biomedical Sciences in Milwaukee. n

Work at American College of Radiology During her 23-year tenure at the American College of Radiology (ACR) Clinical Research Center, Dr. Owen served as project director of the Quality Research in Radiation Oncology (QRRO) project. As the leader of QRRO, she was vital in the development of detailed clinical performance measures and survey processes to measure quality of care benchmarks in radiation oncology nationwide. “PCS produced national data for the radiation oncology practice that assessed the quality of radiation oncology throughout all types of practices. Over the years, QRRO evolved to address and measure highly specific quality measures in this constantly evolving, technically advanced specialty,” Dr. Owen said. “The major impact was to help cre-

More from ASTRO See pages 104-107 for more news from ASTRO

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The ASCO Post | OCTOBER 15, 2013

PAGE 86

Journal Spotlight Breast Cancer

Increased Alcohol Consumption Between Menarche and Pregnancy Increases Breast Cancer Risk By Matthew Stenger

dult alcohol consumption during the previous year is related to breast cancer risk, and breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. In a study reported in Journal of the National Cancer Institute, Ying Liu, MD, PhD, of Washington University School of Medicine in St. Louis, and colleagues assessed the association between alcohol consumption between menarche and first pregnancy and risk for breast cancer and proliferative benign breast disease.1 They found that increased alcohol consumption before pregnancy was associated with increased risk for both breast cancer and benign breast disease.

Drinking Before Pregnancy A total of 1,609 breast cancer cases between 1989 and 2009 were identified. Ageadjusted incidence rates were 197 cases per 100,000 person-years among women who had ≥ 15 g/d alcohol intake before first pregnancy and 144/100,000 person years among nondrinkers before first pregnancy. After adjustment for age, questionnaire year, current body mass index, age at menarche, menopausal status, average body size between 5 and 10 years of age, family history of breast cancer in mother or sisters, postmenopausal hormone use, total duration of breast-feeding, and parity and age at first pregnancy, the cumu-

Drinking After Pregnancy Age-adjusted breast cancer incidence rates were 195/100,000 person-years for ≥ 15 g/d alcohol intake after first pregnancy and 138/100,000 person-years for nondrinking after first pregnancy. The adjusted relative risk for breast cancer for alcohol intake after first preg-

[This study] provides evidence that alcohol consumption before first pregnancy was dose-dependently associated with increased risk of both proliferative [benign breast disease] and breast cancer, independent of drinking after first pregnancy.

Study Details The study involved data from 91,005 parous women in the Nurses’ Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60,093 women who had no history of benign breast disease or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative benign breast disease risk. Among the 91,005 women, 20.4% did not drink alcohol between menarche and first pregnancy and 3.8% reported moderate to high alcohol consumption (≥ 15 g/d, or at least approximately 1.3 drinks per day). Compared with nondrinkers, women who drank alcohol between menarche and first pregnancy were younger by 1 to 2 years at baseline and, after adjustment for age, were older at first pregnancy by 2 to 3 years and were more likely to have a first-degree family history of breast cancer (7% vs 5%). Cumulative average alcohol consumption between menarche and pregnancy was moderately correlated with both current drinking at baseline and cumulative average drinking since first pregnancy.

P = .051 for trend); relative risk was not significant for those with cumulative average intake of 0.1–4.9 g/d (1.05, 95% CI = 0.90–1.22) or 5.0–14.9 g/d (1.07, 95% CI = 0.89–1.29) and was borderline significant for those with intake ≥ 15.0 g/d (1.34, 95% CI = 1.00–1.80).

—Ying Liu, MD, PhD, and colleagues

lative average alcohol consumption between menarche and first pregnancy was associated with increased risk for breast cancer with a relative risk (RR) per 10 g/d intake (approximately 6 drinks/ week) of 1.13 (95% confidence interval [CI] = 1.03–1.24; P = .01 for trend). Relative risk was not significant for those with cumulative average intake of 0.1–4.9 g/d (1.08, 95% CI = 0.94–1.23) or 5.0–14.9 g/d (1.11, 95% CI = 0.94–1.32) and was significant for those with intake ≥ 15.0 g/d (1.41, 95% CI = 1.07–1.86). After additional adjustment for drinking after first pregnancy, the relative risk for drinking before first pregnancy remained borderline significant (1.11 per 10 g/d intake, 95% CI = 1.00–1.23;

New Data on Drinking and Breast Cancer Risk ■■ Risk for breast cancer was significantly increased by 13% for each 10 g/d

increase in alcohol consumption between menarche and first pregnancy and by 11% after adjustment for drinking after pregnancy.

■■ Risk associated with increased drinking appeared to be greatest among women with longer duration between menarche and first pregnancy.

nancy was 1.11 per 10 g/d intake (95% CI = 0.99–1.24; P = .06 for trend); relative risk was not significant for those with intake of 0.1–4.9 g/d (1.09, 95% CI = 0.93–1.28), 5.0–14.9 g/d (1.17, 95% CI = 0.95–1.43), or ≥ 15.0 g/d (1.30, 95% CI = 0.93–1.83). With additional adjustment for cumulative drinking before first pregnancy, the relative risk was 1.09 per 10 g/d (95% CI = 0.96–1.23; P = .20 for trend); relative risk was not significant for those with intake of 0.1– 4.9 g/d (1.04, 95% CI = 0.86–1.26), 5.0– 14.9 g/d (1.10, 95% CI = 0.87–1.40), or ≥ 15.0 g/d (1.21, 95% CI = 0.84–1.76).

Time Between Menarche and Pregnancy Risk was greater among women with ≥ 10 years between menarche and first pregnancy (RR per 10 g/d 1.21, 95% CI = 1.08–1.36) compared with those with a duration of < 10 years (RR = 0.87, 95% CI = 0.69–1.10; P = .01 for interaction). Relative risk was 1.14 (95% CI = 0.97–1.34) among those with a duration of 10 to 14 years and 1.25 (95% CI = 1.06–1.48) among

those with a duration of ≥ 15 years. Analysis by estrogen receptor (ER) and progesterone receptor (PR) status showed that cumulative drinking before first pregnancy tended to be more strongly related to risk of ER-positive/ PR-positive tumors (RR = 1.18 per 10 g/d intake, 95% CI = 1.03–1.34) compared with the risk for ER-positive/ PR-negative tumors (RR = 0.86, 95% CI = 0.60–1.22) and ER-negative /PRnegative tumors (RR = 0.84, 95% CI = 0.60–1.16; P = .06 for heterogeneity).

Proliferative Benign Breast Disease A total of 970 proliferative benign breast disease cases were confirmed by central histology review. The relative risk for benign breast disease per 10 g/d intake between menarche and first pregnancy was 1.16 (95% CI = 1.02–1.32), which was greater than risk associated with drinking after pregnancy (RR = 0.94, 95% CI = 0.79–1.11; P = .08 for heterogeneity). Age-adjusted incidence rates were 298/100,000 person-years for ≥ 15 g/d intake and 271/100,000 person-years for nondrinkers. The association between alcohol consumption before first pregnancy and proliferative benign breast disease appeared to be restricted to women with longer duration between menarche and first pregnancy. The investigators concluded: “[This study] provides evidence that alcohol consumption before first pregnancy was dose-dependently associated with increased risk of both proliferative [benign breast disease] and breast cancer, independent of drinking after first pregnancy. This increase in risk tended to be more pronounced among women with a longer time interval between menarche and first pregnancy compared with women with a shorter interval, consistent with breast cancer risk models…. Reducing alcohol consumption during this period may be an effective prevention strategy for breast cancer.” n

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. Liu Y, Colditz GA, Rosner B, et al: Alcohol intake between menarche and first pregnancy: A prospective study of breast cancer risk. J Natl Cancer Inst. August 28, 2013 (early release online).

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Journal Spotlight

Alcohol Consumption Between Menarche and Pregnancy and Breast Cancer Risk: Factors in Risk Accumulation By Graham A. Colditz, MD, DrPH

n a study recently published in the Journal of the National Cancer Institute and summarized in this issue of The ASCO Post, we found a relationship between alcohol intake between menarche and first pregnancy and risk for breast cancer. Placing this study in context can help us interpret the data and the implications for prevention of breast cancer. When in life will we gain the most benefit from prevention programs? How much should we change lifestyle, for how long, and at what age? And when we have known carcinogens, such as alcohol, are there other components of lifestyle (for example, diet or physical activity) that can counter their adverse effects?

rates is now seen in Asian countries as they pass through the economic and epidemiologic transition.6,7

Key Time Interval Animal models of breast cell proliferation together with human data sup-

port a slower rate of risk accumulation after the first pregnancy. This evidence continued on page 88

Known Carcinogens Alcohol is a known breast cancer carcinogen. The International Agency for Research on Cancer (IARC), which reviews scientific evidence against defined criteria, lists alcohol as a breast carcinogen.1 It is also well known to cause head and neck cancer, colorectal cancer, and liver cancer. We also know that reproductive factors including menarche, first pregnancy, number and spacing of children, and age at menopause drive in large part a woman’s lifetime risk of breast cancer.2,3 Risk accumulates across the life course with the rate of increase in accumulated tissue damage highest from menarche to first pregnancy. With industrialization, we have seen age at menarche drop from an average of 17 or 18 in lowincome agrarian societies, to around 12 in high-income countries.4,5 Parity has decreased (from 6 or 7 to an average of around 2), and age at first birth has increased with greater access to education and safe contraception for women. With these changes, we have an increase in breast cancer incidence. Incidence has increased in industrialized countries over the past 100 years, and this increase in incidence Dr. Colditz is Associate Director, Prevention and Control, Alvin J. Siteman Cancer Center, and Niess-Gain Professor, Washington University School of Medicine, St. Louis.

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Journal Spotlight

Alcohol and Breast Cancer Risk continued from page 87

shows that the interval from menarche to first pregnancy is the time for most rapid accumulation in risk.8 With industrialization, this time interval has been extended, perhaps by more than 15 years. In the current study, we add alcohol to the underlying accumulation through the early reproductive

lifestyle factors in this time period that may increase or decrease risk. We, and others, have studied physical activity in this time period and show that it is also related to protection against breast cancer.12,13 Diet in this time period is less commonly studied, in part because following women from adolescence to adult years and actual breast cancer development takes so long. Concern that recall of diet is somewhat less accurate

Clearly, more studies are warranted to build on these data and to show how alcohol increases risk, how diet may reduce risk, and how we can use markers of risk to better understand the pathways involved in risk increase and risk reduction. —Graham A. Colditz, MD, DrPH

years and observe that the adverse effect of alcohol in the breast cells during this interval is greatest when the interval is longer. One challenge of studying adolescent exposures and breast cancer risk is that prospective studies are hindered by the extended time interval from menarche or adolescence to the years when breast cancer is diagnosed. To help overcome some of the elapsed time, we have used benign breast lesions as an intermediate marker of risk.9 Proliferative benign lesions double a woman’s risk for invasive breast cancer.10 From this study, it is also clear that higher alcohol intake in adolescence and early adult years drives an increase in risk for benign breast lesions that carry the highest risk of subsequent breast cancer.11 By using these proliferative benign lesions as an endpoint, we shorten the interval for follow-up and see that the risk associated with higher alcohol consumption is also present for these premalignant lesions. Together, these data show resoundingly that this time period from menarche to first full-term pregnancy is critical for breast cancer risk accumulation.

Other Risk Factors From these data, one would therefore infer that we should explore other

has limited the number of studies asking women in their 30s to recall past diet and then following them over time for development of breast lesions.14,15 We have overcome some of this difficulty with our study of daughters of women participating in the Nurses’ Health Study (NHS) II, in which we assessed diet in the teenage years and followed participants to their 20s and early 30s. It was found that higher vegetable protein and vegetable fat intake is related to lower risk of benign breast lesions confirmed by breast biopsy16. We also asked women in the first Nurses’ Health Study and the NHSII to recall their high school diet.17 We followed them forward from this recall and observed that those who reported higher fiber intake (regardless of source from fruit, vegetables, or grains) had significantly lower subsequent risk of proliferative benign breast lesions (those that carry the very highest risk of progression to breast cancer).18 Other components of diet have not been studied as thoroughly in relation to benign lesions, although milk intake has been found to be unrelated to risk,19 and a recent conference presentation showed that higher carotenoid intake was inversely related to risk. Studies of soy intake at the level achieved in the traditional Asian diet

also show that childhood and adolescent intake are strongly inversely related to risk of breast cancer.20,21

Further Research Clearly, more studies are warranted to build on these data and to show how alcohol increases risk, how diet may reduce risk, and how we can use markers of risk to better understand the pathways involved in risk increase and risk reduction. With such information, we will be better positioned to inform prevention strategies that can reduce breast cancer risk through improved diet, physical activity, and limitation of alcohol intake, together leading to a reduced burden of breast cancer in the United States and globally. n Disclosure: Dr. Colditz reported no potential conflicts of interest.

References 1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2007: Lyon France). Alcohol consumption and ethyl carbamate. Lyon, France; International Agency for Research on Cancer; Distributed by WHO Press; 2010. 2. Rosner B, Colditz GA, Willett WC: Reproductive risk factors in a prospective study of breast cancer: The Nurses’ Health Study. Am J Epidemiol 139:819-835, 1994. 3. Colditz G, Rosner B: Cumulative risk of breast cancer to age 70 years according to risk factor status: Data from the Nurses’ Health Study. Am J Epidemiol 152:950-964, 2000. 4. Cho GJ, Park HT, Shin JH, et al: Age at menarche in a Korean population: Secular trends and influencing factors. Eur J Pediatr 169:89-94, 2010. 5. Morris DH, Jones ME, Schoemaker MJ, et al: Secular trends in age at menarche in women in the UK born 1908-93: Results from the Breakthrough Generations Study. Paediatr Perinat Epidemiol 25:394400, 2011. 6. Seow A, Duffy S, McGee M, et al: Breast cancer in Singapore: Trends in incidence 1968-1992. Int J Epidemiol 25:4045, 1996. 7. Jung YS, Na KY, Kim KS, et al: Nation-wide Korean breast cancer data from 2008 using the breast cancer registration program. J Breast Cancer 14:229-236, 2011. 8. Pike MC, Krailo MD, Henderson BE, et al: “Hormonal” risk factors, “breast tissue age” and the age-incidence of breast cancer. Nature 303:767-770, 1983.

9. Berkey CS, Willett WC, Frazier AL, et al: Prospective study of adolescent alcohol consumption and risk of benign breast disease in young women. Pediatrics 125:e1081-e1087, 2010. 10. London SJ, Connolly JL, Schnitt SJ, et al: A prospective study of benign breast disease and the risk of breast cancer. JAMA 267:941-944, 1992. 11. Liu Y, Colditz G, Rosner B, et al: Alcohol intake between menarche and first pregnancy: A prospective study of breast cancer risk. J Natl Cancer Inst. August 28, 2013 (early release online). 12. Maruti SS, Willett WC, Feskanich D, et al: A prospective study of age-specific physical activity and premenopausal breast cancer. J Natl Cancer Inst 100:728-737, 2008. 13. Bernstein L: Exercise and breast cancer prevention. Curr Oncol Rep 11:490-496, 2009. 14. Maruti SS, Feskanich D, Colditz GA, et al: Adult recall of adolescent diet: reproducibility and comparison with maternal reporting. Am J Epidemiol 161:8997, 2005. 15. Maruti SS, Feskanich D, Rockett HR, et al: Validation of adolescent diet recalled by adults. Epidemiology 17:226229, 2006. 16. Berkey CS, Willett WC, Tamimi RM, et al: Vegetable protein and vegetable fat intakes in pre-adolescent and adolescent girls, and risk for benign breast disease in young women. Breast Cancer Res Treat. September 17, 2013 (early release online). 17. Frazier AL, Willett WC, Colditz GA: Reproducibility of recall of adolescent diet: Nurses’ Health Study (United States). Cancer Causes Control 6:499506, 1995. 18. Su X, Tamimi RM, Collins LC, et al: Intake of fiber and nuts during adolescence and incidence of proliferative benign breast disease. Cancer Causes Control 21:1033-1046, 2010. 19. Berkey CS, Willett WC, Tamimi RM, et al: Dairy intakes in older girls and risk of benign breast disease in young women. Cancer Epidemiol Biomarkers Prev 22:670-674, 2013. 20. Wu AH, Yu MC, Tseng CC, et al: Epidemiology of soy exposures and breast cancer risk. Br J Cancer 98:9-14, 2008. 21. Lee SA, Shu XO, Li H, et al: Adolescent and adult soy food intake and breast cancer risk: results from the Shanghai Women’s Health Study. Am J Clin Nutr 89:1920-1926, 2009.

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FDA Update

FDA Approves Neoadjuvant Pertuzumab for Early-Stage Breast Cancer

n September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and docetaxel for patients with early-stage breast cancer in the neoadjuvant setting. Pertuzumab is the first FDA-approved drug for the neoadjuvant treatment of breast cancer. Pertuzumab was approved in 2012 for the treatment of patients with advanced or late-stage HER2-positive breast cancer.

Results are expected in 2016. The most common side effects reported in participants receiving pertuzumab plus trastuzumab and docetaxel were hair loss, diarrhea, nausea, and neutropenia. Other significant side ef-

fects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis. n Reference 1. Gianni L, Pienkowski T, Im YH, et

al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomized multicenter, open-label, phase 2 trial. Lancet Oncol 13:25-32, 2012.

New Indication Pertuzumab’s new indication is for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (tumor > 2 cm in diameter or with positive lymph nodes) who are at high risk of having their cancer re-

turn or metastasize or of dying from the disease. It is to be used in combination with trastuzumab and other chemotherapy prior to surgery and, depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.

Phase II Trial Pertuzumab’s accelerated approval for neoadjuvant treatment is based on a phase II study designed to measure pathologic complete response.1 In the study, 417 participants were randomly assigned to receive one of four neoadjuvant treatment regimens: trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. About 39% of participants who received pertuzumab plus trastuzumab and docetaxel achieved pathologic complete response, compared to about 21% of those who received trastuzumab plus docetaxel. The confirmatory trial for this accelerated approval is being conducted in participants with HER2-positive breast cancer who had prior breast cancer surgery and are at high risk of having their cancer return. More than 4,800 participants are enrolled in this trial, which will provide further data on efficacy, safety, and long-term outcomes.

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The ASCO Post | OCTOBER 15, 2013

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Aftermath of the AIDS Pandemic: Cancer Care in Botswana A Conversation with Bruce A. Chabner, MD By Ronald Piana

he Republic of Botswana is slightly smaller than the state of Texas and with a population of just over 2 million people it is one of the world’s most sparsely populated countries. Botswana was among Africa’s poorest countries at the time it gained independence from the United Kingdom in 1966. Since then, the small nation has transformed its political and economic structure, becoming a stable democracy, and offering its people a modest standard of living.

valuable cancer-care relationships in sub-Saharan Africa. Would you please discuss the long-standing BotswanaHarvard relationship in studying the AIDS epidemic? The partnership was established about 10 years ago to help cope with a very high incidence of HIV infection in an adult population. The Botswana-Harvard partnership has expanded over the years. The partnership now has about 300 people, which is based on the campus of the

The Second Wave of Disease Like many sub-Saharan nations, Botswana was hit hard by the AIDS pandemic. And although the HIV/ AIDS treatment model has emerged as one of the more successful global public health-care initiatives, many sub-Saharan countries including Botswana have experienced a surge in cancers related to immune suppression, the so-called second wave of disease related to AIDS. Outreach and teaching programs have been developed by many in the global oncology community to address the growing cancer care needs in developing nations. Recently, Bruce A. Chabner, MD, Professor of Medicine at Harvard Medical School, and Director of Clinical Research at Massachusetts General Hospital Cancer Center in Boston, and a team of colleagues traveled to Gaborone, the capital of Botswana, to visit hospitals and clinics responsible for physician training and cancer care. Dr. Chabner shared his experience with The ASCO Post.

The Botswana-Harvard Relationship Several institutions in Boston, notably Massachusetts General Hospital and other members of Dana-Farber/ Harvard Cancer Center, have created Bruce A. Chabner, MD, is Professor of Medicine at Harvard Medical School, and Director of Clinical Research at Massachusetts General Hospital Cancer Center in Boston.

dence of HIV-related cancers. Jason Efstathiou, MD, Assistant Professor of Radation Oncology at Massachusetts General Hosptial, leads the MGH team that has established the BOTSOGO initiative to link MGH and physicians in Botswana. He specializes in genitourinary oncology. Dr. Efstathiou and his team traveled to Botswana to collaborate and assist the local oncology community in dealing with complex cases of cervical cancer. The group quickly

Treating cancer patients, whether in Boston or Gaborone is essentially the same. We’re all doctors with the same goal, giving our patients the best care possible. —Bruce Chabner, MD

Princess Marina Hospital, one of the largest hospitals in Botswana. The partnership has a rotating and permanent faculty, including a number of people from Harvard. It’s been a very effective program in establishing research projects and ensuring that drugs were made available to people with HIV infections.

concluded that a brachytherapy facility would best serve the population’s needs, because radioactive seed implantation doesn’t require daily visits to the clinic, sparing patients the burden of multiple, long-distance trips. Anthony Henryk (Tim) Russell, MD, Director of Gynecologic Oncol-

ogy Service at Massachusetts General Hosptial and an expert in cervical cancer, also made several trips to Botswana and set up a brachytherapy facility at the Gaborone private hospital. A radiation therapist, Memory Nsingo, MD, who directs the local facility in Gaborone, became the partner on site to form the collaboration that made it possible. They now treat about 60 cervical cancer patients a month and have become experts at delivering brachytherapy for cervical cancer. This collaboration proved very successful for cancer patients and their doctors.

