VBCC May 2014 Vol 5, No 4

MAY 2014 VOL 5 NO 4

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com ECONOMICS OF CANCER CARE

AVBCC Fourth Conference: Optimizing Value and Stakeholder Integration in Cancer Care

By Wayne Kuznar

Challenges Facing US Cancer Care in 2014: ASCO’s First Annual Report to the Nation

By Eileen Koutnik-Fotopoulos

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dvances in cancer treatment, from detection and diagnosis to drugs, surgical techniques, and new imaging capabilities, have collectively enabled many patients to live longer, healthier lives with or after cancer. However, a new landmark report, “The State of Cancer

Clifford A. Hudis, MD, FACP

Care in America, 2014: A Report by the American Society of Clinical Oncology” (ASCO), identifies the many challenges that will impact the future delivery of cancer care (ASCO. J Oncol Pract. 2014;10:119-143). These challenges include an increasing demand for care, predicted workforce

Continued on page 7

AACR MEETING HIGHLIGHTS

Los Angeles, CA—The Fourth Annual Conference of the Association for Value-Based Cancer Care, held May 6-9, 2014, kicked off 4 days of presentations by oncology stakeholders from across the country, including patients, physicians, pharmacists, nurses, payers, healthcare investors, and drug and diagnostics makers.

The conference was introduced by Co-chairs Gary M. Owens, MD, Continued on page 10

AACR MEETING HIGHLIGHTS

CDK 4/6 Inhibitor Slows Progression of Metastatic Breast Cancer

By Charles Bankhead

© 2014 Engage Healthcare Communications, LLC

By Phoebe Starr San Diego, CA—Preliminary data suggest that a novel agent called AG-221 can induce complete remissions (CRs) in patients with relapsed, refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who harbor mutated IDH2. These

exciting results were achieved in patients with an ominous prognosis who have few or no other treatment options. The data were presented at the 2014 American Association for Cancer Research (AACR) annual meeting.

Continued on page 13

INSIDE

Palbociclib shows striking activity San Diego, CA—Palbociclib, an inhibitor of cyclin-dependent kinase (CDK) 4/6, demonstrated “striking” activity when combined with conventional hormone therapy for patients with metastatic breast cancer, according to the results of an open-label phase 2

AG-221 Achieved Excellent Responses in Relapsed, Refractory Leukemia, Myelodysplastic Syndrome

trial presented at the 2014 American Association for Cancer Research annual meeting.

Patients who received palbociclib in addition to letrozole had a median progression-free survival (PFS) of 20.2 months compared with 10.2 months

Continued on page 14

FROM THE EDITOR . . . . . . . . . . . . . .

The ACA and 2-tiered cancer care

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FDA UPDATE . . . . . . . . . . . . . . . . . . .

Zykadia for metastatic lung cancer

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VALUE PROPOSITIONS . . . . . . . . . . 6 Low-value services cost Medicare billions ECONOMICS OF CANCER CARE . . . .

Frequent mammography screening adds billions to cost

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4TH CONFERENCE . . . 10 Payers’ challenges in ensuring access to cancer care

PERSONALIZED MEDICINE . . . . . . 18 PD-L1 expression potential marker for response to MK-3475 HEALTH POLICY . . . . . . . . . . . . . . . 20 HHS reports highlight the need to address drug shortages BREAST CANCER . . . . . . . . . . . . . . 25 New guidelines for sentinel node biopsy SURVIVORSHIP . . . . . . . . . . . . . . . . 33 Updated NCCN survivorship guidelines PROSTATE CANCER . . . . . . . . . . . . 34 Ultrasound a potential diagnostic tool

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IN THIS ISSUE PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor THE LYNX GROUP President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

FROM THE EDITOR

IN THE LITERATURE

The ACA and two-tiered cancer care

ALK-positive NSCLC responds to ceritinib More…

FDA UPDATE Zykadia approved for metastatic lung cancer

PERSONALIZED MEDICINE

VALUE PROPOSITIONS

Blood test predicts response to enzalutamide More…

Drug maker releasing detailed clinical trials data to the medical community Low-value services cost Medicare billions of dollars More…

Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 10 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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SURVIVORSHIP