Serious Health-Care Issues Is Botswana making headway in its cancer care system? In many ways, Botswana is a country of contradictions. For one, it has a very stable government, unlike many of its neighboring countries. Botswana also has a comprehensive universal health-care system for all its citizens. Comparatively, its per-capita income is also relatively high. It has a rapidly growing economy. That said, the country has serious health-care issues. Although Botswana is building some fine medical facilities, the nation’s biggest challenge is establishing enough training

New Collaboration Would you tell us about the new cancer collaboration in Botswana, informally named BotsOGO (Botswana Oncology Global Outreach)? About two-thirds of the cancers in Botswana are related to the underlying issues of HIV infection. A whole series of HIV-related tumors are increasing in incidence, including cervical cancer, Kaposi sarcoma, various lymphomas, and squamous carcinomas of the skin, head and neck, cervix, and other squamousbased sites. About 3 years ago, the Department of Radiation Oncology at Massachusetts General Hospital was contacted and asked for help in treating this rapidly rising inci-

Dr. Chabner examining a patient on the cancer ward in Gaborone Hospital.

continued on page 92

In the research of advanced cancers

What if the PD-1 checkpoint pathway played an important role in tumor growth? The programmed death 1 (PD-1) checkpoint pathway plays a key role in modulating the immune system. However, some tumors exploit this pathway to evade the bodyâ&#x20AC;&#x2122;s protective immune response to cancer1-5 In a normal state, the immune system recognizes tumors and can mount an active antitumor response6,7 Antigen-presenting cell

Step 1:

Tumor releases antigen8 T cells

Through tumor-immune surveillance, activated T cells can eradicate tumor cells from the body 6,7

Step 2:

Antigen-presenting cells activate T cells that proliferate, migrate to, and attack the tumor8

Tumor

One way that tumors can evade normal immune attack is by exploiting the PD-1 immune checkpoint pathway via the PD-1 receptor1,2,5

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway. This inhibits activated T cells and suppresses T-cell attack1,2,4,5

PD-1 receptor

By exploiting the PD-1 checkpoint pathway, cancer cells evade the immune response and continue to proliferate1,2,6,8 PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2. References: 1. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptopic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 2. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 3. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 4. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 5. Dong H, Strome SE, Salomao DR, et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 6. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 7. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 8. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.bmsimmunooncology.com. ÂŠ2013 Bristol-Myers Squibb Company. All rights reserved. ONCUS13UB01112-02-01 06/13 Printed in USA.

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Cancer Care in Botswana continued from page 90

programs for medical subspecialists such as oncologists, radiation oncologists, and surgical oncologists. Other physician specialists, particularly pathologists, are in very short supply. Another obstacle is establishing community outreach programs and training health-care workers in the oncology sector to perform follow-up visits. Patient health records are not digitized, which fragments the longterm continuum of care. The new medical school at the University of Botswana is graduating its first class of doctors in 2015, so the prospects for improvement are there. But the facilities are simply overwhelmed with cancer patients. A 400-bed university hospital for tertiary care is also under development, but recruiting the necessary medical faculty to operate an institution of that size is an uphill battle. The government is very much behind initiatives that will speed up the process of building a better cancer care

infrastructure, but they have benefitted from the outside. Besides Massachusetts General Hospital, there are many universities from the United States that are collaborating with the Botswana officials and health-care providers. For instance, the University of Pennsylvania has shared expertise in gynecologic oncology, and Baylor University has a physician on site helping develop a pediatric oncology program. Equally important, however, is that the government is very engaged in these collaborations. In fact, next year we plan to have a conference in Botswana with many American cancer centers and hospitals in attendance. The goal is to help develop a roadmap toward building a comprehensive cancer care strategy for Botswana. Is there sufficient access to cancer drugs? The short answer is no. Public access to oncology drugs is largely confined to generic cytotoxic agents; targeted molecules and biologics are cost-prohibitive, limited to private

sources only. Drug shortages for common medicines are a frustrating problem for doctors trying to carry out long-term care. And palliative care medications for nausea and pain are very limited. This is one of the issues to be addressed at the conference.

A Rich Experience How did officials and medical staff receive your team? We were greeted with open arms by everyone, from government ministers to medical school and hospital officials, to the cancer patients on the wards. As a whole, the people of Botswana are incredibly friendly. Although Botswana faces significant challenges, it is a well-adjusted nation with a bright future ahead, particularly if it can harness the economic wealth of its mineral resources. Our team from Massachusetts General Hosptial had a rich experience. It was rewarding for me to see such enthusiasm among our young oncology fellows as they took part in teaching rounds and patient care.

Is there anything to learn from the Botswana experience that is generalizable to care in the United States? Yes, of course. There is a lot to be learned in terms of how to best treat various diseases in a low-resource environment. Naturally, doctors in the United States have almost unlimited access to state-of-the-art drugs and therapies, but we also face our own issues with costs, so there is much to be learned from doctors who work in a environment of constant medical triage. Plus, it’s revitalizing for us to work in close collaboration with doctors and specialists from a totally foreign culture. Treating cancer patients, whether in Boston or Gaborone, is essentially the same. We’re all doctors with the same goal, giving our patients the best care possible. n

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

Editor’s note: For more on experiences in Botswana, see the discussion with Julie Livingston, PhD, MPH, below.

View From a Cancer Ward in Botswana

ulie Livingston, PhD, MPH, is a Professor of History at Rutgers University. She is also an African historian with interdisciplinary training in public health and anthropology. Among other issues, her work considers the challenges of delivering oncology services in southern Africa, where there is a rapidly emerging cancer population. In fact, more than half of all new cancer cases occur in the developing world, and according to epidemiologic studies, those numbers are steadily rising. This crisis is magnified in southern Africa given that the rising cancer incidence is emerging in the shadow of the vast HIV/AIDS phenomenon. Between 2006 and 2009, Dr. Livingston worked and conducted research in a 20-bed cancer ward and its associated clinic in Botswana’s central referral hospital, located in the capital city, Gaborone. Dr. Livingston recently spoke with The ASCO Post.

Early Work in Africa When did you begin working in Africa? I first began working Botswana in the mid-1990s. I had a fellowship that was contingent on learning an African Julie Livingston, PhD, MPH, is Professor of History at Rutgers University. She is also an African historian with interdisciplinary training in public health and anthropology.

language, and I learned Setswana. I really liked the country of Botswana, so I stayed there to do my doctoral dissertation work. I arrived there during

either have a small copay, or if you meet certain criteria, no copay at all. They have a very accessible primary care system that feeds throughout a

The success of the antiretroviral program is important in many ways, for one, it sets a precedent for what’s possible in cancer care in southern Africa. We can all learn from that. Courtesy of the John D. & Catherine T. MacArthur Foundation. See more at http://www .macfound.org/fellows/895

the country’s huge escalation of the HIV/AIDS epidemic. It’s now been about 20 years since I’ve followed the AIDS crisis, and now the overlapping rise in cancer incidence.

A Forward-Looking Country Please describe the cancer ward that was the central focus of your experience between 2006 and 2009. I’m confident that things have improved since I was last there in 2009 because Botswana is a forward-looking country with a very dynamic universal health-care system. Citizens

—Julie Livingston, PhD, MPH

network connected by two large hospitals, one in the North, and one in the South. The cancer care system however, is far more challenged. The cancer ward was in the central referral hospital in Gaborone. It was constantly full, putting unrelenting pressure on the oncologist to turn beds over to provide care for as many patients as possible. The ward draws patients from all over the country. You would have a cattle herder from the Kalahari in a bed next to a banker from Barclays. So universal care is truly universal care in Botswana.

Challenges and Limitations Could you describe the oncology services? Patients needing radiation therapy were sent to the city’s private hospital, all at the government’s expense. The public hospital’s cancer ward offered generic chemotherapy and surgical procedures. Patients with leukemia, on the other hand, had to be sent to South Africa because isolation conditions are nonexistent in Botswana. There are a number of basic cancer treatment essentials that are also lacking. For instance, you can’t really put a port in a patient for chemotherapy because the conditions in the ward don’t allow for the prevention of dangerous infections. Concurrent chemoradiotherapy also is not possible, because there simply is not the necessary medical support system to care for the side effects. Another problem is the shortage of laboratories and tests, and a bottleneck in scheduling time for minor procedures in the surgical theater, to enable biopsies. When I was there, the oncologist was also a skilled cytologist who did all his own cytology. But he returned home to Zimbabwe, leaving a void in that vital diagnostic area. One day you can have an excellent maxillofacial surgeon who fulfills important needs, but if that surgeon

ASCOPost.com | OCTOBER 15, 2013

leaves, the position might go unfilled for quite some time. Or if an expensive technical machine breaks, the hospital will undoubtedly have a hard time negotiating a repair contract with the manufacturer. So, the shortages of resources are compounded with a shortage of qualified health specialists and support infrastructure.

Palliative Care in the Developing World Since many patients in the developing world present with advanced cancers palliative care is essential, but often lacking. What was your experience with palliation in the ward in Botswana? On the broader question of palliation, there is an international network of drug laws in place to prevent the illicit trade of narcotics, which also inadvertently prevents most terminally ill African patients from getting pain relief. However, when this particular ward was opened in 2002, the oncologist in charge pushed very hard to establish an ethos of palliative care. In the context of this particular cancer ward, the medical and nursing staff were fairly attentive to pain issues, compared to what I have seen in other places. They used oral morphine, codeine, pethidine, and nonopioid analgesics. That said, the morphine supply would routinely go in and out of stock. Another problem arises when cancer patients are discharged from the hospital, many of whom live far distances away in rural villages, with no local access to morphine. Another huge gap in cancer care is access to antiemetic agents, making the intersection between untreated pain and nausea a living hell for many cancer patients. However, I’ve seen patients just across the border in Zimbabwe suffering in intractable pain because there are simply no opioid analgesics available in that country. This is something that should not be; it is unnecessary and preventable suffering. How has the AIDS epidemic overlapped with cancer in Botswana? In multiple ways, for example, the public antiviral program and the AIDS industry arrived and shined a bright light that exposed everything, especially the cancers that were already there before. Women with breast cancer, elderly men with multiple myeloma, patients with osteogenic sarcoma were suddenly vis-

PAGE 93

ible because an oncology service was established to treat the cancers that were arising in AIDS patients now on antiretrovirals. There’s a complicated relationship between the two diseases. AIDS is not only creating cancers like Kaposi sarcoma, but the attendant immunosuppression of the disease makes treating cancers all the more challenging.

AIDS has also become Africa’s iconic experience of illness under which all other diseases are measured in the both treatment and suffering. Patients who were successfully treated for AIDS are now living long enough to develop B:8.25”opportunist AIDS-related cancers.T:7.5” I’ve had cancer patients tell me that they wished S:6.75” they had AIDS instead, because

AIDS was treatable and cancer was just too awful. That’s a very powerful statement. The success of the antiretroviral program is important in many ways, for one, it sets a precedent for what is possible in cancer care in southern Africa. We can all learn from that. n Disclosure: Dr. Livingston reported no potential conflict of interest.

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

INVESTIGATIONAL PHASE 3 TRIAL CURRENTLY ACCRUING

Cabozantinib vs everolimus phase 3 trial in metastatic renal cell carcinoma (RCC) KEY ELIGIBILITY CRITERIA • Diagnosis of RCC with a clear cell component

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

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

Cabozantinib 60 mg QD Randomization (1:1)

Global, randomized, open-label, controlled trial

Everolimus 10 mg QD

The ASCO Post | OCTOBER 15, 2013

PAGE 94

Journal Spotlight Genitourinary Oncology

ALSYMPCA Trial: Updated Analysis of Survival With Radium-223 Treatment in Metastatic Prostate Cancer By Matthew Stenger

n a trial (ALSYMPCA trial) reported in The New England Journal of Medicine, Chris Parker, MD, from Royal Marsden Hospital in Surrey, UK, and colleagues compared the alpha emitter radium-223 dichloride (Xofigo) with best standard of care in men with castration-resistant prostate cancer and bone metastases.1 Interim analysis showed that radium-223 treatment was associated with significantly prolonged overall survival, resulting in termination of the trial. An updated analysis, performed before crossover of the control group to radium-223 treatment, confirmed the overall survival advantage.

Study Details In this phase III double-blind trial, 921 patients who had received, were not eligible to receive, or declined docetaxel were randomly assigned to receive six injections of radium-223 at a dose of 50 kBq/kg (n = 614) or matching placebo (n = 307), one injection every 4 weeks, with all patients also receiving the best standard of care. Patients in the radium-223 and placebo groups were well matched for age (median, 71 years in both), race (94% white in both), total alkaline phosphatase levels (< 220 U/L in 57% and 55%), current bisphosphonate use (41% and 40%), any previous use of docetaxel (57% in both), ECOG performance status (0 or 1 in 87% and 86%), WHO cancer pain ladder score (1 in 42% and 45%), extent of disease (6–20 metastases in 43% and 48%, >20 in 32% and 30%), and receipt of externalbeam radiation therapy within 12 weeks after screening (16% in both). Median levels of hemoglobin, albumin, total alkaline phosphatase, and prostate-specific antigen (PSA) were similar at baseline.

Significantly Improved Overall Survival A prespecified interim analysis involving 809 patients showed that radium-223 treatment was associated with significantly prolonged overall survival compared with placebo (median, 14.0 vs 11.2 months,

hazard ratio [HR] = 0.70, P = .002). An updated analysis in all 921 patients, performed before crossover from placebo to radium-223, showed a similar survival advantage for radium-223 treatment (median, 14.9 vs 11.3 months, HR = 0.70, P < .001). The investigators found no significant heterogeneity among subgroups, including those with baseline total alkaline phosphatase ≥ 220 U/L, with and without current bisphosphonate use, with and without previous docetaxel use, with performance status of 0 or 1, with 6 to 20 and > 20 metastases, and with or without opioid use. Thus, the evidence suggests that the benefit of radium-223 is consistent across all subgroups examined. All main secondary efficacy endpoints supported the benefit of radium-223, including significantly prolonged time to first symptomatic

ALSYMPCA Update ■■ Radium-223 treatment plus best standard of care was associated with

significantly prolonged overall survival compared with best standard of care in men with metastatic castration-resistant prostate cancer and bone metastases.

■■ Radium-223 treatment was associated with significantly prolonged time to first symptomatic skeletal event, time to increase in total alkaline phosphatase level, and time to increase in PSA level.

■■ Radium-223 treatment was associated with low myelosuppression rates and fewer adverse events.

P < .001), with this reduction being sustained 4 weeks after the last injection in more radium-223 patients (14% vs 4%, P < .001).

Safety Radium-223 treatment was associated with lower rates of any adverse event (93% vs 96%, grade 3 or 4 adverse events (56% vs 62%), serious adverse events (47% vs 60%), and

The treatment of prostate cancer has evolved since the trial began, with new data on the use of cabazitaxel, abiraterone, and enzalutamide in patients who have received docetaxel. The excellent safety profile of radium-223 and the non-overlapping mechanism of action make radium-223 potentially suitable for use either sequentially or in combination with these other agents. —Chris Parker, MD, and colleagues

skeletal event (median, 15.6 vs 9.8 months, HR = 0.66, P < .001), time to increase in total alkaline phosphatase level (HR = 0.17, P < .001), and time to increase in PSA level (HR = 0.64, P < .001). In addition, significantly more radium-223 recipients had alkaline phosphatase response (≥ 30% reduction, P < .001) and normalization of total alkaline phosphatase level (P < .001). A ≥ 30% reduction in PSA blood levels at week 12 occurred in more patients in the radium-223 group (16% vs 6%,

adverse events leading to study drug discontinuation (16% vs 21%). Hematologic adverse events of grade 3 or higher included anemia in 13% of patients in both groups, thrombocytopenia in 6.5% and 2%, and neutropenia in 3% and 1%. Grade 3 febrile neutropenia occurred in one patient in each group. The most common nonhematologic adverse events of grade 3 or higher were bone pain (21% in the radium-223 group and 26% in the placebo group), fatigue (5% and 6%), and spinal cord com-

pression (3.5% and 6%). Serious adverse events that occurred in ≥ 5% of patients in the radium-223 group or the placebo group consisted of bone pain (10% and 16%), anemia (8% and 9%), and spinal cord compression (4% and 5%). Assessment of quality of life using the Functional Assessment of Cancer Therapy–Prostate (FACTP) questionnaire showed that more patients in the radium-223 group had meaningful improvement (≥ 10 point increase in score) during treatment (25% vs 16%, P = .02) and that the radium-223 group had a smaller reduction in score from baseline to week 16 (mean change, −2.7 vs −6.8, P = .006). The investigators noted, “The treatment of prostate cancer has evolved since the trial began, with new data on the use of cabazitaxel [ Jevtana Kit], abiraterone [Zytiga], and enzalutamide [Xtandi] in patients who have received docetaxel. The excellent safety profile of radium-223 and the non-overlapping mechanism of action make radium-223 potentially suitable for use either sequentially or in combination with these other agents.” A phase I/ II trial of radium-223 combined with docetaxel in patients with castrationresistant prostate cancer and bone metastases is underway (ClinicalTrials.gov number, NCT01106352). n Disclosure: The trial was funded by Algeta and Bayer HealthCare Pharmaceuticals.

Reference 1. Parker C, Nilsson S, Heinrich D, et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213-223, 2013.

ASCOPost.com | OCTOBER 15, 2013

PAGE 95

Journal Spotlight

Radium-223 and Beyond in Metastatic Castration-Resistant Prostate Cancer By Maha Hussain, MD, FACP, FASCO

etastasis to bone is the hallmark of prostate cancer and a major source of disease-related morbidity and mortality. In addition to prostate cancer cells, other major players in the vicious interactive cycle of prostate cancer bone metastasis are osteoblasts, osteoclasts, and mineralized bone matrix—together producing a heterogeneous mixture of osteoblastic and osteolytic lesions, the net effects of which, if uncontrolled, include bone pain, pathologic fractures, cord compression, and disease progression leading to death. Therefore, the targeting of bone in this disease has been a clinical and research focus for several decades, including evaluation of numerous interventions targeting different key pathways. Several agents have received FDA approval based on pain palliation or reduction of skeletal-related events. The first bone-targeted agent to be approved was strontium chloride Sr-89, with other subsequently approved agents including zoledronic acid, samarium Sm-153 lexidronam pentasodium (Quadramet), and denosumab (Xgeva). However, none of these agents demonstrated a significant effect on objective disease progression or survival. Furthermore, most were tested in an era with limited effective therapy for management of metastatic castrationresistant prostate cancer.

Radium-223 Trial In a recently reported phase III trial, radium-223 (Xofigo), an alpha emitter that selectively binds to areas of increased bone turnover in bone metastases, was associated with significantly prolonged overall survival (14.9 months) as compared with placebo (11.3 months) in patients with metastatic castration-resistant prostate cancer with or without prior docetaxel therapy. Dr. Hussain is Cis Maisel Professor of Oncology, Professor of Medicine and Urology, Associate Director for Clinical Research, Co-Leader, Prostate Cancer Program, University of Michigan Comprehensive Cancer Center.

It is important to highlight that patients included in the study were not excluded based on prior docetaxel therapy and were required to have symp-

tomatic bone metastasis with regular use of analgesics or treatment with external-beam radiation therapy for cancer-related bone pain within 12 weeks

from registration. However, patients were excluded if they had a history of or current visceral disease irrespective of continued on page 96

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The ASCO Post | OCTOBER 15, 2013

PAGE 96

Journal Spotlight

Radium-223 in Prostate Cancer continued from page 95

site or significant malignant adenopathy (> 3 cm in the short-axis diameter). Although the study allowed concomitant best “standard of care,” technically that did not involve any agent with a demonstrated impact on survival. The observed survival benefit was consistent across several important patient and disease-related characteristics, including prior docetaxel therapy.

Remaining Questions With its positive impact on survival, radium-223 becomes another important therapeutic agent in the expanding armamentarium of agents that can improve survival in patients with metastatic castration-resistant prostate cancer. However, several questions remain to be answered to help guide optimal use of this and similar agents in everyday practice. For example, although radium-223 significantly prolonged the time to the first symptomatic skeletal event (median, 15.6 vs 9.8 months) compared to placebo, it is not clear what impact it had on pain reduction or elimination. The study required either symptomatic disease with regular use of analgesics or recent treatment

with external-beam radiation therapy for cancer-related bone pain, so it is unclear if the observed effects can be extrapolated to patients with asymptomatic bone metastasis. The trial was conducted in an era predating availability of abiraterone (Zytiga) and

cancer metastasis beyond bone. In addition to lymph nodes, for example, data from the S9916 and TAX-327 studies indicate that at least one-fifth of patients had visceral disease—and this number may increase as patients live longer and get exposed to more agents. Therefore,

Considering the totality of the disease biology and the modest impact on survival with currently approved single agents, it is critical that multitargeted, biologically and mechanistically rational combination therapy strategies be pursued. —Maha Hussain, MD, FACP, FASCO

enzalutamide (Xtandi); therefore, it is not clear if the effects of the agent will be applicable in the setting of a rapidly evolving treatment landscape or whether it may be more optimally used in combination or sequential therapy strategies.

Bone-Targeted Therapy Although bone is the major clinically evident site of disease, data from autopsy series and clinical trials clearly highlight the systemic nature of prostate

within the context of the totality of metastatic castration-resistant prostate cancer disease biology, bone only–targeted therapy as single agent is not adequate—which is why it will be important to see the outcomes of the planned combination trials with radium-223. Another important point worth highlighting is the fact that the results of this trial provide the long-awaited first proof of principle that effective bone-targeted therapy can impact survival—adding another validated target

in addition to androgen receptors and microtubules. Going forward, it will be important to further evaluate the role of this agent in earlier settings—eg, in patients with metastatic castration- resistant prostate cancer and asymptomatic bone metastasis, particularly in combination therapy, and in patients with hormone-sensitive prostate cancer and bone metastasis, in combination with androgen deprivation.

Conclusions The past decade has seen unprecedented progress in the management of patients with metastatic castrationresistant prostate cancer. Although these patients now have many options, the disease continues to be terminal. Considering the totality of the disease biology and the modest impact on survival with currently approved single agents, it is critical that multitargeted, biologically and mechanistically rational combination therapy strategies be pursued. Ideally, this will be done in carefully defined disease populations in order to enhance antitumor effect, maximize benefit /risk ratio, and ultimately produce a more profound impact on survival. n Disclosure: Dr. Hussain will be one of the lead investigators for an upcoming randomized phase II trial sponsored by Bayer.

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PAGE 97

Journal Spotlight

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 (%)

Median PFS

7.8 months

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

0 0

Time (months) AFINITOR plus exemestane (n/N=310/485)

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: •

•

• •

•

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.

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

•

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 e Median duration of treatment 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.

T:14”

B:14.25”

S:13”

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 reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012

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American Society for Radiation Oncology Annual Meeting Prostate Cancer

Long-Term Androgen Deprivation in Patients With Intermediate-Risk Prostate Cancer Does Not Improve Overall Survival

en with advanced prostate cancer typically receive hormonal therapy to reduce the level of androgens in their bodies. Although hormone therapy alone will not cure prostate cancer, lowering androgen levels can reduce the size of prostate tumors or stall their growth. A secondary analysis of the historic Radiation Therapy Oncology Group (RTOG) 9202 prostate cancer trial examined results of men with intermediate-risk prostate cancer who had received long-term hormonal therapy after radiation therapy. Investigators concluded that there were no additional benefits when compared to short-term hormonal therapy. The research was recently presented at the American Society for Radiation Oncology’s 55th Annual Meeting.1

Study Details The original RTOG 9202 trial evaluated the potential benefits of long-term adjuvant androgen depri-

vation for 2 years after initial androgen deprivation when compared to short-term (initial) androgen therapy in mostly high-risk prostate cancer patients receiving external-beam radiation therapy.2 Because some patients with intermediate-risk prostate cancer were included in the study, the current

cer with T2 disease (tumor confined to the prostate), a prostate-specific antigen (PSA) of < 10 ng/mL, and a Gleason score of 7; or who were immediate-risk prostate cancer patients with T2 disease, PSA of 10 to 20 ng/ mL, and a Gleason score < 7. A total of 133 patients were ana-

Most clinicians have felt that ‘more was better’ when it came to blocking testosterone in prostate cancer patients; however, results for the specific endpoints we focused on, overall survival and disease-specific survival, indicate that this was clearly not the case. —Amin Mirhadi, MD

analysis was conducted to determine whether patients in the intermediaterisk subset experienced an additional survival benefit with long-term adjuvant androgen deprivation therapy. Researchers reviewed all patients enrolled in RTOG 9202 categorized with intermediate-risk prostate can-

Long-Term Adjuvant Androgen Deprivation in Prostate Cancer ■■ The current analysis of the RTOG 9202 prostate cancer trial was conducted

to determine if patients in the intermediate-risk subset experienced an additional survival benefit with long-term adjuvant androgen deprivation.

■■ There was no statistical difference in overall survival or disease-specific in the short-term androgen therapy group vs the long-term adjuvant androgen deprivation group.

■■ The data support administering less treatment, which will result in fewer side effects and reduce patients’ overall health-care costs.

lyzed. The long-term adjuvant androgen deprivation group consisted of 59 patients, and the short-term androgen therapy group consisted of 74 patients. Statistical analysis was used to determine overall survival, disease-specific survival, and PSA failure rates. The median follow-up was more than 11 years.

Outcomes There was no statistical difference in overall survival with 10-year estimates of 61% for the short-term androgen therapy group and 65% for the long-term adjuvant androgen deprivation group. Disease-specific survival was found to be 96% in both groups. PSA failure occurred in 38 patients in the short-term androgen therapy group and in 33 patients in the long-

term adjuvant androgen deprivation group. Ten-year PSA failure rates were 53% for the short-term androgen therapy group and 55% for the long-term adjuvant androgen deprivation group (P = .99). “Most clinicians have felt that ‘more was better’ when it came to blocking testosterone in prostate cancer patients; however, results for the specific endpoints we focused on, overall survival and disease-specific survival, indicate that this was clearly not the case,” said Amin Mirhadi, MD, lead author of the study and a radiation oncologist at Cedars-Sinai Medical Center in Los Angeles. “These data support administering less treatment, which will result in fewer side effects and reduce patients’ overall healthcare costs.” n Disclosure: Dr. Mirhadi reported no potential conflicts of interest.

References 1. Mirhadi AJ, Hunt D, Hanks GE, et al: Effect of long-term hormonal therapy (vs short-term hormonal therapy): A secondary analysis of intermediate risk prostate cancer patients. American Society for Radiation Oncology 55th Annual Meeting. Abstract 61. Presented September 23, 2013. 2. Hanks GE, Pajak TF, Porter A, et al: Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 21:3972-3978, 2003. Prostate Cancer

Fewer Weeks of Neoadjuvant Hormone Therapy Reduces Side Effects in Patients With Intermediate-Risk Prostate Cancer: RTOG 9910

shorter course of androgen suppression therapy prior to radiation therapy, when compared to an extended course of androgen suppression therapy, yields comparable outcomes and fewer adverse effects for intermediate-risk prostate cancer patients, according to research presented recently at the 55th Annual Meeting of the American Society for Radiation Oncology (ASTRO).1 The study confirmed a disease-specific survival rate

of 95% when patients received fewer weeks of neoadjuvant total androgen suppression.

RTOG 9910 The multi-institutional phase III trial, Radiation Therapy Oncology Group (RTOG) 9910, evaluated 1,490 patients with intermediate-risk prostate cancer from 152 institutions in the United States and Canada. Patients were accrued from 2000 to 2004 and

followed for an average of 9 years. The average age of the men was 71 at the time of accrual. The patients were stratified and randomly assigned into two groups. Group 1 consisted of 752 patients who received 8 weeks of neoadjuvant total androgen suppression, and group 2 consisted of 738 patients who re-

ceived 28 weeks of neoadjuvant total androgen suppression. Both groups then received 8 weeks of externalbeam radiation therapy and concurrent total androgen suppression. Cumulative incidence was used to estimate and test efficacy for diseasespecific survival, prostate-specific antigen (PSA) failure, locoregional tumor progression, and distant metastasis. Overall survival rates were estimated continued on page 105

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American Society for Radiation Oncology Annual Meeting RTOG 9910

Sometimes, preliminary research leads us to assume that more treatment is better, but this study serves as a strong cautionary note to put the promising treatment to the test.

continued from page 104

via the Kaplan-Meier method and efficacy tested with log rank.

Results There was no statistical difference in disease-specific survival between the two arms; there were 30 prostate cancer deaths in group 1, for a 10year disease-specific survival rate of 95%, and 24 prostate cancer deaths in group 2, for a 10-year disease-specific survival rate of 96%. There were 200 additional deaths not attributable to

—Thomas M. Pisansky, MD

prostate cancer in group 1 for a 10year overall survival rate of 66%, and 196 such deaths in group 2, for a 10-

Neoadjuvant Hormonal Therapy in Intermediate-Risk Prostate Cancer ■■ The 10-year disease-specific survival rate in patients receiving 8 weeks

of neoadjuvant total androgen suppression was 95% vs 96% in patients receiving 28 weeks of therapy.

■■ Hot flashes and erectile dysfunction were more common in patients receiving 28 weeks of neoadjuvant total androgen suppression.

■■ The study confirmed high disease-specific survival and low clinical relapse

through 10 years with short-term neoadjuvant total androgen suppression.

year overall survival rate of 67%. By 10 years, 27% of patients had a PSA failure (using the newer RTOG-ASTRO definition of nadir plus 2 ng/dL), 5% had locoregional recurrence, and 6% had distant metastasis. Hot flashes and erectile dysfunction were more common in group 2. “Sometimes, preliminary research leads us to assume that more treatment is better, but this study serves as a strong cautionary note to put the promising treatment to the test,” said Thomas Pisansky, MD, lead author of the study and Professor of Radiation Oncology at the Mayo Clinic in

Rochester, Minnesota. “Overall, both groups had very, very good outcomes, but patients assigned to group 2 had more side effects from androgen suppression than [patients in] group 1, who received only 8 weeks of neoadjuvant total androgen suppression. Now, investigators know the upper boundary of how much androgen suppression is needed in this group of patients. The results have substantial importance because they can alter the research strategy to one in which investigation can now concentrate on ways to simplify the treatment and further reduce side effects.” n

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

Reference 1. Pisansky TM, Hunt D, Gomella LG, et al: Radiation Therapy Oncology Group 9910: Phase III trial to evaluate the duration of neoadjuvant total androgen suppression and radiation therapy in intermediate-risk prostate cancer. American Society for Radiation Oncology 55th Annual Meeting. Abstract 1. Presented September 23, 2013. Brain Tumors

Protecting Hippocampus During Whole-Brain Radiation Substantially Reduces Rate of Cognitive Decline

rotecting the stem cells that reside in and around the hippocampus substantially reduces the rate

eration for patients receiving wholebrain radiotherapy,” said co–principal investigator, Minesh P. Mehta, MB, ChB, Professor of Radiation Oncology at the University of Maryland School of Medicine. “We found that

Significant Decline in Memory Loss Based on previous research, the predicted rate of cognitive decline at 4 months for patients receiving wholebrain radiation for brain metastases

Whole-Brain Radiation and Cognitive Decline ■■ Based on previous research, the predicted rate of cognitive decline at 4

months for patients receiving whole-brain radiation for brain metastases was 30%.

Vinai Gondhi, MD

of cognitive decline in patients during whole-brain radiotherapy without a significant risk of recurrence in that area of the brain, a new study shows. Results of the phase II clinical trial of patients with brain metastases were presented recently by co–principal investigator Vinai Gondhi, MD, of Central DuPage Hospital Cancer Center in Warrenville, Illinois, at the American Society for Radiation Oncology’s 55th Annual Meeting.1 “Memory loss, especially shortterm recall, is an important consid-

■■ In the trial, which treated patients with brain metastases with hippocampal avoidance intensity-modulated radiation therapy, the observed rate of cognitive decline was 7%.

■■ The median survival for the participants was 6.8 months. Three patients

(4.5%) experienced progression of their disease in the hippocampal region, within the expected range.

reducing the radiation dose to the stem-cell niches surrounding the hippocampus during treatment was clearly associated with memory preservation without an inordinate risk of relapse in that portion of the brain. The findings far exceeded our expectations.”

was 30%. Researchers designed the clinical trial so that a positive result would be a rate reduced by half, to 15%. The observed rate in the trial was actually 7%—significantly better than the baseline rate. With a third fewer patients to evaluate, the rate of decline observed at 6 months was 2%, al-

though comparable data from the historic control study were not available. “These phase II results, while not absolutely conclusive, offer very important insights which we hope to validate in a larger, randomized phase III clinical trial,” said Dr. Mehta, who is also a radiation oncologist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center and chairs the Brain Tumor Committee of the Radiation Therapy Oncology Group (RTOG).

Study Details Patients in the study, the majority of them with lung cancer that had metastasized to the brain, were treated with intensity-modulated radiation therapy, which enabled doctors to shape the radiation beams to avoid the hippocampus. Researchers used a standardized cognitive function assessment—the Hopkins Verbal Learning Test (HVLT)—to measure continued on page 106

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PAGE 106

American Society for Radiation Oncology Annual Meeting Gynecologic Oncology

Cisplatin Plus Radiation Therapy for Advanced Cervical Cancer Improves Disease-Free Survival vs Radiotherapy Alone

dding the chemotherapy drug cisplatin to a treatment plan of radiation therapy and high–dose rate brachytherapy for patients with stage IIIB cervical cancer is beneficial, according to research presented recently at the American Society for Radiation Oncology’s 55th Annual Meeting.1

Study Details The randomized, controlled trial studied a total of 147 women in Brazil with stage IIIB squamous cell cervical cancer. Each patient received externalbeam radiation of 45 Gy to the pelvic region in 25 fractions, 14.4 Gy boost to the compromised parametrium, and high– dose rate brachytherapy in the amount of four weekly fractions of 7 Gy prescribed to point A (the crossing of the uterine artery and the ureter). Seventy-five patients received only radiation therapy and high–dose rate brachytherapy treatment (the radiation therapy group), and 72 patients received radiation therapy and high– dose rate brachytherapy plus weekly intravenous doses of 40 mg/m2 of cisplatin during the pelvic radiotherapy sessions (the cisplatin plus radiation

Whole-Brain Radiation and Cognitive Decline continued from page 105

patients’ baseline memory, such as their ability to recall information immediately or after a delay, with followup at 2, 4, and 6 months. A total of 113 patients were recruited between 2011 and 2013; investigators were able to evaluate 42 patients at 4 months and 29 patients at 6 months. The median survival for the participants was 6.8 months. Three patients (4.5%) experienced progression of their disease in the hippocampal region, which was within the expected range. Dr. Mehta said that the radiation affects cognitive function by damaging nerve cells as well as

therapy group). The research was conducted from 2003 through 2010, with follow-up lasting until January 2013.

Survival Outcomes Kaplan-Meier survival curves were performed comparing the 5-year disease-free survival and the overall survival of the cisplatin-plus-radiotherapy group and the radiation therapy alone group. Differences in survival were assessed utilizing the log-rank test. Patients in the cisplatin plus radi-

Cisplatin Plus Radiation in Patients With Cervical Cancer ■■ Patients with stage IIIB cervical cancer receiving cisplatin plus radiation

therapy and high–dose rate brachytherapy had significantly better diseasefree survival than those who did not receive cisplatin.

■■ Toxicity levels in the cisplatin-plus-radiotherapy group were similar to those in the radiotherapy-alone group.

group, with grades 1 and 2 acute toxicity at 37.5% for cisplatin-plus-radiotherapy group, and 28% for the radiotherapy-alone group (P = .29). Late

We believe that these results demonstrate that this combined treatment protocol is safe to offer to patients and provides some beneficial improvements—in disease-free survival and toxicity levels. —Antonio Zuliani, MD

Zuliani, MD, lead author of the study and a radiation oncologist at Campinas State University in Campinas, Brazil. “We were pleased by an increase in local control and the very low toxicity rates. We believe that these results demonstrate that this combined treatment protocol is safe to offer to patients and provides some beneficial improvements—in disease-free survival and toxicity levels.” n Disclosure: Dr. Zuliani reported no potential conflicts of interest.

ation therapy group had significantly better disease-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.28–0.98, P = .04) and had a better overall survival, but without statistical significance (HR = 0.67, 95% CI = 0.37–1.183, P = .16). Toxicity levels in the cisplatinplus-radiotherapy group were similar to those in the radiation therapy alone

toxicity grades 3 and 4 were 9.7% for the cisplatin-plus-radiotherapy group and 3% for the radiotherapy-alone group (P = .29). “In testing a new approach of chemotherapy with traditional externalbeam radiation therapy and high– dose-rate brachytherapy, we were extremely cautious about possible toxicity for the patients,” said Antonio

Reference 1. Zuliani AC, Sarian LO, Esteves SC, et al: Efficacy of concomitant cisplatin plus radiotherapy and high dose rate brachytherapy vs radiotherapy alone for stage IIIB epidermoid cervical cancer. A 10-year randomized controlled trial. American Society for Radiation Oncology 55th Annual Meeting. Abstract 8. Presented September 22, 2013.

stem cells, which help to regenerate nerve cells that support memory formation. “These stem-cell niches

are targeting the stem-cell niches in and around the hippocampus,” he said.

control seizures or swelling in the brain. The cancer itself may also have an effect. The research was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute. n

These phase II results, while not absolutely conclusive, offer very important insights which we hope to validate in a larger, randomized phase III clinical trial. —Minesh Mehta, MB, ChB

are exquisitely sensitive to radiation and are involved in neurogenesis.… Although we call it hippocampalavoidance radiotherapy, we really

He noted that factors other than radiation may also contribute to cognitive decline in patients with brain metastases, including medicines to

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

Reference 1. Gondi V, Mehta MP, Pugh S, et al: Memory preservation with conformal avoidance of the hippocampus during whole-brain radiotherapy for patients with brain metastases: Primary endpoint results of RTOG 0933. American Society for Radiation Oncology 55th Annual Meeting. Abstract LBA1. Presented September 23, 2013.

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American Society for Radiation Oncology Annual Meeting

ASTRO Offers Five Recommendations as Part of Choosing Wisely Campaign

he American Society for Radiation Oncology (ASTRO) released its list of five radiation oncology-specific treatments that are commonly ordered but may not always be appropriate as part of the national Choosing Wisely® campaign, an initiative of the American Board of Internal Medicine Foundation. ASTRO recommends detailed patient-physician discussion before these five treatment options are prescribed. ■■ Don’t initiate whole-breast radiotherapy as a part of breast conservation therapy in women age ≥ 50 with early-stage invasive breast cancer without considering shorter treatment schedules Whole-breast radiotherapy decreases local recurrence and improves survival of women with invasive breast cancer treated with breast conservation therapy. Most studies have utilized “conventionally fractionated” schedules that deliver therapy over 5 to 6 weeks, often followed by 1 to 2 weeks of boost therapy. Recent studies, however, have demonstrated equivalent tumor control and cosmetic outcome in specific patient populations with shorter courses of therapy (approximately 4 weeks). ■■ Don’t initiate management of lowrisk prostate cancer without discussing active surveillance. Patients with prostate cancer have a number of reasonable management options. These include surgery and radiation, as well as conservative monitoring without therapy in appropriate patients. ■■ Don’t routinely use extended fractionation schemes (> 10 fractions) for palliation of bone metastases. Studies suggest equivalent pain relief following 30 Gy in 10 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. A single treatment is more convenient but may be associated with a slightly higher rate of retreatment to the same site. Strong consideration should be given to a single 8 Gy fraction for patients with a limited prognosis or with transportation difficulties. ■■ Don’t routinely recommend proton beam therapy for prostate cancer outside of a prospective clinical trial or registry. There is no clear evidence that proton beam therapy for prostate cancer offers any clinical advantage over other forms of definitive radiation therapy. Clinical trials are necessary to establish a possible

advantage of this expensive therapy. ■■ Don’t routinely use intensity-modulated radiation therapy (IMRT) to deliver whole breast radiotherapy as part of breast conservation therapy. Clinical trials have suggested lower

rates of skin toxicity after using modern 3D conformal techniques relative to older methods of 2D planning. In these trials, the term “IMRT” has generally been applied to describe methods that are more accurately defined

as field-in-field 3D conformal radiotherapy. While IMRT may be of benefit in select cases where the anatomy is unusual, its routine use has not been demonstrated to provide significant clinical advantage. n

At first glAnce, we sAw Achievement. with focus, we see even more potentiAl. A closer look at targeting CD20 may bring new possibilities into view

cD20: A significAnt tArget The advent of monoclonal antibody therapies has helped transform the treatment of hematologic malignancies.1 CD20 is an important target due to its unique features and presence on a majority of B cells.2 The success of targeting CD20 is due, in part, to the ability to activate cell death through a variety of potential mechanisms.2 In addition, CD20 is a stable antigen that is not typically downregulated or shed upon antibody binding.2

Targeting CD20 is an important strategy for hematologic malignancies, including chronic lymphocytic leukemia (CLL).3 Despite clinical developments, certain patients with hematologic malignancies, including CLL, lack clear or effective treatment options and trade-offs between efficacy and tolerability are often made.3 To meet these needs, we continue to research anti-CD20 antibodies that optimize the potential of this target.

ADvAncements in tArgeting cD20 There is an opportunity to make additional clinical gains with new treatment options for a broader range of patients.3 As a leader in targeted treatments for B-cell malignancies, we remain committed to advancing the science of targeting CD20 in an effort to improve clinical outcomes for patients with hematologic malignancies, including CLL.

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

The ASCO Post | OCTOBER 15, 2013

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Patient’s Corner

Cancer Does Not Discriminate

Learning my young son had cancer was the first shock. The second was discovering how many children die from the disease. By David Plotkin, as told to Jo Cavallo

ooking back, my son Max’s fall as he was running after another little boy while playing baseball was such a blessing. Although he landed on his right arm, the fall didn’t seem severe enough to cause him to cry out in such excruciating pain. But after several hours of icing the bruise failed to relieve the swelling and his discomfort, my wife Annemarie decided to take Max to the Hospital for Special Surgery in New York for an x-ray. The news was not good. The orthopedic surgeon said the x-ray showed a lesion on the bone that could be either osteomyelitis or, worse, cancer. He recommended that we take Max to Memorial Sloan-Kettering Cancer Center for further tests. Max was just a week shy of his fourth birthday. A biopsy of the bone lesion showed that Max had B-cell primary non-Hodgkin lymphoma (NHL) of bone, an extremely rare subtype of NHL in children. In fact, this dis-

A Child’s Resilience From the moment we learned of Max’s diagnosis, my wife and I decided to be honest with him and explain as much as he could understand about his diagnosis and the chemotherapy he would soon be subjected to. We told Max that he had a very serious “booboo” called cancer and that he was going to have to take very strong medicine to make it go away. “What if the boo-boo is stronger than the medicine?” Max asked Annemarie. “Then we will find other medicine,” she replied. It was the only time over the next 2 years that Max showed any fear about his disease. He remained brave throughout his treatment and was unfazed by comments from other children about his bald head or chubby, pale body—the result of the prednisone. In 2009, Max was declared cancerfree. While we feel incredibly blessed, we live every day with the fear of recur-

As I looked around the clinic, I saw parents from all over the world and from different walks of life. We had nothing in common, except the same worried expression on our faces and a singular goal: to save our children. —David Plotkin

ease occurs so rarely in children, the oncologists at Memorial SloanKettering told us that there are only about 40 pediatric cases in the United States and that they hadn’t treated any children with it. What made the diagnosis even worse was that the cancer had metastasized to the bone in Max’s left leg. Because he now had stage IV disease, the oncology team prescribed an aggressive, 2-year chemotherapy regimen of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone).

rence or the development of secondary cancers and other late side effects from his treatment.