Frequent mammography screening for breast cancer adds billions to cost More…

Use of survivorship care plan lagging More…

DRUG UPDATE

4TH CONFERENCE

Imbruvica (ibrutinib) for relapsed chronic lymphocytic leukemia

Optimizing value and stakeholder integration in cancer care More…

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP President, Wilshire Oncology Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

Michael Kolodziej, MD National Medical Director, Oncology Solutions Aetna, Hartford, CT

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy, Aetna, Hartford, CT

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA

Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA

Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD President W-Squared Group Longboat Key, FL

Ted Okon, BS, MBA Executive Director Community Oncology Alliance, Washington, DC

Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881, circulation@valuebasedcancercare.com

VOL. 5

The Center for Medicare and Medicaid Innovation: Cancer More…

ECONOMICS OF CANCER CARE

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

HEALTH POLICY

Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com • Telephone: 732-992-1536 • Fax: 732-992-1881.

POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

MAY 2014

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From the Editor

The Affordable Care Act and Two-Tiered Cancer Care: Is This a Bad Thing?

By Craig Deligdish, MD

Managing Director, Oncology Resource Networks, Orlando, FL; Editor-in-Chief, Value-Based Cancer Care

D

efining and improving quality and outcomes in the care of patients with cancer is difficult, so it is interesting that we are now having a dialogue regarding the potential for a two-tiered healthcare system. Can we really define second-class cancer care if we have difficulty grading, measuring, identifying, or even defining first-class cancer care?

The Affordable Care Act (ACA) has mandated coverage to many people who previously did not have coverage provided by their employer or by the federal government, who did not want to purchase insurance coverage, or who could not afford it. Now, as a result of Medicaid expansion and enrollment in the exchanges, millions of Americans who previously did not have health insurance are getting it either at no cost or at a lower cost than what they would have paid on their own.

The medical and the lay communities are challenged with differentiating and measuring quality and outcomes from one provider to another and from one hospital system to another.

Therefore, we are frequently left with cost as the defining factor in the determination of value. Recently, much has been written about the development of a two-tiered Canadian-style healthcare system.

In his May 23, 2013, article in Forbes, “Coming Soon To America: A TwoTiered, Canadian-Style Health Care System” (www.forbes.com/sites/john goodman/2013/05/23/coming-

soon-to-america-a-two-tiered-canadi an-style-health-care-system/), John Goodman discusses the evolution toward a two-tiered system, which was under way before President Obama came into office. He points out that the ACA has accelerated this process by creating a system that will require a number of essential benefits. The concern from Goodman’s perspective is that there will not be a sufficient amount of physicians to care for the patients covered by the ACA. Limited resources will result in a system similar to the Canadian system, in which patients with one form of insurance have access to care, and those with another form of insurance have less access. The fact that some of the benefits provided to patients covered by the exchanges may be only partially covered with a 40% coinsurance is emblematic of this concern.

But then, is a two-tiered healthcare system problematic? The goal of the ACA is, in part, to ensure coverage for all Americans. Coverage does not mean premium healthcare, and it does not mean that all Americans will have the same coverage at the same cost.

The ACA was partially designed to provide patients who previously did not have health insurance with essential benefits. Before the ACA, patients generally had access to treatment for cancer, whether it was based on the provision of community health providers, contributions from pharmaceutical companies, or community and public hospital systems. Today, access

to these systems has been narrowed, and many commercial insurance providers, as well as health exchanges,

have constricted networks that limit access to some providers. This has resulted in some degree of outrage.

However, is there anything wrong with a two-tiered system? The

European and Australian systems of healthcare, as well as healthcare in many Westernized countries whose governments provide healthcare to all citizens, have generally resulted in the two-tier system. Is that better than no healthcare at all?

The philosophy in the United States has always been to provide access to everything. In the United States, consumers make a choice based on cost, value, and quality. Should healthcare be any different? When someone goes to the supermarket, that person chooses between the store brand and the premium brand. Should healthcare be any different? Has the US government changed that philosophy, or is healthcare so different from everything else that is purchased and consumed?

Consumers of healthcare in the United States will find themselves needing to make more choices, yet at times they may find that their choices are limited, and that there may not be sufficient transparency for them to make their choices.

Patients and consumers will need to choose between a narrow network and a wide network, a health plan with essential benefits and a plan with a comprehensive benefit plan, generic versus brand, and centers of excellence versus centers of value. Health plans and consumers will need to make choices considering the cost and the limited resources that are available to them.