Paying Forward When Max was diagnosed in 2007, I was a hedge fund trader and the financial collapse was just months away. I was struggling to make a living and eventually left my firm, not knowing if I would ever return to Wall Street. The life of my son was far more important than any one trade, and I was searching for a larger purpose. Despite the volatility rocking the stock market, our family was fortu-

David and Annemarie Plotkin with their children Max, Alexander, and Ella.

nate and could afford to be with Max around the clock while he was in the hospital getting treatment. Plus, we lived only a block away from the cancer center and could run home to take a break, have a few moments of “normal” time, and make sure our younger son Alexander, then 2, was doing well. Other families weren’t and aren’t so fortunate. As I looked around the clinic, I saw parents from all over the world and from different walks of life. We had nothing in common, except the same worried expression on our faces and a singular goal: to save our children. When Max got sick, I learned two shocking statistics: Cancer is the leading cause of death from disease among children in the United States, and research in pediatric cancers is woefully underfunded. We wanted to give back to a medical system that had given us so much, and in 2007, I walked away from my career to launch the Max Cure Fund for Pediatric Research at Memorial Sloan-Kettering. Our primary mission is to establish an immune cell therapy laboratory in pediatric cancers at the institution,

and we’ve raised nearly $1 million in that effort. We have also partnered with the Samuel Waxman Cancer Research Foundation to fund research in pediatric cancers.

Life-Altering Lesson Our other focus now is to provide financial assistance to low-income and military families who have children with cancer, because poverty should not be a reason for a child to die from cancer, and military families shouldn’t have to struggle financially and fight for their children’s lives while their spouses are away fighting for our country. Our family has learned a life-altering lesson: Cancer does not discriminate, and it can touch anyone at any time. With Max as our inspiration, Annemarie, my father Richard, and I have adopted a new purpose in life and are dedicated to helping find cures for pediatric cancers so other children like Max can survive and live a long and healthy life. n David Plotkin is the founder of the Max Cure Foundation (www.maxcurefoundation.org).

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Future of Oncology Advances in Medical Oncology Over the Next Decade A Conversation With José Baselga, MD, PhD By Jo Cavallo

he next 10 years are expected to usher in unprecedented advances in oncology, including molecularly driven diagnostic and therapeutic developments, whole genome sequencing that results in true precision-based medicine, survivorship care plans that address long-term quality of life concerns, and teambased, cross-disciplinary approaches to research. However, continued reductions in research funding due to the Federal sequester threaten to slow and even halt momentum just as the ability to detect and define cancer based on its panomic characteristics, rather than on tumor site alone, so it can be more effectively treated is reaching a turning point. The ASCO Post recently spoke with José Baselga, MD, PhD, Physician-in-Chief at Memorial SloanKettering Cancer Center (MSKCC) in New York, about the progress being made in the treatment of both early-stage and metastatic disease, the care of long-term survivors, new approaches to research, and the roadblocks and opportunities that lie ahead.

Precision-Based Medicine and Immunology How will cancer therapies change over the next decade? We will see advances in treatment on multiple fronts. There are two areas that I predict will have the biggest advances. One is that our capacity to interrogate tumors is going to improve, so the whole genome mutational landscape of every tumor will make every tumor different. We will, therefore, be able to develop therapies that are much more effective and that will be determined on a tumor-by-tumor basis. Breast cancer is going to split into at least 20 to 25 diseases, and the same applies to colon, lung, and ovarian cancers, so we are going to have a fermentation of the tumor subtypes. Knowing the mutational landscape of every tumor will allow us to predict the clinical behavior of José Baselga, MD, PhD, is Physician-inChief at Memorial Sloan-Kettering Cancer Center in New York, New York.

that tumor. Further, it will allow us to deliver on the promise of precisionbased medicine in which we will be able to define the best cocktail of therapies for a particular tumor. That is one prediction. The second big advance is the total revolution that is happening on the immunology front, especially with immune therapies such as PD-1 and PD-L1, but also with genetically engineered T-cells modified with a chimeric antigen receptor (CAR). So, precision-based medicine and immunology are going to be the two major fronts for advances in cancer care over the next few years.

Screening and Prevention Will some types of cancer become preventable over the next decade? That is an area where we need to make more progress. Prevention is going to be key, but we don’t un-

the country. The cost of sequencing tumors will drop dramatically and the results from the testing will determine therapy. This year at MSKCC we are going to sequence 15,000 tumors in metastatic diseases. Will greater progress be made in more effective therapies for difficult to treat cancers like lung and pancreatic? Oh, yes, there is no question. The key issue in pancreas and lung cancers is finding a way to target the KRAS gene mutation. But I’m hopeful. There are a number of initiatives in very good labs around the country that are beginning to identify ways to target KRAS. In lung cancer we have therapies that target the epidermal growth factor receptor and the ALK gene, among others. In pancreas cancer it is going to be tougher to solve the problem because the science is more complex and the stroma also

The mutational landscape of every tumor will allow us to predict the clinical behavior of that tumor and deliver on the promise of precisionbased medicine in which we will be able to define the best cocktail of therapies for that particular tumor. —José Baselga, MD, PhD

derstand well, with some exceptions, what are the determinants of cancer and how to prevent them from happening. I think once we have plasma-based DNA assays that can be routinely employed as screening tools, we can envision a situation in which we can begin to identify whether something is cooking. But at this point, it is very difficult for us to identify whether a tumor is developing or advancing, and if we can’t identify these processes, it is very difficult to prevent their occurrence.

Gene Sequencing and Targeted Treatments Will whole genome sequencing be routinely incorporated into clinical care? Yes, it will become routine across

plays a big role in the disease, but there are very exciting data coming along. At MSKCC, we have decided to establish a pancreatic carcinoma center and we are committed to finding solutions for this difficult cancer. Will it actually be possible to cure more cancers vs converting them into chronic illnesses? We don’t know. There are a proportion of melanoma patients treated with immune therapies who have not relapsed. Are these patients cured? We will need to follow them over a longer period of time to answer that question. There are some HER2-positive breast cancer patients who have metastatic disease, and the disease doesn’t come back after treatment. I think now, howev-

er, the realistic endpoint in patients with metastatic disease is to improve survival. But down the line, the next stop after survival is cure, and we could be just a few cells away from accomplishing cure in metastatic disease. For early-stage cancers, for example, patients with HER2-positive disease, we are curing over 90% of patients. Who would have thought that would be possible a few years ago? So in a disease that was lethal not that long ago, over 90% of patients are now cured. It is in metastatic disease where we still have challenges.

Quality of Life in Survivors With more people surviving cancer, how will survivorship care plans and surveillance need to be improved to ensure survivors’ long-term quality of life? This is a big question. All the cancer centers will need to work on improving survivorship plans. At MSKCC, we are creating a survivorship center where a number of issues will be addressed. Point number one is the well being of survivors. Second is determining who should take care of these patients down the line. We [oncologists] are going to be very, very busy taking care of new patients. More importantly, we want the patients who are survivors to be transferred back to where they belong for health care, which is back to their communities and back to the primary care setting. At MSKCC, we will soon be performing bone marrow transplants on an outpatient basis, and we are building a hotel to house these patients while they recover from their transplant. We need to determine how to physically condition these patients through diet and exercise programs so they are in good shape and able to tolerate the treatment. Then, very importantly, we need to address survivorship issues and to identify long-term sequelae. These are patients who are at risk of developing secondary tumors. What do we do about that? Addressing the question of how to maintain quality of life in long-term survivorship will be an area of tremendous importance, and we need to bring scien-

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Future of Oncology tific methodology to the problem to make progress.

Team Science and Intellectual Curiosity Will the concept of a team-based, cross-disciplinary approach to research lead to faster development of new treatments? There is no question that the idea of a team of scientists working together is important, but at the same time, the power of the individual mind is

sponses, and the majority of patients did not respond at all. But in the one patient with the very good response, the tumor disappeared and never recurred. The lead investigator, David B. Solit, MD, [of MSKCC’s Human Oncology and Pathogenesis Program] questioned why has this one patient had responded so well to everolimus. With the help of a team of investigators, Dr. Solit sequenced the whole tumor and found that it had a TSC1 mutation,

I think the biggest threat of all is the lack of federal support for research. Will young, smart, college graduates be interested in pursuing a career in science if there is uncertainty about support and funding for research, or will they look to other careers because they don’t see a future in biomedical research? —José Baselga, MD, PhD

equally important. There are going to be major discoveries made because one astute clinician/researcher is going to find something is different in his or her research and pursue it. For example, in a small study at MSKCC, patients with advanced bladder cancer were treated with everolimus (Afinitor), and using conventional criteria, it was a negative study.1 There was one person who had a very good response from the drug, three others had minor re-

which is known to be involved in the mTOR signaling pathway. Everolimus works by inhibiting the pathway. Dr. Solit went back over his records and found that every patient in the trial who had a minor response had a TSC1 deletion. We have since opened up a bladder cancer trial in which any patient whose tumor possesses a TSC1 mutation is being offered everolimus. So, yes, there are certainly advantages to the team-science approach,

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code– reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

but it will not be able to substitute the intellectual curiosity and the drive of one smart investigator who will be relentless in the pursuit of identifying why a patient may be responding to therapy. Research needs both approaches. We need team science and we need very smart individuals to be fully engaged and freethinkers, so they can be daring and push investigations on their own.

Understanding the Panomics of Cancer

he panomics of cancer include the networks of molecular pathways and characteristics of tumor microenvironment that interact to drive the development of each individual’s cancer, response to treatment, and longterm toxicities. n

Challenges and Opportunities What impediments to advances in oncology do you see over the next decade? There are multiple threats to continued progress. I think the biggest threat of all is the lack of federal support for research. It is very worrisome. Are we going to be able to attract the best and the brightest people to medicine and to oncology? Will young, smart college graduates be interested in pursuing a career in science if there is uncertainty about support and funding for research, or will they look to other careers because they don’t see a future in biomedical research? The other major threat is are we going to have proper reimbursement for all the complex care that we are delivering? So we need to find a way in which we can deliver care that is affordable, but we also need to make sure that this care is reimbursed. The challenges are there and we need to look into finding solutions for

Source: Shaping the Future of Oncology: Outcomes of the ASCO Board of Directors Strategic Planning and Visioning Process, 2011-2012.

them, but the most important message here is that despite any threats we have, we are perhaps at a turning point in our fight against cancer. This is a very exciting time to be involved in treating and researching cancer. This is the moment for which we have been waiting so very long. When people come to me with concerns, I remind them that, yes, there are always problems to overcome, but we were never, ever, so close to making a big impact in cancer as we are today. This is perhaps the most exciting time ever to be in the field of oncology. n Reference 1. Iyer G, Hanrahan AJ, Milowsky MI, et al: Genome sequencing identifies a basis for everolimus sensitivity. Science. August. 23, 2012 (early release online).

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

The code will scan automatically.

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

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

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Integrative Oncology Herb-Drug Interactions in Oncology

By K. Simon Yeung, PharmD, MBA, LAc, Jyothirmai Gubili, MS, and Barrie Cassileth, MS, PhD, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center

hroughout the history of humankind, plants have been used as medicine. Although modern pharmaceuticals replaced reliance on botanicals in the last century at least in the developed world, the use of herbs once again has risen. This increased

Headings (MeSH) term, defined as “The effect of herbs, other PLANTS, or PLANT EXTRACTS on the activity, metabolism, or toxicity of drugs.” However, fewer than 1,000 articles have been indexed under this heading since its introduction.

Oncology practitioners should keep an open mind and help patients select herbs that are safe and effective, and explain the reasons for rejection when an herbal product has the potential to cause harm. —K. Simon Yeung, PharmD, MBA, LAc, Jyothirmai Gubili, MS, and Barrie Cassileth, MS, PhD

popularity has occurred over the past 2 decades following passage of the Dietary Supplement Health and Education Act. Patients with cancer are especially drawn to the use of herbal supplements to relieve symptoms and also as alternative “treatments” per se. Up to 40% of cancer survivors self-medicate with such products.1,2 Given that these patients also use many prescription drugs, interactions caused by polypharmacy are common and problematic.

Surge of Interest The discovery that both grapefruit juice and St. John’s wort produced significant interactions with prescription drugs led to a surge of interest in the study of herb-drug interactions. In 2004, “Herb-drug Interaction” was introduced as a Medical Subject

Although acute medical problems caused by herb-drug interactions are rare, complications and death have been reported.3 In a systematic review of 890 pairs of herb-drug interactions,4 St. John’s wort was found to cause the majority of herb-drug interactions (147), followed by ginkgo (51) and kava kava (41). Warfarin (105) was identified as the drug most frequently involved, followed by insulin (41) and aspirin (36). Among drugs used in oncology, cases involving cyclosporine (16), heparin (14), and tamoxifen (11) have been reported. Avoiding combinations of such herbs and drugs would greatly reduce the risk of harmful effects. However, patients with cancer tend to use herbs that are promoted as alternative cures. In addition, new anticancer drugs continue to be approved for use.

GUEST EDITOR

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.mskcc. Barrie R. Cassileth, MS, PhD org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. These factors make identification of herb-drug interactions in the cancer patient population especially challenging.

Mechanisms To understand the precise effects of herb-drug interactions in humans, both the herb and drug need to be studied together in a clinical setting. However, few such studies have been conducted. Understanding the mechanisms may help predict interactions that result in harmful effects. The clinical effects of herb-drug interactions depend on many factors.

Studies conducted to date have focused on pharmacokinetics to determine the absorption, distribution, metabolism, and elimination of simultaneous use of herbal products and drugs. The actions of microsomal enzymes of the cytochrome P450 (CYP) family and membrane transporters such as P-glycoprotein, which play important roles in absorption and metabolism, have also been investigated. Data from such studies can help develop better drugs. Similarly, information on herbal substances has also become more readily available due to advances in screening techniques.

Learn More About

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

www.mskcc.org/aboutherbs

continued on page 116

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

ZELBORAF (n=337)

6 8 OS (months)

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.

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

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Integrative Oncology Herb-Drug Interactions continued from page 112

Laboratory studies find that many herbal constituents inhibit or induce CYP enzymes. Therefore, it is likely that they interfere with the metabolism of substrate drugs. For an anticancer drug such as lapatinib (Tykerb), which is a major CYP3A4 substrate,

dose adjustment may be required when used together with an herb that is a strong CYP3A4 inducer (eg, St. John’s wort) or CYP3A4 inhibitor (eg, horse chestnut). Another example is tamoxifen, a drug that relies on CYP2D6 and CYP3A4 to be metabolized to its active form. Herbs like valerian Safety:7" and turmeric, which inhibit these en-

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

* 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

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

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

increased the absorption of drugs like cyclosporine by 38%, tacrolimus by 110%, sunitinib (Sutent) by 11%, and oxycodone by 67%.6 Another example is hyperforin, the major constituent in St. John’s wort, which induces both cytochrome P450 and P-glycoprotein by activating the pregnane X receptor.7 Human studies show that hyperforin reduces plasma levels of irinotecan8 and imatinib (Gleevec)9 by more than 40% when used concurrently. St. John’s wort also decreases overall plasma levels of warfarin, cyclosporine, and tacrolimus. Certain herbs can cause significant pharmacodynamic interactions when used with drugs used in cancer treatment. Examples include phytoestrogens vs hormones; “blood thinning” herbs vs anticoagulants; antioxidants vs chemotherapeutic agents; and immunostimulant herbs vs immunosuppressants. Phytoestrogens are herbal compounds that mimic estradiol. Foods containing phytoestrogens, such as soy, have been shown to confer protective effects against breast cancer. However, genistein, an isoflavone present in soy, may stimulate the proliferation of breast tumors and interfere with the action of tamoxifen.10 Phytoestrogenic effects are also exerted by ginseng, dong quai, and red clover. They are best avoided by patients with hormone-sensitive cancers.

Chemotherapy-Herb Interactions 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

zymes, can therefore make tamoxifen less effective. Furanocoumarins—compounds found in the rind of grapefruit—can irreversibly bind with CYP3A4 in the intestine. When consumed together, they have been reported to cause a sevenfold increase in the absorption of simvastatin.5 Grapefruit juice also

Several studies document interactions between chemotherapy agents and some commonly used herbs. For example, anthracyclines, platinum compounds, alkylating agents, bleomycin, and epipodophyllotoxin—all of which generate free radicals for their cytotoxic effects—interact with antioxidants.11 Therefore, herbs that exert antioxidant effects such as grape seed and pine bark extracts should be avoided by patients on chemotherapy until more is known about their safety.12 To avoid the risk of herb-drug interactions, most hospitals in the United States discourage inpatient use of herbal supplements through strict policies. Only 8% of hospitals have herbal supplements in their formularies.13 In the outpatient setting, a practitioner can minimize risk by asking patients about their dietary supplement use during consultations. Although herbs have not been proven to treat or prevent cancers, continued on page 117

ASCOPost.com | OCTOBER 15, 2013

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News Psychosocial Oncology

American/International Psychosocial Oncology Societies Host Event to Support Science and Practice of Psychosocial Care for Patients With Cancer By Jo Cavallo

ecently the American Psychosocial Oncology Society (APOS) and the International Psycho-Oncology Society (IPOS) held a fundraising event, Cruise for a Cause: Improving Psychosocial and Supportive Cancer Care, to raise money to advance the science and practice of psychosocial care for patients with cancer. The event was held onboard a private motor yacht, Francine, which cruised around the Hudson River in New York. More than 50 guests attended the event.

Screening Programs for Psychosocial Distress in Cancer Centers The cruise included a discussion by Ruth McCorkle, PhD, RN, the Yale School of Nursing Florence S. Wald Professor of Nursing and Professor

Mark Lazenby, PhD

Lazenby, PhD, Director of APOS, on a 5-year educational program at APOS, the National Institutes of Health, and Yale New Haven Hospital to promote the use of screening programs for psychosocial distress in cancer centers. The discussion was moderated by Jimmie C. Holland, MD, Wayne E. Chapman Chair at Memorial SloanKettering Cancer Center, and founder of APOS and IPOS.

an Honorary Member of AORTIC. In Africa, cancer is increasingly becoming a critical public health problem with cervical cancer among the most frequently diagnosed cancers and leading causes of cancer death in women. In November, AORTIC will hold its 9th International Cancer Conference, “Cancer in Africa: Bridging Science & Humanity,” in Durban, South Africa. The conference will bring together an international group of oncology health care professionals, patient advocates, and government leaders to discuss how the impact of cancer can be reduced in African nations. In addition to improving medical

care for patients with cancer in Africa, Dr. James Holland stressed the importance of treating the psychological side effects of having cancer as well. “Psychosocial cancer care is a human right,” said Dr. Holland.

For More Information To learn more about psychosocial oncology and the medical care of patients with cancer in Africa, visit: ■■ American Psychosocial Oncology Society, www.apos.org ■■ International Psychosocial Oncology Society, www.ipos.org ■■ African Organization for Research and Training in Cancer, www.aorticafrica.org n

Psychosocial Care as a Human Right

Ruth McCorkle, PhD, RN

of Epidemiology; Director of Psycho-Oncology at the Smilow Cancer Center at Yale New Haven Hospital; and a cofounder of APOS, and Mark

Herb-Drug Interactions continued from page 116

studies indicate that some herbs, such as ginger and ginseng, are effective in relieving treatment-associated symptoms. Oncology practitioners should keep an open mind and help patients select herbs that are safe and effective, and explain the reasons for rejection when an herbal product has the potential to cause harm. If use of an herb is approved, they should monitor adverse effects by encouraging patients to report any signs and symptoms. n Disclosure: Drs. Yeung and Cassileth and Ms. Gubili reported no potential conflicts of interest.

References 1. Gansler T, Kaw C, Crammer C, et al: A population-based study of prevalence of

Dr. Holland also moderated a discussion presented by James F. Holland, MD, Professor of Medicine, Hematology and Medical Oncology at Mount Sinai Hospital in New York City. Dr. James Holland talked about his work with the African Organization for Research and Training in Cancer (AORTIC), an African-based nongovernmental organization that is dedicated to promoting cancer control and palliation in Africa. Dr. Holland is

Jimmie C. Holland, MD, and James F. Holland, MD

complementary methods use by cancer survivors: A report from the American Cancer Society’s studies of cancer survivors. Cancer 113:1048-1057, 2008. 2. Mao JJ, Cronholm PF, Stein E, et al: Positive changes, increased spiritual importance, and complementary and alternative medicine (CAM) use among cancer survivors. Integr Cancer Ther 9:339-347, 2010. 3. Haller C, Kearney T, Bent S, et al: Dietary supplement adverse events: Report of a one-year poison center surveillance project. J Med Toxicol 4:84-92, 2008. 4. Tsai HH, Lin HW, Simon Pickard A, et al: Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: A systematic literature review. Int J Clin Pract 66:1056-1078, 2012. 5. Lilja JJ, Kivisto KT, Neuvonen PJ:

Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther Nov 64:477-483, 1998. 6. Won CS, Oberlies NH, Paine MF: Influence of dietary substances on intestinal drug metabolism and transport. Curr Drug Metab 11:778-792, 2010. 7. Moore LB, Goodwin B, Jones SA, et al: St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97:7500-7502, 2000. 8. Mathijssen RH, Verweij J, de Bruijn P, et al: Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:12471249, 2002. 9. Frye RF, Fitzgerald SM, Lagattuta TF, et al: Effect of St John’s wort on imatinib

mesylate pharmacokinetics. Clin Pharmacol Ther Oct 76:323-329, 2004. 10. Liu B, Edgerton S, Yang X, et al: Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res 65:879-886, 2005. 11. Weiger WA, Smith M, Boon H, et al: Advising patients who seek complementary and alternative medical therapies for cancer. Ann Intern Med 137:889-903, 2002. 12. Lawenda BD, Kelly KM, Ladas EJ, et al: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 100:773-783, 2008. 13. Ananth S: 2010 Complementary and Alternative Medicine Survey of Hospitals. Samueli Institute, 2011. Available at www.samueliinstitute.org. Accessed September 13, 2013.

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ASCO State Affiliates Focus on the Wisconsin Association of Hematology & Oncology By Jo Cavallo

he Wisconsin Association of Hematology & Oncology (WAHO) is among the youngest of ASCO’s State Affiliates. Formerly known as the Wisconsin Association of Medical Oncologists, WAHO was officially formed just 2 years ago and is already having an impact on on-

patients. In Wisconsin, as in many states, physicians are leaving private practice and becoming employees of hospitals. This shift poses a number of challenges to oncologists and their patients. We formed WAHO so we could provide an educational vehicle for

We formed WAHO so we could provide an educational vehicle for oncologists to keep them up-to-date on new cancer advances and also give them a forum for exchanging ideas. —Federico A. Sanchez, MD

cologists and patients with cancer throughout the state. With 60 members, WAHO is the largest organization in Wisconsin representing oncologists and hematologists and has initiated an aggressive program to preserve private oncology practices to ensure patients have continued access to high-quality cancer care. WAHO is also on the frontlines of tackling difficult issues confronting oncologists and their patients, including maintaining adequate physician reimbursement by the Centers for Medicare & Medicaid Services, supporting introduction of an Oral Chemotherapy Parity Bill, and ensuring patients have access to enrollment in clinical trials. The ASCO Post talked with WAHO’s President, Federico A. Sanchez, MD, about his association’s challenges and his goals for its future.

Challenges and Opportunities The original ASCO State Affiliate, the Wisconsin Association of Medical Oncology, became inactive 10 years ago. Why was it important for you to revitalize your state society? I knew that being an ASCO State Affiliate would give oncologists the collective power to improve care for

oncologists to keep them up-to-date on new cancer advances and also give them a forum for exchanging ideas. Oncologists are a collegial group of medical professionals. In the past, it was possible to consult with colleagues about a difficult case. But now huge health-care companies like Aurora Health Care in Wisconsin manage many oncology

practices and hospitals, so the ability to have that kind of one-on-one consultation is nearly gone. The only way to protect that kind of relationship from disappearing altogether was through the formation of WAHO. You currently have 60 members. Do you expect to increase membership soon? There are about 400 oncologists in Wisconsin, and through membership drives we hope to increase membership to at least 200 within a year. What are some of the current challenges you face? Our challenges are similar to the ones other societies are facing. One of our biggest concerns is how to bring quality oncology care to the uninsured or underinsured population. Some of those issues will be resolved once the state establishes the health-care exchanges required by the Patient Protection and Af-

Fast Facts ■■ The Wisconsin Association of Hematology and Oncology (WAHO) was formed in 2011.

■■ WAHO’s President is Federico A. Sanchez, MD. ■■ Currently, WAHO has 60 members. ■■ WAHO’s mission is to promote the highest professional standards of

oncology and hematology in Wisconsin; to provide oncologists and hematologists a forum for exchanging ideas, data, and knowledge necessary to provide the most up-to-date care available; to support the search for more effective treatments by enrolling patients in welldesigned clinical trials; to assist oncologists and hematologists in providing their patients with the best treatment available, including treatments available only through clinical trials; and to serve as a resource to insurers in the definition of standards of care for oncology and hematology.

■■ WAHO holds one full membership conference every year and presents

educational meetings every 12 weeks. This year’s annual conference, which is being held this month, includes information on molecular diagnostics in metastatic breast cancer; clinical trends in pathways for payers, providers, and health-care evolution; and reforming the payment system for oncology.

fordable Care Act in 2014. I am also planning on opening a clinic for our Latino population, which is our largest underserved minority group in Wisconsin. We are also very involved in supporting the introduction and passage of an Oral Chemotherapy Parity Bill, which our legislators, so far, have refused to even introduce for a vote. To help convince legislators of the importance of this bill, WAHO is collecting data from big health institutions that provide specialty care like Froedtert & Medical College of Wisconsin and Aurora Health Care pharmacies to figure out what percentage of the population needs help in paying for oral cancer drugs and which patients are being sent to charity institutions for treatment or are declaring medical bankruptcy. Once we have that information, we will be able to use it to counteract the claim by health insurance companies that cancer patients are not having a problem making the copayments on these oral medications.

Making Voices Heard What else would you like readers of The ASCO Post to know about WAHO? There are some states that have not yet gone through the experience of having corporate health-care organizations buy out private oncology practices, but readers should be aware that eventually these kinds of buyouts will happen in all states. One way that we will be protected is to make sure that we stay informed and engaged both locally and nationally. Through our activism we can make our voices heard and become co-creators in the development of health-care pathways for the best treatment of our patients. n

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Announcements

Felice Schnoll-Sussman, MD, Named Director of Jay Monahan Center for Gastrointestinal Health at NewYork-Presbyterian/Weill Cornell

ewYork-Presby terian/Weill Cornell Medical Center has appointed Felice Schnoll-Sussman, MD, Director of its Jay Monahan Center for Gastrointestinal Health. Dr. Schnoll-Sussman, has served as the Center’s Director of Research since 2007 and Acting Director since

its commitment to provide comprehensive, patient-centered care for people with digestive cancers.” The Jay Monahan Center was

founded in 2004 in honor of the late husband of journalist and talkshow host Katie Couric. The stateof-the-art, multidisciplinary model

of integrated patient care focuses on cancers of the colon, rectum, pancreas, stomach, liver, esophagus, and related gastrointestinal organs. n

Felice Schnoll-Sussman, MD

2012. As Director, Dr. Schnoll-Sussman will lead a team of physicians, nurses, and staff to provide comprehensive care for patients with or at risk of developing gastrointestinal cancers, as well as to conduct clinical trials and other research activities. Dr. Schnoll-Sussman is an Associate Professor of Clinical Medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College. Her research interests and expertise include esophageal disorders, screening and surveillance of colorectal cancer in high-risk patients, capsule endoscopy, novel uses of endoscopic ultrasonography, and the biology and management of pancreatic cystic neoplasms. After receiving her medical degree from Mount Sinai School of Medicine, Dr. Schnoll-Sussman completed residency training in internal medicine at NYU School of Medicine, where she served as chief resident, and a fellowship in gastroenterology at Memorial Sloan-Kettering Cancer Center. “We are thrilled that Dr. SchnollSussman will be taking on the role as director of the Jay Monahan Center,” said Steven J. Corwin, MD, CEO of NewYork-Presbyterian Hospital. “Having previously served as CoDirector of Patient Care at our Center for Advanced Digestive Care, Dr. Schnoll-Sussman is ideally suited to lead the Jay Monahan Center and

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2013

2013 Oncology Meetings October International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cl inical+Trials+Workshops 64th Annual Scientific Meeting of The Royal Australian and New Zealand College of Radiologists October 17-20 • Auckland, New Zealand For more information: http://www. ranzcr2013.com/index International Stereotactic Radiotherapy Conference October 19-20 • Houston, Texas For more information: www.mdanderson.org/conferences 4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in 18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 19-23, 2013 • Boston, Massachusetts For more information: www.aacr.org

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

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

November

Advanced Breast Cancer Second International Consensus Conference November 7-9 • Lisbon, Portugal For more information: www.abc-lisbon.org/

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

Illinois Medical Oncology Society 2013 Membership Conference October 25 • Itasca, Illinois For more information: www.imos-illinois.com XIII Michelangelo Seminar: Breast Cancer, the Immune System, and New Immunotherapeutic Opportunities October 25 • Milan, Italy For more information: www.fondazionemichelangelo.org Northern New England Clinical Oncology Society Annual Meeting October 25-26 • Stowe, Vermont For more information: www.nnecos.org 12th International Kidney Cancer Symposium October 25-26 • Chicago, Illinois For more information: www. kidneycancer.org/knowledge/learn/ medical-education-cme/ Twelfth Annual International Conference on Frontiers in Cancer Prevention Research October 27-30, 2013 • National Harbor, Maryland For more information: www.aacr.org

10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

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

15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org Nevada Oncology Society Fall Membership Conference October 30 • Reno, Nevada For more information: www.nos-nevada.com

Multidisciplinary Symposium on Head and Neck Cancer November 2 • Chicago, Illinois For more information: www.gotoper.com/conferences Georgia Society of Clinical Oncology 4th Annual Winship Gastrointestinal Cancers Symposium November 2 • Atlanta, Georgia For more information: http:// www.gasco.us/meetings-topic. php?meetingid=92 EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ Diagnostic Development Tutorial November 5-7 • Brussels, Belgium For more information: www.markersincancer.eu SITC Workshop on Personalized Cancer Immunotherapy November 7 • National Harbor, Maryland For more information: www.sitcancer.org/2013

International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw 11th Annual School of Breast Oncology November 7-10 • Atlanta, Georgia For more information: www.gotoper.com/conferences Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro Society for Immunotherapy of Cancer (SITC) 28th Annual Meeting November 8-10 • National Harbor, Maryland For more information: www. sitcancer.org/2013 New York Lung Cancer Symposium November 9 • New York, New York For more information: www.gotoper.com/conferences Academy of Oncology Nurse Navigators 4th Annual Navigation and Survivorship Conference November 14-17 • Memphis, Tennessee For more information: aonnonline.org/conference African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

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Oncology and the Arts

Donatori di Musica Initiative Creates a Unique Environment for Oncology Patients By Ronald Piana

“Surely again, to heal men’s wounds by music’s spell.” —Euripides, Medea (480-406 BC)

ommonly defined as organized sound, music has a unique power to stir human emotions, moods, and impressions. The salutary effect of music on the sick has been reported since antiquity. Aristotle and Plato wrote about music’s ability to “heal and purify the soul.” In 1914, a JAMA article reported the benefits of a phonograph in postoperative recovery wards. Over the past few decades, the oncology community has begun to integrate various forms of music therapy into the continuum of care, especially in the setting of palliative care. The following case history describes the origins of an Italian music therapy program called Donatori di Musica (music donors), which is a network of musicians and hospitals— mostly oncology departments—that organizes concerts in Italian hospitals. All of the musicians play for free and the concerts are private events, offered to patients and their relatives.

The Right Key In June 2007, Gian Andrea Lodovici walked into the oncology department of the Carrara City Hospital in Carrara, Italy, for treatment of gastric cancer. The hospital’s Chief of Oncology, Maurizio Cantore, MD, recalled that at that first visit, Signor Lodovici was unfocused and completely disinterested in what his oncologist was saying. “My concern was to quickly find a way to communicate with him because he was like a great wall without any doors to enter. I realized that the only chance I had was to speak about music, and it proved the right key with which to open a door,” Dr. Cantore told The ASCO Post. Music was a natural way for Dr. Cantore to open communication with his patient. Since 2003, a piano has had a prominent place on his oncology ward, and local musicians have regularly performed for his cancer patients. Besides, Dr. Cantore’s new patient,

Gian Andrea Lodovici, was Italy’s greatest producer of classical music.

About Donatori di Musica

More Than Chemotherapy

Dr. Cantore, a 57-year-old hematologist/oncologist, heads an oncology team that sees about 1,000 new cancers patients a year. His department’s therapeutic strategies emphasize a multidisciplinary approach, so that a tumor can be looked at “from different angles, in order to design therapeutic strategies combining locoregional or systemic therapies, such as intra-arterial chemoembolization, stereotactic radiotherapy, and radiofrequency ablation,” he explained.

reated in 2009, Donatori di Musica is a nonprofit network of musicians, health-care professionals, volunteers, patients, and their families, who organize free concerts in oncology departments throughout Italy. Only established professional musicians are invited to perform, and since the program’s inception, over 200 musicians have presented more than 160 concerts for thousands of inpatients in oncology departments throughout Italy. Each performance ends with a buffet, during which patients and performers mingle. Taken together, these elements make Donatori di Musica concerts unique. n Dr. Cantore explained how he broke through this almost impenetrable communication barrier. “When I asked Gian Lodovici to help me with his music, he suddenly realized that he

It would be worthless to have seen the most beautiful concert of the century if the magical relationships created during the concert ceased to exist afterward. But the beauty and the importance of the donors’ music program are even more visible in the days following the concert. —Maurizio Cantore, MD

“Over the years, we have also developed a deep expertise in the treatment of pancreatic cancer, seeing about 70 new patients a year,” said Dr. Cantore. He added, “But cancer treatment is more than chemotherapy. We integrated arts and humanity programs at the hospital to promote optimum life experiences for our patients and their caregivers, with activities, education, and a general environment that encourages a creative and constructive response to illness.” When asked to elaborate on his famous patient’s state of mind as he entered the hospital for treatment of gastric cancer, Dr. Cantore replied, “During the previous year, Gian Lodovici was completely absorbed by his cancer. His life was centered on chemotherapy and CT scans. The future had no meaning to him as a person or as an artist. He only imagined a dayto-day existence in his pajamas with an intravenous catheter in his arm. His soul was dead. Nobody needed him but he needed everyone.”

was still a living man and artist with an unwelcome tenant, but with a wonderful apartment full of light.”

Reconnecting to the World Dr. Cantore said that his patient’s relationship with the oncology staff quickly changed after becoming involved in the music project for inpatients. “He began listening to our treatment proposals and discussed them with us. Finally, we were fighting the disease together. The music project had given him a new reason to live and a goal to realize. He was reconnected to the world he once knew.” After being totally engaged in organizing classical concerts in Dr. Cantore’s oncology department, Signor Lodovici died of his cancer in January 2008. “But in 6 months, Gian Andrea had organized the first season of extraordinary concerts with performances by six established musicians. Through this work, he created a touchable link between the world of oncology and the world of

music,” Dr. Cantore said. “In 2008, our oncology department hosted one of the most important concert seasons in Italy, with 26 concerts from March to December,” he continued. “This initiative spread quickly, and many musicians offered to perform for cancer inpatients. Other oncology departments were eager to participate in the project. The Donatori di Musica network was born.”

Unique Opportunity Dr. Cantore explained what the music program means to him as an oncologist caring for the most vulnerable of patients. “Donatori di Musica is an extraordinary way to create meaningful relationships in an environment where it is easier to speak, explain, and ask. It offers a unique opportunity to share and discuss therapeutic choices as compared to the current informed consent required by the law. All parts of a concert are important, from the logistical preparation to the unforgettable moments of the concert itself.” He continued, “To me, the phase of the donors’ concerts that is most important is what follows. It would be worthless to have seen the most beautiful concert of the century if the magical relationships created during the concert ceased to exist afterward. But the beauty and the importance of the donors’ music program are even more visible in the days following the concert,” he said. Summing up his wholistic approach to cancer care, Dr. Cantore commented, “A daily life in oncology is made up of victories and defeats, of tears and hugs. It is made up of science, skin, and heart.” n

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Advocates in Oncology For 2 Decades, Nancy Davenport-Ennis Has Worked to Ensure Access to Health Care for All Patients Diagnosed With Life-Threatening Illness By Jo Cavallo

enport-Ennis’ oncologist assured her that her prognosis was good. Married and raising two teenage daughters, Beth, then 18, and Fran, then 14, and teaching full-time, the news came as a relief.

Life-Changing Events

Nancy Davenport-Ennis

s a young girl, Nancy DavenportEnnis remembers hearing her parents tell stories about families struggling to pay their health-care expenses following a diagnosis of a serious illness like cancer. But it wasn’t until 3 decades later when she was coping with her own diagnosis of breast cancer and the breast cancer diagnosis of a friend that she really understood the devastating financial consequences a cancer diagnosis imposes on patients and their families. It was that realization that compelled Mrs. Davenport-Ennis to launch the Patient Advocate Foundation and the National Patient Advocate Foundation in 1996. Born in Niagara Falls, New York, in 1944, Mrs. Davenport-Ennis’ first vocation was teaching English at Bethel High School in Hampton, Virginia. In December of 1989, after finding a lump in her right breast and receiving a diagnosis of cancer, Mrs. Davenport-Ennis underwent a mastectomy. Six months later, she had a second mastectomy when cancer was detected in her left breast. Despite her two bouts with cancer, Mrs. Dav-

When a close friend of hers, Cheryl Grimmel, 31, was diagnosed with stage IV breast cancer soon after Mrs. Davenport-Ennis’ second mastectomy and was told to put her affairs in order, she had 6 months to live, it set a chain of events in motion that would put Mrs. DavenportEnnis on a new career path as patient advocate. “We helped Cheryl get into a clinical trial and she lived for 3½ years. But, despite the fact that Cheryl had health insurance, the insurer refused to pay the costs associated with the trial, including a bone marrow trans-

tional—dilemma of having health insurance but denied coverage of medical costs incurred by clinical trials, Mrs. Davenport-Ennis volunteered with the Virginia Task Force for Insurance Reform and fought for passage of Virginia House Bill 240, which mandated that insurers offer and make available coverage for the treatment of breast cancer with highdose chemotherapy and autologous bone marrow or stem cell transplantation. The bill passed in 1994, just months before Ms. Grimmel’s death. Two days after the bill was signed into law, the health commissioner of Virginia announced that the state would make the provisions in the bill a standard feature of health insurance plans at no additional cost to consumers. Mrs. Davenport-Ennis then elicited sponsors and organized task forces in several other states to enact similar bills to provide coverage for

I knew if I did not get involved in helping drive healthcare policy reform nothing would change for so many Americans faced with catastrophic illness. —Nancy Davenport-Ennis

plant, putting her at financial risk,” said Mrs. Davenport-Ennis. “Cheryl’s number-one concern in the remaining days of her life was that she not leave her family in medical debt. It was such a tragedy to see a young woman having to face her own death while worrying about paying her medical bills.” To help other cancer patients caught in the financial—and emo-

How to Find Out More for Your Patients With Cancer ■■ The Patient Advocate Foundation has assisted more than 650,000 patients, and provided educational programs and information on resolving health insurance, workplace discrimination due to illness, and financial issues to millions more through its website. Visit the Patient Advocate Foundation at http://www.patientadvocate.org/ ■■ The National Patient Advocate Foundation lobbies for improvements in access to health care through regulatory and legislative reform at the state and federal level. Visit the National Patient Advocate Foundation at http://www.npaf.org/

high-dose chemotherapy and bone marrow transplant for patients with breast cancer or non-Hodgkin lymphoma. Her efforts were successful in seven states: Tennessee, Missouri, Florida, New York, New Hampshire, New Jersey, and California.

Turning a Tragedy Into a Challenge The night of Ms. Grimmel’s funeral, Mrs. Davenport-Ennis and her husband, Jack Ennis, began putting plans in place that would ensure on a national level that patients with serious diseases would have an ally in securing health insurance and in resolving insurance, employment discrimination, or financial issues related to their illness. Those plans would become the basis for Mrs. Davenport-Ennis’ two-pronged approach to providing aid for people with cancer and other life-threatening diseases: the Patient Advocate Foundation, a national nonprofit

organization that provides legal and financial assistance and help navigating insurance appeals, resolving medical debt, and maintaining employment; and the National Patient Advocate Foundation, which lobbies for improvements in access to health care through regulatory and legislative reform at the state and federal level. “When we got home from Cheryl’s funeral, I said to Jack, ‘This is supposed to be me.’ I still get emotional thinking about it because it was a time in my life when I had one daughter in college and another graduating from high school, and I was focused on their well-being. But I knew if I did not get involved in helping drive health-care policy reform nothing would change for so many Americans faced with catastrophic illness,” said Mrs. Davenport-Ennis. Mrs. Davenport-Ennis spent the next 2 years becoming educated about health-care issues and consulting with nonprofit organizations on how to build the foundations’ infrastructure and network of case workers, attorneys specializing in health care, oncology nurse case managers, oncologists, social workers, and former insurance industry case managers she would need to operate the foundations. On September 4, 1996, she launched the Patient Advocate Foundation and the National Patient Advocate Foundation.

A Legacy of Success Over its 17-year history, the Patient Advocate Foundation has assisted more than 650,000 patients, and provided educational programs and information on resolving health insurance, workplace discrimination due to illness, and financial issues to millions more through its website. In 2009, the National Patient Advocate Foundation supplied data on the huge increase in patients with preexisting medical conditions being refused care by health insurers to sponsors of the Patient Protection and Affordable Care Act. That information was used to form the central provision of the law: a ban on lifetime benefit limits and preexisting continued on page 128

The ASCO Post | OCTOBER 15, 2013

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Advocates in Oncology Nancy Davenport-Ennis continued from page 127

condition exclusions. Although Mrs. Davenport-Ennis expects full implementation of the Affordable Care Act to be challenging, she is confident it will provide access to millions of Americans without health insurance. “As a new federal program there will be bumps in the road to full implementation, and we will have to be prepared to lend a hand to newly diagnosed cancer patients who may need supplemental financial or other help,” said Mrs. Davenport-Ennis. “But at least we can begin the process of keeping our population healthier for a longer period of their lives because they will now have basic health services available to them.”

She is also grateful to the contributions her daughters, Beth Patterson, President, Mission Delivery for Patient Advocate Foundation and Fran Castellow, MSEd, President, Operations for Patient Advocate Foundation, have made to the foundations’ record of achievements. “The girls saw what happened to

Cheryl and how Jack and I helped her get into the clinical trial and resolve some of her medical debt, so there has always been a feeling in our family to want to make life better for patients and their families,” said Mrs. Davenport-Ennis. “For me, personally, there has been no greater honor than to work with our wonderful

volunteers and my family to help patients get the medical care they need without having to worry about going bankrupt in the process. I don’t want other patients with cancer to have to worry like Cheryl did about how they will pay for their care when their main focus should be on getting well.” n

A Family Affair In July, Mrs. Davenport-Ennis stepped down at Chief Executive Officer of the Patient Advocate Foundation and the National Patient Advocate Foundation, but remains Chairman of their Board of Directors. She credits the success of the foundations to the generosity of their Board of Directors and scientific committee members as well as the volunteer oncologists, nurses, case managers, social workers, attorneys, insurance agents, and members of the pharmaceutical industry that make the work of Patient Advocate Foundation and National Patient Advocate Foundation possible.

The ASCO Post

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

Boxed Warning And Additional Important Safety Information

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• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly Embryo-Fetal Death and Severe Birth Defects or through seminal fluid, to participate in the Erivedge • Erivedge capsule can cause fetal harm when pregnancy pharmacovigilance program by contacting administered to a pregnant woman based on its the Genentech Adverse Event Line at (888) 835-2555 mechanism of action Blood Donation • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months risks. Advise female patients of the need after the last dose of Erivedge for contraception during and after treatment and advise male patients of the potential risk Nursing Mothers of Erivedge exposure through semen • Inform female patients of the potential for serious • Advise patients to contact their healthcare provider adverse reactions in nursing infants from Erivedge, ERIV3D0021_F_Transformation_Print_Update_ASCO_r3.indd immediately if they suspect they 1(or, for males, their taking into account the importance of the drug to female partner) may be pregnant the mother

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Announcements Pediatric Oncology

St. Jude Children’s Hospital Appoints Larry Kun, MD, Clinical Director

t. Jude Children’s Research Hospital officials have named Larry Kun, MD, as Clinical Director and Executive Vice President. Dr. Kun will guide all aspects of clinical care and oversee clinical operations, clinical effectiveness

Larry Kun, MD

practices and patient care quality programs for the 7,800 patients who are treated or receive post-treatment care at St. Jude each year. Dr. Kun has served as Chair of the St. Jude Department of Radiological Sciences and will remain in that position.

TRANSFORM THE TREATMENT OF DIFFICULT ADVANCED BASAL CELL CARCINOMA ((aBCC) ERIVEDGE IS A UNIQUE ORAL THERAPY (Not actual size)

• Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, and invasiveness), some patients may not be candidates for surgery or radiation1,2 • Erivedge is an oral treatment option dosed as a 150-mg capsule once daily until disease progression or unacceptable toxicity3 • Erivedge reduced lesions in patients with aBCC1,3 Objective response rates (ORR) by IR from ERIVANCE1,3* ORR (95% CI)

laBCC (n=63)

mBCC (n=33)

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

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

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

Median duration of response (months) (95% CI)

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

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

See what you can offer your patients with aBCC at www.Erivedge.com References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179. 2. Walling HW, et al. Cancer Metastasis Rev. 2004;23:389-402. 3. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 5/29/13 2:53 PM

Dr. Kun brings more than 35 years of academic and patient care experience to his new role. He succeeds Joseph Laver, MD, who has accepted a position at Stony Brook University Hospital in New York. n

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PAGE 130

Announcements

William E. Evans, MD, Director, St. Jude Children’s Research Hospital, to Retire in July 2014

t. Jude Children’s Research Hospital recently announced that William E. Evans, MD, Director and CEO, has decided to retire from his

executive post in July of 2014. Dr. Evans has been with the organization for more than 40 years and has served as CEO for the past 10 years.

Indelible Mark on History of St. Jude’s “Under Dr. Evans’ leadership, we have achieved the best outcomes

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

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

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

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

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

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

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

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

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

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

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

William E. Evans, MD

Safety:10"

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

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

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

worldwide for the most frequent forms of childhood cancer, launched an $85 million effort to identify the genomic drivers of the most aggressive childhood cancers, and expanded

our facilities by more than 500,000 square feet,” said Terry Burman, Chairman of the St. Jude Board of Governors. “His significant contributions have made an indelible mark on our history, resulting not only in improved survival for children with cancer, but in better long-term quality of life.” An expert in pharmacogenomics, Evans came to St. Jude as a student in 1972. “I learned from true pioneers and was given boundless opportunity to excel in an environment where collaboration and innovation are the norm,” said Evans. “My leadership philosophy has been a simple one: Stay on mission and make St. Jude a place where great people can do their best work.”

Decade of Leadership Dr. Evans said his decade of service reflects a pattern at St. Jude that contributes to its success. “I believe a dynamic, best-of-class organization like St. Jude benefits from new leadership every 10 years to sustain the energy needed to lead the fight against pediatric cancer and other devastating diseases. Indeed, this has been our track record, with five CEOs in our first 51 years.” The St. Jude Board of Governors will conduct an international search to select a successor to Dr. Evans, and the process will include potential internal and external candidates. While Dr. Evans is expected to leave the CEO position next summer, he has agreed to serve until his successor is on board. n

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Awards

PCORI Board Approves $114 Million for Patient-Centered Outcomes Research

he Patient-Centered Outcomes Research Institute (PCORI) Board of Governors recently approved 71 awards, totaling more than $114 million over 3 years, to fund comparative clinical effectiveness research designed to answer questions most important to patients and those who care for them. The awards include the first 19 under the priority area of Accelerating Patient Centered Outcomes Research and Methodological Research.

National Priorities for Research With these latest awards, made under PCORI’s five National Priorities for Research, the institute has approved more than $303 million since 2012 to support patient-centered comparative clinical effectiveness research to date and is on track to commit more than $400 million in research support in 2013. The awards, approved during a special Board webinar/teleconference, include studies of ways to improve care for and the health of people with several types of cancer, heart disease, chronic pain, obesity, diabetes, kidney disease, autism, respiratory disorders, and various mental health conditions. Several projects will explore ways to support patient and family caregiver decision-making, reduce health disparities, and improve healthcare delivery systems. The first group of studies selected to improve research methods include efforts to improve the applicability of data collected through new sources, such as electronic health records and social media sites for clinical research;

methods to engage minority patients and caregivers as active partners in patient-centered health research; and ways to improve the existing methods for studies with few outcome events, such as treatments for rare diseases and newly marketed therapies.

Thorough Review and Formal Contract All 71 projects were approved by the Board pending completion of a business and programmatic review by PCORI staff and completion of a formal award contract. “These studies were selected from among hundreds of applications for

Joe Selby, MD, MPH

awards are part of PCORI’s third cycle of funding announcements made under the first four of its national research priorities and were selected from among more than 440 applications. The other 19 projects were se-

To select projects for funding, PCORI relies on a competitive review process…to evaluate proposals on the basis of scientific merit, how well they engage patients and other stakeholders, their methodological rigor, and how well they fit within PCORI’s national research priorities. their scientific rigor and their potential to fill important information gaps and help patients and their caregivers make more informed decisions about their care,” said PCORI Executive Director Joe Selby, MD, MPH. “Each of these projects will engage patients and other stakeholders in meaningful ways with researchers to tackle critical health problems that affect tens of millions of people nationwide,” Dr. Selby said. “We are confident these studies will lead to meaningful improvement in the quality and efficiency of care and to improvements in outcomes that are important to patients.” Fifty-two of the newly approved

lected from among 133 applications submitted under PCORI’s inaugural call for proposals focused on improving methods.

Competitive Review Process To select projects for funding, PCORI relies on a competitive review process in which scientists, patients, caregivers, and other stakeholders help to evaluate proposals on the basis of scientific merit, how well they engage patients and other stakeholders, their methodological rigor, and how well they fit within PCORI’s national research priorities. The newly approved awards will

go to 48 institutions in 20 states and Washington, D.C. With this latest round of funding, PCORI has approved support for a total of 197 projects at institutions in 35 states and Washington, D.C. PCORI’s funding announcements consist of three annual cycles and seek proposals for research that will provide patients and those who care for them with the evidence-based information needed to make better-informed health decisions. In addition to the 19 awards under PCORI’s methods priority, 24 projects address the priority area of Assessment of Prevention, Diagnosis, and Treatment Options; 13 respond to Improving Healthcare Systems; nine to Addressing Disparities; and six to Communication and Dissemination Research.

National Patient-Centered Clinical Research Network In addition to the latest research projects approved for funding, PCORI’s Board also approved a $9 million contract to a consortium led by Harvard Pilgrim Health Care Institute to serve as the Coordinating Center for a new national data network being developed through PCORI. The proposed new National Patient-Centered Clinical Research Network is intended to improve the nation’s capacity to conduct comparative effectiveness research efficiently and learn from the health-care experiences of millions of Americans by creating a large network of health data representative of patients from across the country. Details on the approved awards, including the project name, principal investigator, research institution, and abstract, are provided on the PCORI website (pcori.org). n

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The ASCO Post | OCTOBER 15, 2013

PAGE 132

Health-Care Policy Issues in Oncology

Straight Talk: The Future of Medical and Health Research By Ronald Piana

early 200 scientists and stakeholders in the research community attended Research!America’s National Health Research Forum on September 12, at the Newseum’s Knight Conference Center in Washington, DC. Research!America’s President and CEO, Mary Woolley,

tionship between companies and regulators. When Ms. Clift asked about the challenges facing the FDA, Dr. Hamburg said, “Our role is not only to work with the scientific community both in academia and in industry to really identify where are the promises in science and technology today and how we can leverage them into real-world products. [But also], how can we do the research from the very beginning in ways that support the regulatory requirements and enable us to really make the best use of now increasingly limited dollars as we build on discoveries and move them across the finish line into the products that matter for people?”

Michelle Miller

could lead to a “loss of talented workers. My goal as FDA commissioner is to help make sure we are delivering on the promises of science and technology, and today I see putting a national strategy in place as part of my mission even though many of the pieces of this

Mary Woolley

opened the program. “The theme for this program is straight talk, and that is exactly what we need these days. Our goal today is to speak candidly about the future of medical and health research,” said Ms. Woolley. Ms. Woolley then turned the lectern over to Bart Peterson, JD, Senior Vice President of Corporate Affairs and Communications at Eli Lilly and Company, who delivered a brief keynote speech. Mr. Peterson’s message, one that reverberated throughout much of the program, was a challenge to increase research funding. “Public funding for research, which is so threatened today, is absolutely critical to the future and we care about that as much from the private sector perspective as anybody else does,” said Mr. Peterson.

Which of those investigators [whose funding was affected by sequestration] would have been the Nobel Prize winner we would celebrate in 20 years? We’ll never know. —Francis Collins, MD, PhD

Dr. Hamburg also pointed out that funding cuts, especially the sequestration cuts relating to industry-paid user

Sequester Impacts Public Health

Making the Best Use of Limited Resources Eleanor Clift, Contributing Editor for Newsweek and The Daily Beast, moderated the first of three panels, which included FDA Commissioner Margaret Hamburg, MD. The discussion focused on innovation within the pharmaceutical industry and the rela-

ecosystem ... are far outside our area of activity but essential to it.” The panel members unanimously stressed the importance of pursuing novel therapeutic avenues that, despite risk, offer innovate ways to approach cancer. The group ended with a clarion call for more research dollars.

Eleanor Clift

fees, have been detrimental to the FDA. “It was an unexpected and unfortunate hit, people are stretched very thin,” she said. According to Dr. Hamburg, the consequential extra heavy workload

The second panel moderated by CBS News correspondent Michelle Miller, took a panoramic view of American health care, much of which was not cancer-specific. One interesting observation pertaining to prevention was made by Tom Frieden, MD, MPH, Director of the Centers for Disease Control and Prevention (CDC).

He noted that the Patient Protection and Affordable Care Act would help bring preventive measures to people who otherwise would not have access to them. For instance, a recent study found that only 32% of American girls were current on their human papillomavirus (HPV) vaccinations, commenting that the HPV vaccination rate in Rwanda is 85%. According to Dr. Frieden, budget cuts and sequestration are hampering the CDC’s ability to distribute HPV vaccines to people who need them. As a result, he said, “there will be more cases of cervical cancer.”

Research and Innovation The third panel discussion focused on fostering an innovation culture and research as a national priority. This was moderated by Norman Ornstein, PhD, Resident Scholar at the American Enterprise Institute, and a Contributing Editor for National Journal and The Atlantic. Dr. Orenstein set the tone by charging Washington, DC’s polarized political climate for the decline in research funding. Francis Collins, MD, PhD, Director of the National Institutes of Health stressed that while scientific progress is at a level he could not have foreseen 10 years ago, it suffers from lifeless support in Congress. Once again, sequestration was blamed. Dr. Collins said that it alone would force NIH to cut 650 research projects in Fiscal Year 2014. “Which of those investigators would have been the Nobel Prize winner we would celebrate in 20 years? We’ll never know,” Dr. Collins said. The take-away message was to alert Congress to the perils of cutting biomedical research funding. Tony Coles, MD, Chairman and CEO of Onyx Pharmaceuticals said that while public-private partnerships are important in the drug development process, these cannot replace the value of government-supported research. n

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Perspective Health-Care Policy

Value in Cancer Care continued from page 1

poor value in cancer care and allows resolution of those elements that are accessible. For example, provision of symmetrical access to high-quality care, by overcoming barriers of poverty, language, and geographical isolation while providing the key advances in modern oncology, should improve national cancer survival figures without blowing out the budget. This philosophy contrasts with the continued reluctance of some medical institutions to accept indigent, Medicare, or Medicaid patients, thus protecting their bottom lines from loss, an approach that is unfair to the community—cherry-picking the wealthiest, most educated and robust patients (who also have the strongest health insurance coverage) may lead to partial falsification of outcomes (that is, the publication of data drawn from treatment of the “star” patients, which many politicians and community leaders may fail to understand when they nonchalantly translate the resulting highly selected data into expectations for the population at large). A successful formula also requires easily accessible tertiary level cancer care close to home, with access to clinical trials, optimal patient support and navigation, and access to the benefits of the genomic revolution as parts of routine cancer care. It also has to be refined by the establishment of an evidence-based set of standards for diagnosis and treatment, which are routinely used by physicians.

Challenging Issues In many major centers, outreach clinics have been established as a mechanism to provide easier intake for the health-care system, without necessarily providing key resources for consumers residing long distances from the centers. In the United States in recent times, less than 5% of patients are enrolled in clinical trials,2 and it is clear that there are significant disparities of access to high-level cancer programs.3 We are now attempting to address these challenging issues in the Carolinas. Charlotte, the largest city in North Carolina, with a population approaching 1 million (and a referral base of around 2 million people) has not had local access to a comprehensive-style cancer center. Specifically, there has been paucity of locally available bone marrow transplant facilities and of

phase I and investigator-initiated clinical trials, although the latter have been intermittently available on a small scale. Quaternary cancer services have been provided by outstanding cancer centers at Emory, Duke, Wake Forest, and UNC Chapel Hill, but have often required travel of more than 3 to 4 hours for geographically isolated patients and for those living in Charlotte who require more sophisticated cancer services. Carolinas HealthCare System, an amalgam of more than 40 hospitals and medical centers spanning North Carolina and South Carolina, employs more than 2,000 physicians, more than 50,000 staff, and sees more than 11,000 new cancer cases per year. The system has traditionally avoided national marketing and, thus, has not been very well known beyond the Carolinas. It was logical, as the system has expanded to be one of the largest not-for-profit health systems in North America, to make the decision to establish a ter-

3. easy availability of clinical trials, with access close to home throughout North Carolina and South Carolina 4. a single, central institutional review board for cancer trials covering the whole system, facilitating swift and synchronous, system-wide activation of studies 5. central protocol review and monitoring system, with initial protocol submissions via tumorspecific teams 6. central oversight of a tightly controlled clinical trials unit, with central training and monitoring of staff 7. centralized connections and data capture for each hospital tumor registry with ability to measure outcomes and costs of care 8. extensive patient support services, including patient navigation linked throughout the system, standard operating procedures for emergency departments

Challenge is engaging, and the sense that we are embarking as a team on an adventure that will lead to better care, outcomes, and value, rather than focusing on the litany of surrogate endpoints that politicians and health economists seek, has led to superb cooperation and esprit de corps. —Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

tiary referral cancer center that would serve the Carolinas, and which would attempt to provide a system of cancer care closer to home contrary to the more conventional models.

Strategy and Tactics To evolve the concept of the Levine Cancer Institute, we created a series of regional cancer strategy committees that linked into a central oversight team, which was charged with developing the strategy and tactics to create a center with the following 10 key features: 1. multidisciplinary clinics with standard operating procedures and protocols of management 2. system-wide interdisciplinary tumor boards and conferences, augmented by electronic two-way video conferencing to connect geographically isolated oncology teams

throughout the system, palliative care and pain management services, specific cancer-focused pastoral care, and live or videolinked genetic counseling 9. availability of subspecialty services, such as bone marrow transplantation, phase I clinical trial units, and sophisticated radiation techniques and equipment in as accessible a fashion as possible 10. a focus on translational bench research that is focused specifically on the clinical emphases of Levine Cancer Institute—early programs have focused on cancer pharmacology, stem cell biology of hematologic disorders and molecular prognostication with availability of a cost-effective, molecular testing platform where appropriate.

Swiftly Launched Initiatives We have moved quite swiftly to launch these initiatives, beginning in April 2011. In addition to the planning activities working centrifugally throughout the system, we developed a plan for a six-story academic, electronic, and organizational focal point: The new Levine Cancer Institute central building <photo available?>—180,000 square feet of clinical, electronic conferencing, and patient support facilities—was erected and opened in just 18 months. The building is relatively unique, with its emphasis on system-wide communications, patient support resources, a hub for genetic counseling system-wide services, and as a base for the translational science that underpins our clinical trials. Linked phase I trial facilities are being developed at Levine Cancer Institute–Roper St Francis Center, Charleston, SC, and Levine Cancer Institute at Northeast Hospital, Concord, NC, to augment the role of the 12-bed phase I unit at the Levine Cancer Institute academic headquarters. Of particular importance, we have created a system of programs and protocols that are available on a password-protected intranet, supported by clearly defined treatment pathways developed by our tumor-specific teams. This ensures congruence of practice by the team members with the plans of the Levine Cancer Institute, and avoids internal competition or lack of support for defined treatment and research programs. The development of a medical staffing system that would serve the needs of the patients and our initiatives was an early imperative. Carolinas HealthCare System has been served by an extensive cadre of well-trained medical, radiation, and surgical oncologists, constituting a mixed staffing model of employed faculty and independent, practice-based physicians. Our strategy for the system throughout the Carolinas has been to link with selected hospitals and their staffs, establishing contractual relationships with the hospital leadership and personal and professional relationships with their physicians, which included the provision of centrally controlled Levine Cancer Institute clinical trial units. Where needed, additional faculty members have been recruited from a range of other cancer centers. Academic and programmatic leadership has been drawn from Na-

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Perspective

tional Cancer Institute–designated comprehensive cancer centers.

Expanding Staff For the Charlotte region, we expanded our staff in two ways. First, the medical oncologists of three oncology practices that provided services for the Charlotte region hospitals were invited to join the Levine Cancer Institute as staff physicians, adding to the Blumenthal Cancer Center faculty members. Several administrative leaders were selected from these groups. Additional clinical needs have been met by a program of active recruitment from major cancer centers. Radiation oncology services are provided by the Southeast Radiation Oncology team, whose leaders have taken on the radiation oncology leadership of the Levine Cancer Institute. Surgical Oncology services have been provided by staff physicians from the Charlotte region Carolinas HealthCare System hospitals in a relatively conventional matrix, augmented by active national recruitment, with established leaders from Charlotte retaining their seminal roles. Other specialties have been recruited in a distributed fashion across the system. One of the keys to our success has been active engagement, which has involved many physicians in private practice within our system. For example, our initiative known as “The Flying Squad,” named after the rapid

Levine Cancer Institute, Carolinas Health-Care System, Charlotte, North Carolina

deployment police force in the inner city region of London, involves a highly mobile, specifically trained nurse and support team that can be dispatched to the home setting to assist with symptom control, routine and frequent measurement of clinical trial parameters, blood collection, and a range of other services. This program is led by a surgeon in private practice in Albemarle, NC. Similarly the Cancer Patient Navigator Program is led by a diagnostic radiologist in private practice, who has a strong interest in patient support strategies.

Challenges Ahead Hopefully the readers of this discussion will find it provocative and interesting, and may believe that the

model and its 10 key features may actually change patterns of cancer care in the United States. By improving access, trial participation, quality of care, the use of structured and defined pathways that include appropriate incorporation of palliative care, and precision of outcome measurement, we believe that we will improve value for patients via the Porter-Teisburg equation cited above. This, in turn, should bring down overall costs for the population that we serve (which includes insured, Medicare, Medicaid, and uninsured patients). None of our team is in any doubt that this will be complex and demanding, and there will be many hurdles to overcome—removal of silos, challenges of reimbursement (particularly with a health insurance

industry that is itself challenged, undergoing change, and unaccustomed to innovation), maintenance of momentum and standards of clinical practice and research, and the evolution of the panoply of electronic support tools needed to foster our aims. Equally challenging is the lack of easy “fit” with the mechanisms inherent in the National Institutes of Health for funding and rules regarding programmatic oversight for a multisite cancer center. Nevertheless, challenge is engaging, and the sense that we are embarking as a team on an adventure that will lead to better care, outcomes, and value, rather than focusing on the litany of surrogate endpoints that politicians and health economists seek, has led to superb cooperation and esprit de corps. Our ultimate goal is to improve cancer survival in the Carolinas, but it will take some time to know whether we are successful. n Disclosure: Dr. Raghavan reported no potential conflicts of interest.

References 1. Porter ME, Teisberg EO: How physicians can change the future of health care. JAMA 297:1103-1111, 2007. 2. Raghavan D: An essay on rearranging the deck chairs: What’s wrong with the cancer trials system? Clin Cancer Res 12:1949-1950, 2006. 3. Goss E, Lopez AM, Brown CL, et al: American Society of Clinical Oncology policy statement: Disparities in cancer care. J Clin Oncol 27:2881-2885, 2009.

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Dermatologic Events in Oncology How to Recognize and Manage Ipilimumab-Induced Dermatologic Adverse Events By Jennifer Nam Choi, MD

pilimumab (Yervoy) is a fully humanized immunoglobulin (Ig) G1 monoclonal antibody that binds to and inhibits cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). It acts as a T-cell potentiator, leading to increases in T-cell activation and interleukin-2 secretion. Ipilimumab is U.S. Food and Drug Administra-

terocolitis, hepatitis, hypophysitis, uveitis, and skin-related side effects. Skin-related adverse events include rashes, pruritus, and vitiligo. The overall incidence of all-grade rash and high-grade rash is 24% and 2%, respectively. The ipilimumab-associated cutaneous eruption is characterized by

While there is no known treatment for ipilimumab-induced vitiligo, prevention of photosensitivity or sunburn in depigmented areas is important. —Jennifer Nam Choi, MD

tion–approved for the treatment of late-stage (metastatic or unresectable) melanoma and is the first drug to demonstrate a survival benefit in the setting of metastatic melanoma.

Ipilimumab-Related Adverse Events Treatment with ipilimumab is associated with numerous immunerelated adverse events, including en-

discrete, erythematous, minimally scaly, pruritic papules that can coalesce into thin plaques, most often involving the trunk and extremities (Fig. 1). The face and head are less frequently involved, and palms and soles are usually spared. The rash usually occurs early in the course of treatment, in the first 3 to 4 weeks after the first dose; however, rash development earlier or

Fig. 1: Ipilimumab-associated rash. Photo courtesy of Matthew Burke, APRN.

even after completion of therapy is possible. The rash can worsen with each ipilimumab dose and can be associated with a significant increase in peripheral eosinophilia. Histologically, epidermal spongiosis, papillary dermal edema, and a perivascular lymphocytic infiltrate with eosinophils can be seen. The risk of rash associated with ipilimumab does not appear to be dose-dependent. Usually well tolerated, the cutaneous eruption is often self-limited, but can take weeks to months to resolve. Pruritus, or itch, has been reported to occur in up to 31% of patients on ipilimumab. Pruritus can be associated with both rashes and dry skin, but may also occur separately as a direct result of enhanced immune system activation in the skin. Vitiligo, or depigmentation of the skin, can also develop as a result of ipilimumab treatment, but has been reported in only 2% to 4% of patients (Fig. 2). Such depigmentation tends to be irreversible and can be limited or widespread.

Treatment Recommendations For grades 1 and 2 rashes, treatment consists of topical corticoste-

Fig. 2: Vitiligo caused by ipilimumab therapy.

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. roids. For grade 3 rashes, oral corticosteroids may be required, such as oral prednisone at 1 mg/kg daily, while ipilimumab is held until rash improvement. For grade 4 rashes, oral corticosteroids at higher doses, such as oral prednisone at 1 to 2 mg/ kg daily, may be required, and perma-

ASCOPost.com | OCTOBER 15, 2013

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Dermatologic Events in Oncology nent discontinuation of ipilimumab must be considered. For pruritus, general recommendations include use of alcohol-free emollient creams to moisturize the skin. Cold compresses, oatmeal baths, and topical corticosteroids may be helpful in relieving pruritus. Systemic antihistamines can also be beneficial. Nonsedating secondgeneration antihistamines, such as loratadine, cetirizine, and fexofenadine are recommended for daytime treatment, whereas first-generation, sedating antihistamines, such as diphenhydramine and hydroxyzine, are generally recommended for nighttime use. Doxepin, a tricyclic antidepressant, has also been used successfully in reducing pruritus, and is available in both topical and oral preparations. Special caution should be taken when prescribing antihistamines and antidepressants to patients with cancer—particularly in the elderly—to avoid oversedation. Other agents,

including GABA agonists (eg, gabapentin) and aprepitant (neurokinin-1 receptor antagonist), are being investigated as potential antipruritic agents. While there is no known treatment for ipilimumab-induced vitiligo, prevention of photosensitivity or sunburn in depigmented areas is im-

portant. Patients should be advised to use a broad-spectrum sunscreen of SPF 30, applied every 2 hours to sunexposed areas, in addition to wearing sun-protective clothing, sunglasses, and broad-rimmed hats. Additionally, avoidance of direct sun exposure between 10:00 AM and 4:00 PM is recommended.

Recognition and treatment of ipilimumab-induced cutaneous reactions are important, as they are a common manifestation of immune-related side effects. Proper management can help in maintaining a patient’s treatment with ipilimumab. n Disclosure: Dr. Choi reported potential conflicts of interest.

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Read the October Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Myeloid Growth Factors

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

• NCCN Guidelines® insights: Ovarian Cancer In this section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• imatinib-induced Bone edema: Case report and review of Literature • Adolescent and young Adult Colorectal Cancer • Targeting Angiogenesis in Advanced Non–small Cell Lung Cancer • implementing routine screening for Distress, the sixth vital sign, for Patients with Head and Neck and Neurologic Cancers • will Biosimilars Gain Momentum?

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In the News Issues in Public Health

What You Need to Know About E-Cigarettes By Charlotte Bath

“I

’ve seen a lot of puzzled people,” Alexander V. Prokhorov, MD, PhD, said, referring to people who see others using electronic or e-cigarettes. That puzzlement can go beyond wondering why people are smoking in public places and whether they are breaking the law, or just being annoying, to questions such as what are they smoking and how does it affect bystanders and the environment? E-cigarettes, as defined by the FDA, “are battery-operated products designed to deliver nicotine, flavor, and other chemicals. They turn nicotine, which is highly addictive, and other chemicals into a vapor that is inhaled by the user.”1 There are a lot of unknowns about e-cigarettes and what chemicals they contain, and those unknowns and the increasing popularity of e-cigarettes, particularly among young people, have Dr. Prokhorov and many others concerned. Dr. Prokhorov is Director of the Tobacco Outreach Program, Co-director of the e-Health Technology Program, and Professor in the Department of Behavioral Science at The University of Texas MD Anderson Cancer Center in Houston. “We really don’t know what is in ecigarettes,” said Dr. Prokhorov. “There are so many different factories abroad that manufacture these products, how do we know that the quality is con-

sistent and the amount of nicotine is consistent? We don’t. That’s the problem.”

Largely Unregulated The FDA does not currently regulate e-cigarettes unless they are marketed for therapeutic purposes. And,

had been listed in an FDA agenda and reported by the media as the estimated date for issuing a proposed rule, the FDA “doesn’t rule out the publication of the proposed rule happening before or after a date. The agency can’t speculate on timing,” according to the FDA spokesperson.

This is not the first attempt of the tobacco industry to [market] an alternative cigarette that would be high-tech… This time it looks like they succeeded. —Alexander V. Prokhorov, MD, PhD

“There are currently no electronic cigarettes that are FDA-approved for therapeutic purposes,” according to an FDA spokesperson. “The FDA intends to propose a regulation that would extend the agency’s ‘tobacco product’ authorities—which currently only apply to cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco—to other categories of tobacco products that meet the statutory definition of ‘tobacco product,’” the spokesperson wrote in response to an e-mail inquiry from The ASCO Post. Although October 2013

In a “Room for Debate” feature in The New York Times,2 Anne Joseph, MD, MPH, Wexler Professor of Medicine at the University of Minnesota, and President of the Society for Research on Nicotine and Tobacco, noted that e-cigarettes are “more accurately called electronic nicotine delivery systems, or ENDS.” According to Dr. Joseph, “A few studies demonstrate that ENDS deliver lower levels of many tobacco toxins than traditional cigarettes, but dangerous chemicals in addition to nicotine, like acetaldehyde, a natural substance found in tobac-

Expect Questions About E-Cigarettes

Are e-cigarettes harmful to bystanders?

What are e-cigarettes?

Currently there is not evidence of harmful effects caused by second-hand vapor from e-cigarettes. “Certainly there is no comparison with conventional cigarettes,” said Dr. Prokhorov.

-cigarettes are in the news, in advertising, and in stores, and because their public use is still largely unregulated, they may be in your face. Being prepared to answer questions about their use may help patients make wise decisions. Electronic cigarettes or e-cigarettes, as defined by the FDA, “are battery-operated products designed to deliver nicotine, flavor, and other chemicals. They turn nicotine, which is highly addictive, and other chemicals into a vapor that is inhaled by the user.”

Are e-cigarettes harmful to users? E-cigarettes do not appear to be as harmful as conventional cigarettes, but because they are largely unregulated, what they contain is not really known. As mentioned above, they do contain nicotine, which is highly addictive. Other chemicals that have been reported include acetaldehyde and benzene. Also unknown is what chemicals are

used in the flavorings added to e-cigarettes.

Are e-cigarettes regulated by the U.S. Food and Drug Administration? The FDA regulates e-cigarettes only if they are marketed for therapeutic purposes, and there are currently no electronic cigarettes that are FDA-approved for therapeutic purposes. “Further research is needed to assess the potential public health benefits and risks of electronic cigarettes and other novel tobacco products,” according to n FDA spokesperson. Consumers may submit voluntary adverse event reports to FDA for electronic cigarettes through the MedWatch program at fda.gov/Safety/MedWatch/default.htm. n

co, and benzene, a petroleum-based chemical, can certainly be measured in their emissions. The amount of these substances varies considerably because e-cigarettes are still unregulated.” E-cigarettes also contain flavorings, such as cherry, bubble gum, and chocolate, that appeal to young people. “Every time a new flavor is introduced, you really don’t know what it is. What kinds of chemicals are used? If inhaled, what do they do to the body? We don’t know. I certainly hope that the FDA would pay close attention to regulating these substances,” said Dr. Prokhorov. “I am not saying that e-cigarettes are more harmful that conventional cigarettes; by no means, absolutely not,” Dr. Prokhorov said. “But if manufacturers use some kind of unsafe substance to make an e-cigarette a certain flavor, it could be pretty harmful without us even knowing.”

Gateway to Smoking “E-cigarette experimentation and recent use doubled among U.S. middle and high school students during 2011 to 2012, resulting in an estimated 1.78 million students having ever used ecigarettes as of 2012,” according to survey data reported by the Centers for Disease Control and Prevention.3 “Moreover, in 2012, an estimated 160,000 students who reported ever using e-cigarettes had never used conventional cigarettes.” Asked if that finding indicates that e-cigarettes may serve as a gateway to smoking traditional cigarettes, Dr. Prokhorov replied, “Absolutely.” New and high-tech products tend to attract young people, he said, adding, “This is not the first attempt of the tobacco industry to [market] an alternative cigarette that would be hightech.” A product introduced a few years ago relied on heated, but not burning, tobacco, to imitate the smoking process, but “that one was a failure, I guess mainly because it didn’t produce any kind of cigarette smoke, as in this case,” meaning the vapor produced by e-cigarettes. “But this time it looks like they succeeded. [E-cigarettes] have all of these elements; they have the battery; they have the heating element; they have the cartridge with nicotine and flavoring; and it imitates the smoking process. There is a smoke-like ritual. continued on page 144

Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

To learn more about this study, please visit www.ClinicalTrials.gov.

The ASCO Post | OCTOBER 15, 2013

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In the News

E-Cigarettes continued from page 142

You actually inhale something that looks like smoke and exhale something that looks like smoke. Essentially you get what you want to get—you get your nicotine and you get your ritual,” said Dr. Prokhorov. “E-cigarettes come in all kinds of shapes and sizes and some of them look very much like cigarettes, with a white part and a filter part. Others look nothing like cigarettes,” Dr. Prokhorov explained. “They look like some sort of contemporary, super futuristic-looking gadgets. Kids are enticed by these things. They like to own cool gadgets.” All this can “lead to some kids who would never think about starting cigarette smoking to try something that is perceived to be much less harmful. And that is how these e-cigarettes are positioned—as virtually harmless,” Dr. Prokhorov said, but “e-cigarettes could be an introduction to the whole tobacco world for them.”

Nicotine Is Still a Poison The nicotine in e-cigarettes and the possibility of a quick descent into nicotine dependence concern Dr. Prokhorov greatly. “We used to think that nicotine dependence develops over a reasonably long period of time, but there are some studies that claim that with a certain genetic makeup, you can actually develop nicotine dependence very quickly,” he said. “Once you develop nicotine dependence, if you are not fully satisfied with e-cigarettes, it makes it an easier experience to switch to conventional cigarettes.” Nicotine, he noted, “is still a poison. A certain amount of nicotine can kill you. If you overdose, it can kill you. That brings up another issue. Kids sometimes do silly things,” like issue each other extreme challenges. So while e-cigarettes may not be as harmful as conventional cigarettes, “I am still concerned by extended use of these products by young people,” Dr. Prokhorov said.

Smoking-Cessation Tool? A recent study in the Lancet4 reported that e-cigarettes can work at least as well as nicotine patches in helping smokers to quit. “But when you look at the results, one-third of e-cigarette users continue to use e-

cigarettes, whereas 8% of patch users continue to use patches at 6 months after the quit date, when in fact the “treatment” in the study was supposed to end 11 weeks after the quit date. To me, that suggests that e-cigarettes can delay quitting. Instead of quitting cigarettes over a certain period of time, people continue using these nicotine products,” said Dr. Prokhorov. He acknowledged that it is possible that someday e-cigarettes might be shown to be an effective aid for individuals interested in quitting smoking traditional cigarettes. But until the products are regulated, there will always be unanswered questions about safety of the manufacturing practices for the products.

“We have to be very careful about the potential downsides of e-cigarettes and certainly research this as carefully as we can to see if they are helpful to quitting smoking,” Dr. Prokhorov said. “I am a researcher and I would like to see convincing evidence that the ecigarette, as a nicotine delivery device, is both safe and effective before marketing it as a cessation aid is permitted. Although one study showed comparable results as nicotine replacement therapy, it is important to note that the nicotine medications have been used for decades and considered to be a “clean” form of nicotine. In contrast, e-cigarettes deliver not only nicotine but also other potentially harmful chemicals,” he added.

Smoking App for Teens

-cigarettes are one of the many issues addressed in the Tobacco-Free Teens app developed at MD Anderson Cancer Center in Houston. “What we are trying to say to teens is that you might as well avoid trying any of the cigarettes, or small cigars, or nicotine delivery devices, such as e-cigarettes,” explained Alexander V. Prokhorov, MD, PhD, Director of the Tobacco Outreach Program, Co-director of the e-Health Technology Program, and Professor in the Department of Behavioral Science at the University of Texas MD Anderson Cancer Center in Houston. “Using a nontobacco product that does not have all the tar and all those carcinogens and irritants, certainly puts you in a sort of less dangerous situation,” said Dr. Prokhorov. “But you have to be aware of the fact that e-cigarettes contain nicotine and nicotine leads to nicotine dependence, because it was shown very convincingly by researchers that nicotine is just as addictive as cocaine and marijuana and nicotine dependence can be your problem for the rest of your life if you aren’t able to get rid of it.” The new app teaches that, “Both physical and mental performance are compromised if you are a smoker,” Dr. Prokhorov said. “The myth is that smoking helps you concentrate. Well it does maybe for the short-term, but if you have nicotine dependence and you don’t have that cigarette, you can’t think about anything else, but having another cigarette. There goes all your concentration and you start experiencing those withdrawal symptoms that unfortunately show up much quicker than we thought.”

Inspired by ASPIRE The Tobacco-Free Teens app was largely drawn from MD Anderson’s ASPIRE (A Smoking Prevention Interactive Experience), an online tobacco prevention and cessation program targeted to middle and high school students. “The program is not designed just for smokers or for spit tobacco users. It is designed for everybody. So if you are a nonsmoker, you still can learn skills to be a good advocate,” said Dr. Prokhorov. “ASPIRE is an evidence-based program. It is featured in the Cochrane Review favorably,” said Dr. Prokhorov. “ASPIRE has been reviewed by the National Cancer Institute and is now included in the Research Tested Intervention Programs (RTIPS) database. So we are pretty confident that ASPIRE is a working program with a strong prevention potential.” ASPIRE can be accessed at mdanderson.org, and the Tobacco-Free Teens app is available for free on the Apple iTunes Store. n Disclosure: Dr. Prokhorov reported no potential conflicts of interest.

“There is a lot of debate going on within the tobacco control community about this issue,” Dr. Prokhorov acknowledged. Some advocate manufacturing only e-cigarettes and doing away with traditional cigarettes. “My big problem with that is that I haven’t seen any document that would tell me that as of a certain date, the production of conventional cigarettes is going to stop. As long as we have conventional cigarettes available, there is always the danger of starting with e-cigarettes and switching to regular cigarettes.”

Bad Old Days Some states have indoor smoking restrictions for e-cigarettes as well as conventional cigarettes, but according to Dr. Prokhorov, there is not much evidence of harmful effects caused by second-hand vapor from e-cigarettes. “Certainly there is no comparison with conventional cigarettes,” he said. “But the problem I see here is, we just reached a level where society has certain rules, and a certain vision, a certain perception of smoking in public places,” and using e-cigarettes in public places “is reminiscent of the times” of smoke-filled hallways, theaters, trains, and planes. Also reminiscent of the smoky days and haze of yore are the advertisements for e-cigarettes, some featuring celebrities and glamourizing smoking. “Kids are watching,” Dr. Prokhorov said. n

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

References 1. U.S. Food and Drug Administration: Electronic cigarettes (e-cigarettes). Last updated April 25, 2013. Available at http://www.fda.gov/newsevents/publichealthfocus/ucm172906.htm. Accessed October 2, 2013. 2. Joseph AM: Room for debate: More trials, more disclosure. New York Times, August 20, 2103. Available at www.nytimes.com. Accessed October 2, 2013. 3. Notes from the field: Electronic cigarette use among middle and high school students—United States, 20112101. MMWR Morbid Mortal Wkly Rep 62:729-730, 2013. 4. Bullen C, Howe C, Laugesen M, et al: Electronic cigarettes for smoking cessation: A randomised control trial. Lancet. September 9, 2013 (early release online).

ASCOPost.com | OCTOBER 15, 2013

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In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Mindfulness-Based Stress Reduction Therapy for Patients With Distress Mindfulness-based cancer recovery was shown to be superior to supportive-expressive group therapy “for decreasing symptoms of stress and also for improving overall quality of life and social support” among women who had stage I to III breast cancer and were assessed as experiencing distress, researchers reported in the Journal of Clinical Oncology. “Improvements were clinically meaningful,” the study authors stated. Mindfulness-based cancer recovery included meditation and yoga; Supportive expressive group therapy included expression of emotions and group support. Both are “well-validated group interventions for cancer support,” the authors noted, “but the two have never been directly compared.” The current trial did that, randomizing 271 patients, in a 2:2:1 allocation ratio to either mindfulness-based cancer recovery, supportive-expressive group therapy, or a 1-day stress management control program. The study participants had to have completed all treatments except hormonal or trastuzumab (Herceptin) therapy at least 3 months before.

Similarities and Differences The similarities between interventions were the group format, size, structure, and contact hours. Differences between the two groups were in content, focus, and theoretical underpinnings. The focus of supportive-expressive group therapy was on group support and emotional expression, whereas the focus of mindfulness-based cancer recovery was on mindfulness meditation, yoga practice, and sustaining mindful awareness in day-to-day life. “Women in mindfulness-based cancer recovery improved more over time on stress symptoms compared with women in both the supportive-expressive group therapy (P = .009) and control (P = .024) groups. Per-protocol analyses showed greater improvements in the mindfulness-based cancer recovery group in quality of life compared with the control group (P = .005) and in social support compared with the sup-

portive-expressive group therapy group (P = .012),” the researchers reported. In addition, diurnal salivary cortisol slopes, as measured from saliva samples collected by participants for 3 days before randomization and 3 days after intervention completion, were maintained over time for both interventions but become flatter for the control group. “Because abnormal or flattened cortisol profiles have been related to both poorer psychological functioning and shorter survival time in breast, lung, and renal cell carcinoma, this finding may point to the potential for these psychosocial interventions to improve biologic processes related to both patient-reported outcomes and more objective indices. More work is needed to fully understand the clinical meaning of these parameters in primary breast cancer,” the researchers wrote. “Mindfulness-based cancer recovery helps facilitate development of positive emotional regulation strategies such as acceptance and gently extinguishes unhelpful strategies including worry, rumination, and experiential avoidance. As participants allow graduated exposure to feared thoughts and feelings during meditation practice, cultivated in an accepting and nonjudgmental environment, feared stimuli lose much of their power. The result is often a sense of heightened control, calm, peace, and serenity, even in the face of the many uncontrollable elements of cancer,” the authors stated. “Given this continually growing evidence of efficacy,” of mindfulnessbased cancer recovery, the authors concluded, “cancer treatment centers should consider providing such interventions to needy patients as a routine part of comprehensive clinical care.” Carlson LE, et al: J Clin Oncol 31:3119-3126, 2013.

MULTIPLE MYELOMA Pomalidomide In Patients With Disease Progression Who Are Refractory to Bortezomib and Lenalidomide The second-generation immunomodulatory drug pomalidomide (Pomalyst) “has shown impressive results in patients with multiple myeloma who are refractory to lenalidomide [Revlimid] and bortezomib [Vel-

cade],” according to a review of clinical data leading to the drug’s approval by the FDA. In February, the FDA approved pomalidomide 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. “Pomalidomide is well tolerated, with minimal toxicity, features important for a drug that is targeted for heavily treated, multiple relapsed patients,” reported the authors of the review, published online by Blood. The review also provided advice for physicians who are prescribing the drug for patients, including information about dosing, toxicities, and special populations. “Available data suggests that efficacy and toxicity are similar at the 2 mg and 4 mg dose levels,” the authors noted.

Toxicity Data “Fatigue is the most commonly reported adverse effect, with 62% of patients experiencing any fatigue and 8% experiencing fatigue of grade 3 or higher,” the authors noted. Grade 3/4 neutropenia occurred in 26% to 66% of patients. Less common hematologic toxicities were anemia, with grade 3/4 in 17% of patients, and thrombocytopenia, with grade 3/4 in 13% of patients. The incidence of thromboembolic events in the studies reviewed was low, 2% to 3%, and similar to patients treated with other immunomodulatory drugs. “Prophylactic treatment with aspirin is a reasonable strategy to prevent thromboembolic complications in these patients and has been successfully used in pomalidomide clinical trials to date,” the authors stated. A large multicenter randomized phase III trial “established that pomalidomide “is safe and well tolerated in myeloma patients with moderate renal failure (clearance < 60 mL/min), but no data is available for patients with severe renal failure,” the authors wrote. A trial currently accruing patients is expected to address this issue. Data are not available regarding the use of pomalidomide in pediatric patients, or dosing, safety, or efficacy in patients with liver failure.

Ongoing studies are testing pomalidomide in combination with other drugs in patients with relapsed or refractory multiple myeloma. These studies include a phase I/II trial of pomalidomide, dexamethasone, and pegylated liposomal doxorubicin (Doxil), and a phase III trial comparing bortezomib and dexamethasone with and without pomalidomide. Lacy MQ, McCurdy AR: Blood. August 23, 2013 (early release online).

SKIN CANCER Sunscreen Use Infrequently Discussed With Patients Although the incidence of skin cancer in increasing, “the rate at which physicians are mentioning sunscreen at patient visits is quite low, even for patients with a history of skin cancer,” according to an analysis of data from more than 18.30 billion patient visits. “Sun-protection counseling ranks among the lowest topics of primary prevention discussed between physicians and patients,” the study authors wrote in JAMA Dermatology. The National Ambulatory Medical Care Survey was used to identify the frequency of sunscreen recommendations during patient visits to nonfederal outpatient physician offices at U.S. ambulatory care practices between 1989 and 2010. The results showed that physicians mentioned sunscreens at approximately 12.83 million visits or 0.07%. “The frequency of sunscreen recommendation was 12 times greater for patient visits associated with a diagnosis of skin disease compared with visits with no reported skin disease,” the authors stated, but that was still less than 1% of visits. “Analysis by physician specialty revealed that dermatology visits accounted for most of the appointments associated with sunscreen recommendation (86.4%), followed by visits with general and family practitioners (9.6%), pediatricians (1.4%), other specialists (1.4%), and internists (1.1%),” the data showed. Still continued on page 146

The ASCO Post | OCTOBER 15, 2013

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In the Literature

Emerging Clinical Data continued from page 145

just 1.6% of all dermatology visits included a mention of sunscreens. “In addition, sunscreen was mentioned by dermatologists at 11.2% of visits associated with a diagnosis of active or remote history of skin cancer. This low frequency of sunscreen rec-

ommendation by dermatologists is concerning because dermatologists saw more than 20 times the number of patients with a history of skin cancer (7.1 million) compared with general/family physicians (320,000). Moreover, the frequency with which dermatologists recommended sunscreen to this population of patients

was significantly less than that of general/family physicians (11.2% vs 55.5%),” the authors noted. While no differences in sunscreen recommendations were found based on patients’ sex or ethnicity, there were differences by race and age group. “Compared with black patients, white patients were 9 times

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

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

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

more likely to be recommended sunscreen. Children and adolescents were recommended sunscreen the least compared with all patient age groups,” the analysis showed. “The findings are concerning because children and adolescents get the most sun exposure of any age group, as they tend to spend much of their time playing outdoors. Up to 80% of sun damage is thought to occur before age 21 years, and sunburns in childhood greatly increase the risk for future melanoma,” the authors wrote. They pointed out that new guidelines advise pediatricians to discuss sun protection with patients and to be strong proponents of other sunprotective policies. Akamine KL, et al: JAMA Dermatol. September 4, 2013 (early release online).

PROSTATE CANCER Shiftworkers Likely to Have Increased Risk A strong positive association with shiftwork and elevated prostate-specific antigen (PSA) level was found in an analysis of three National Health and Nutrition Examination Survey (NHANES) studies. “Our data support the notion that sleep or circadian disruption is associated with elevated PSA, indicating that shiftworking men likely have an increased risk of developing prostate cancer,” sleep medicine and public health investigators reported in the Journal of the National Cancer Institute. “This analysis included 2,017 working men aged 40 to 65 years, which may be extrapolated to represent approximately 31,576,504 men in the United States,” the investigators explained. There were 1,784 nonshiftworkers and 233 shiftworkers, defined as those who worked regular nightshifts or rotating shifts. “Approximately 25% of the United States population is currently engaged in nondaytime or rotating shiftwork,” the investigators noted. Shiftworkers were slightly younger, less likely to be married and have health insurance, and had lower education and income levels, and a statistically significant shorter average duration of sleep, 6.2 hours vs 6.7 hours for nonshiftworkers (P < .001). The two groups of workers had a similar body mass index (BMI). A single PSA test was obtained for

ASCOPost.com | OCTOBER 15, 2013

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In the Literature

each of the study participants as part of the NHANES laboratory examination and used to determine total and percentage free PSA. “Low percentage free PSA has recently been shown to better predict aggressive disease and to improve the specificity in predicting disease compared with using total PSA alone,” the authors explained. “To further evaluate the relationship between shiftwork and PSA level, we created a combined variable to define those with high risk of developing aggressive disease, including only those with percentage of free PSA less than or equal to 25% and total PSA of 4.0 ng/mL or greater compared with those defined as low risk, including only those with percentage free PSA greater than 25% and total PSA less than 4.0 ng/mL.”

Key Findings Among shiftworkers, 5.6% had a total PSA level of 4.0 ng/mL or greater, compared to 2.8% of nonshiftworkers. Adjusted for age, BMI, race/ethnicity, health insurance, average hours of sleep per night, and months on the current job, the multivariable model odds ratio for having total PSA 4.0 ng/mL or greater among shiftworkers compared to nonshiftworkers was 2.62 (95% CI = 1.16–5.95; P = .02). “In comparisons of high and low risk for aggressive disease, 5.6% of shiftworkers fell into the high risk category compared with 2.6% of nonshiftworkers,” the authors wrote. Adjusted for age, BMI, race/ethnicity, health insurance, average hours of sleep per night, and months on the current job, the multivariate model odds ratio for having a total PSA result of 4.0 ng/mL or greater and a free PSA result less than or equal to 25% among shiftworkers compared to nonshiftworkers was 3.13 (95% CI = 1.38–7.09; P = .01). The investigators explained that they also “examined the relationship between shiftwork and PSA values by sextile categories (<1.01, 1.01–2.00, 2.01–3.00, 3.01–4.00, 4.01–10.00, >10.00) that have been shown to be predictive of future prostate cancer development.” Results showed that for men aged 45 years or older with total PSA levels of 1.00 ng/ mL or less, the absolute risk of future prostate cancer and mortality was less than 1.6%. “ In contrast, for men with a PSA value of 10.00 ng/

mL or greater, the risk of developing prostate cancer was 35% for men aged less than 45 years, 41% for men aged 45 to 49 years, and increased stepwise to 88% for men aged greater than 75 years. Likewise, the absolute risk of mortality for men with a PSA value of 10.00 ng/mL or greater was 9.8% for men aged less than 45 years, 16% for men aged 45 to years 49, and increased to a peak risk of 52% among men aged 60 to 64 years. Based on these projections, it is likely that a greater proportion of the shiftworkers in our dataset will develop and die from prostate cancer in their lifetimes,” the researchers wrote. “The World Health Organization categorized shiftwork involving circadian desynchrony as a ‘probable carcinogen’ based on studies of breast cancer risk in female shiftworkers. This study supports the notion that shiftwork may relate to an increased risk in prostate cancer among men,” the authors stated. Flynn-Evans EE, et al: J Natl Cancer Inst 105:1292-1297.

PANCREATIC CANCER High-Quality Diet May Reduce Risk Consuming a high-quality diet, consistent with the Dietary Guidelines for Americans 2005, may reduce the risk of pancreatic cancer, a dietary pattern analysis study found. “This finding contrasts with previous studies showing limited associations with specific foods or nutrients,” the authors reported in the Journal of the National Cancer Institute ( JNCI). Dietary pattern analysis, however, “may better predict disease risk than individual food or nutrient intakes for several reasons,” the authors stated. These reasons include possible biologic interaction or synergy between foods and it may be easier to detect diet-related associations with disease by comparing overall diets of poor or high quality rather than intake of an isolated food or nutrient. Adherence to the Dietary Guidelines for Americans 2005 was measured by the Healthy Eating Index 2005 (HEI-2005). Using responses to food frequency questionnaires returned in 1995 and 1996, the investigators calculated the HEI-2005 score for 537,218 men and women in the National Institutes of Health-Amer-

ican Association of Retired Persons Diet and Health Study, including 2,383 identified with incident, exocrine pancreatic cancer. Participants who met the most dietary guidelines had a statistically significant reduced risk of pancreatic cancer compared with those who met the fewest guidelines (hazard ratio [HR] = 0.85, 95% CI = 0.74 to 0.97). There was also a statistically significant interaction with the HEI2005 score and body mass index (BMI) among men (P = .03) but not in women (P = .24). This interaction was stronger among overweight and obese men than among men of normal weight.

Qualifying Remarks “HEI-2005 was not specifically designed for the purpose of overall cancer prevention,” the authors noted. “Also, the [food frequency questionnaire] measured consumption in categories, thus not capturing specific food intakes beyond the maximum category. However, the HEI-2005 score accounts for total calories and was designed to include limits for moderation components, accounting for excess consumption of foods thought to contribute to poor health outcomes.” An editorial accompanying the JNCI article pointed out that in the time since the article was submitted, the U.S. Department of Agriculture and the National Cancer Institute “have released another update to the index, the HEI–2010. This more recent index incorporates specific dietary guidance that was added to the

2010 Dietary Guidelines for Americans, including increased evidence that inclusion of finfish and shellfish and limitations on refined grain consumption were important components of healthy dietary patterns. Other components of the HEI–2005 were renamed or slightly modified for the HEI–2010 to better reflect current evidence.” Three large U.S. cohorts, including the NIH-AARP cohort, are being analyzed with the HEI–2010 and other dietary pattern indices, such as the Mediterranean Diet Score, in relation to cancer-specific, cardiovascular-specific, and total mortality. “Using data from the NIH–AARP Diet and Health Study, the MultiEthnic Cohort Study, and the Women’s Health Initiative, investigators in the Dietary Patterns Methods Project are applying consistent and standardized methodology across the cohorts to examine the associations of index-based scoring systems for dietary patterns with total and disease-specific mortality outcomes,” the editorial continued. Similar to the results of the earlier study, “it is hoped that the type of evidence obtained from Dietary Patterns Methods Project analyses can inform public health nutrition guidance in more meaningful and practical ways than would reductionist analyses focusing on single foods or nutrients.” n Arem J, et al: J Natl Cancer Inst105:1298–1305, 2013. Ballard-Barbash R, et al: J Natl Cancer Inst105:1265–1267, 2013.

The ASCO Post | OCTOBER 15, 2013

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Letters to the Editor End-of-Life Care

‘Doing Nothing’ Is Not an Option

applaud The ASCO Post for continuing to raise awareness about futile medical care at the close of life with the recent publication of a commentary by Dr. Chandrakanth Are (“A Great Privilege to Die Beneath an

Open Sky,” The ASCO Post, September 15, 2013, page 1). I would suggest, however, that we should neither use the phrase “nothing can be done,” nor teach this to younger physicians. As much as I

agree with Dr. Are that it is harder and more time-consuming not to operate or not to prescribe a drug, the phrase “do nothing” is devastating to patients and their families. Instead, the approach I suggest

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needs to be taught to young physicians and explained to patients and their families is that “given the circumstances, we are changing the course of care.” This means that a time has come when the patient is too weak to tolerate additional chemotherapy, surgery, or radiation treatment, and we would propose instituting aggressive palliative measures to relieve his or her symptoms. We hope to stabilize the condition and not to make things worse. We are doing something. We are not walking away and abandoning the patient. Something can be done and will be done. In my years of my personal experience as a medical oncologist, the patients and families almost always accept such an approach. This approach

Something always can be done, even if doing something means sitting by the side of a patient and holding his hand. —Khalid Rehman, MD, FACP

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also keeps some hope alive that if (miraculously) the patient becomes better, stronger, and capable of receiving another round of active treatment, that it will be considered. As time passes, patients and their families may start to let go and appreciate the palliative measures being instituted. “Doing nothing” is not an option. Something always can be done, even if doing something means sitting by the side of a patient and holding his hand. n —Khalid Rehman, MD, FACP New York, New York Letters continued on page 150

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PAGE 149

In Memoriam

Jane Weeks, MD, MSc, National Leader in Outcomes Research, Dies at 61 By Ronald Piana

n September 10, Jane Carrie Weeks, MD, MSc, a prominent researcher at Dana-Farber Cancer Center, died of cancer in her Boston home. She was 61. At the time of her death, Dr. Weeks was Professor of Medicine at Harvard Medical School, Professor of Health Policy and Management at

their experiences and preferences. Last June, when Dr. Weeks received a 2012-13 William Silen Lifetime Achievement in Mentoring Award from Harvard Medical School, her Dana-Farber colleague Deborah Schrag, MD, said, “Jane asks the critical questions about how we deliver clinical care — questions that have changed the way we think about and practice cancer medicine at its most profound level. In addition to her powerful intellect and analytic rigor, Jane is the consummate mentor. Her trainees now populate the field of health services research in oncology across the country.”

Advancing Comparative Effectiveness Research

Jane Weeks, MD, MSc

the Harvard School of Public Health, Director of the Mc-Gaw-Patterson Center for Population Sciences, and Chief of the Division of Population Sciences in the Department of Medical Oncology at Dana-Farber. While Dr. Weeks’ legacy in oncology is replete with achievements, it is her groundbreaking work in the field of outcomes research and health-care disparities that will perhaps have the longest lasting impact on cancer care. Outcomes research is the applied investigation that provides evidence about which interventions are most effective in a given patient population. The results of outcomes research are often used to inform legislative bodies that make crucial decisions about health-care policy. Although outcomes research is a heady discipline of macro-analysis and statistics, it all boils down to delivering better and more equitable care for patients with cancer, taking into consideration

In 1995, Dr. Weeks founded DanaFarber’s Center for Outcomes and Policy Research, which fosters crossdisciplinary health services research in cancer. An early researcher in the causes of disparities in care, in 2001

clinical care continuum, Dr. Weeks was also a pioneer in comparative effectiveness research. Her original work in this field enabled an understanding of the population-wide impact of cancer treatments and has helped guide decision-making at the clinical as well as policy level. Among her myriad leadership roles, Dr. Weeks led the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS), a 6-year NCI-funded study that examined the experiences of 10,000 patients across the nation through the course of their treatments. Well-known for her brilliance, Dr. Weeks was widely sought after to help stimulate creative thinking and create collaborations built on forward-looking ideas. Speaking about her death, Dana-Farber President Edward Benz, Jr., MD, called Dr. Weeks, “One of the true intellectual pillars of the Harvard medical community.”

Jane asks the critical questions about how we deliver clinical care — questions that have changed the way we think about and practice cancer medicine at its most profound level. —Deborah Schrag, MD

Dr. Weeks had a leadership role in creating Dana-Farber’s Initiative to Eliminate Cancer Disparities (IECD), which provided a centralized and coordinated structure for addressing the complexities of cancer disparities—it was among the nation’s first wholly integrated, inter-institutional, multipronged approaches. Understanding the need for adding more value to the

Cost-Effectiveness In a chapter of Holland-Frei Cancer Medicine, 6th Edition (B C Decker, Inc., July 2003), Dr. Weeks wrote, “In the United States, although not necessarily in all the developed countries, it is generally believed that the physician should function as the patient’s advocate in these discussions and should offer any treatment likely

to be of net benefit, regardless of the cost to society…but all practitioners must have some understanding of issues of cost and cost-effectiveness if they are to have any voice in the debate over allocation of health care dollars and other resources.” She made that important observation a decade ago, well ahead of today’s national discussions of escalating health care costs.

Nurturing the Next Generation of Scientists Dr. Weeks’ innovative approach at mentoring has improved the field of oncology. “I worked with Jane for many years; she was instrumental in my career,” said Stephanie J. Lee, MD, MPH, a bone-marrow transplant researcher at the Fred Hutchinson Cancer Researcher Center, and a former mentee of Dr. Weeks. “My work in allogeneic transplantation is very different from Jane’s work but she was able to easily bridge that gap and mentor me, applying all of her knowledge and insight into my work. Many people feel like you must be in the same field to be a good mentor, but a great mentor like Jane doesn’t have to have content expertise in your particular subspecialty. Jane mentored many people in various specialties. She was very good at understanding people’s needs, and her insights were always spectacularly correct.” Dr. Weeks is survived by her husband, Barrett Rollins, MD, PhD, Linde Professor of Medicine at Harvard Medical School and Chief Scientific Officer and Faculty Dean for Academic Affairs at Dana-Farber Cancer Institute. n

 In Memoriam

Jane Carrie Weeks, MD, MSc September 10, 2013 

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The ASCO Post | OCTOBER 15, 2013

Letters to the Editor

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

To Die Beneath an Open Sky

read the essay by Chandrakanth Are, MBBS, FRCS, FACS, published recently in The ASCO Post and found it both thoughtful and compelling (“A Great Privilege to Die Beneath an Open Sky,” The ASCO Post, September 15, 2013, page 1). Dr. Are made one statement with which I take exception, however, and that is that “no prior discussions had been held with the patient or the family to determine the appropriate course of action in emergency situations.” As a practicing oncologist, I have found that many patients and family members do not recall these difficult conversations, or may only recall portions of conversations about prognosis. There is research that suggests even after very

frank, open discussions, patients’ beliefs are not always concordant with the information that they have been provided. There is a pejorative sentiment that seems to be increasingly rampant in the medical community, which is that medical oncologists don’t talk to their patients, or that they don’t provide their patients with truthful prognostic information. Dr. Are himself indicates that even after he explained the futility of his intervention, the patient and his family still wanted “everything done.” To me, this means that the patient and his family may have been listening to Dr. Are and his team, but they were not hearing the information. n —Elizabeth D. Simmons, MD Bellflower, California

Platinum-Based Treatment of Triple-Negative Breast Cancer

he last issue of The ASCO Post reports encouraging results with platinum-based treatment of triple-negative breast cancer (September 15, 2013). We predicted these findings 4 years ago in a presentation at the 2009 Breast Symposium.1 We compared the activity of a series of agents (platinum, taxane, alkylating agent, and anthracycline) tested in cell cultures of fresh biopsy specimens of triple-negative breast cancer, in comparison with the activity in non–triple-negative breast cancer, previously untreated ovarian cancer, platinum-resistant ovarian cancer, and late-relapse ovarian cancer. We reported the following conclusions: 1. Estrogen receptor (ER)-negative breast cancer is dramatically more sensitive to cisplatin than is ER-positive breast cancer. 2. HER2-negative breast cancer is slightly more sensitive than is HER2positive disease. 3. ER-negative/HER2-negative breast cancer is more sensitive than is ER-negative/HER2-positive disease. 4. Poorly differentiated breast and ovarian tumors are more sensitive than are moderate and well-differentiated tumors. 5. Non–triple-negative breast cancer subsets are more resistant to cisplatin than are cases of platinum-resistant ovarian cancer. 6. Triple-negative breast cancer is equally sensitive to cisplatin as is previ-

ously untreated ovarian cancer, and cisplatin is the most active of the four tested drugs in triple-negative breast cancer. It is gratifying to see the clinical validation for our prediction based on cell culture testing. With regard to the “exciting new assays coming down the pike to help us identify which patients may respond to platinum agents,” there is a very impressive peer review literature confirming the predictive value of fresh tumor cell culture assays with cell death endpoints to reliably predict for the clinical benefit of platinum agents in human neoplasms. These latter tests are already available from licensed clinical laboratories; however, in the absence of results from individualized cell culture testing, the markers that best identify breast cancer patients for platinum therapy are ER-negative, HER2-negative, and Bloom-Richardson Grade 9/9 (data shown in abstract.1) n —Larry Weisenthal, MD, PhD Huntington Beach, California Disclosure: Dr. Weisenthal reported no potential conflicts of interest.

Reference 1. Weisenthal L: Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint. 2009 Breast Cancer Symposium. Abstract 61. Presented October 8-10, 2009.

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC)

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

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

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

Arm 2 IFL+ + Avastin (n = 392) 87%

T:13" S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

Arm 1 IFL+ + Placebo (n = 396) 74%

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

Indications

Most common adverse events

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastintreated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

AVA0001847501

Printed in USA.

(07/13)

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC 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, including Boxed WARNINGS, for additional important safety information.