This will be the new paradigm, and at the end of the day, we will need to ask whether we are better off. n

therapies aimed at these pathways,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It also demonstrates the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval, reflecting the promise of the breakthrough therapy designation program.”

The safety and efficacy of ceritinib were established in a clinical trial with 163 patients with metastatic,

ALK-positive NSCLC. All patients received ceritinib: approximately 50% of the patients had their tumor shrink with this therapy, and this result lasted an average of approximately 7 months.

Reported side effects were mainly gastrointestinal, such as diarrhea, nausea, vomiting, and abdominal pain.

Laboratory abnormalities included increased liver enzymes and pancreatic enzymes, as well as increased glucose levels. (See also article on page 16.)

April 29, 2014 n

In the United States, consumers make a choice based on cost, value, and quality. Should healthcare be any different? Health plans and consumers will need to make choices considering the cost and the limited resources that are available to them.

FDA Update Zykadia Approved for Metastatic, ALK-Positive Lung Cancer The US Food and Drug Admin­ istration (FDA) approved ceritinib (Zykadia; Novartis) for the treatment of patients with metastatic, anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC).

Ceritinib is an ALK tyrosine kinase inhibitor that blocks proteins that promote cancer cell growth. The drug is approved for the treatment of patients with late-stage NSCLC who were previously treated with crizo-

4

tinib, the first and only other ALK tyrosine kinase inhibitor approved by the FDA. The FDA approved ceritinib under the FDA’s accelerated approval process, 4 months ahead of its scheduled final review date, to expedite access to this drug for a patient population with a life-threatening condition and very few treatment options available.

“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific

VALUE-BASED CANCER CARE

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Solid tumor biomarker tests FDA-approved

Targeted therapy depends on reliable test results — don’t fall behind

Ask your lab if they use reimbursed, FDA-approved therascreen companion diagnostics: ■■ The therascreen KRAS RGQ PCR Kit ■■ The therascreen EGFR RGQ PCR Kit

PHCTheraOnc0514V1US

Discover more at www.qiagen.com/therascreen.

For up-to-date licensing information and product-specific disclaimers, see the respective QIAGEN kit handbook or user manual. QIAGEN kit handbooks and user manuals are available at www.qiagen.com or can be requested from QIAGEN Technical Services or your local distributor.

Trademarks: QIAGEN®, therascreen ® (QIAGEN Group).

Sample & Assay Technologies

Advance Care Planning

VALUE PROPOSITIONS Novel 10-Gene Blood Assay a Biomarker for Predicting Breast Cancer Recurrence

Noninvasive, multigene tests are increasingly being developed for a variety of cancers to potentially replace more invasive and often more costly types of testing. The new 10-gene–based assay, called cMethDNA, is highly sensitive and specific for detecting breast cancer recurrence early (Fackler MJ, et al. Cancer Res. 2014;74:2160-2170). The cMethDNA blood-based assay includes a panel of 10 breast cancer–specific genes.

“Currently, the parameters used to find out whether a patient has had a recurrence after being treated successfully is mostly self-reported complaints, followed by imaging studies,” said Saraswati Sukumar, PhD, Professor of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore. “Our goal was to develop a noninvasive assay that can potentially detect recurrence in breast cancer patients before traditional methods, and administer this test during their scheduled visits.”

The 10 genes in the panel include 7 novel markers, AKR1B1, COL6A2, GPX7, HIST1H3C, HOXB4, RASGRF2, and TM6SF1, and 3 previously described markers, ARHGEF7, TMEFF2, and RASSF1.”

“Using cMethDNA, we were able to detect a drop in methylation levels as early as two weeks, and weeks before traditional imaging methods can detect a recurrence,” said Dr Sukumar. “Detecting early on whether or not the treatment is working for a patient can greatly help prevent unnecessary exposure to highly toxic agents, save time, and help initiate other treatments more likely to be beneficial.”

The authors selected the panel of 10 genes that best differentiated between cancer and normal samples to confirm that the blood test detected the presence of cancer DNA in the serum with a sensitivity and specificity of >90%.

Using blood samples from patients with metastatic breast cancer, the cMethDNA assay showed a significant decrease in serum DNA methylation levels in patients who responded to the treatment versus no reduction in patients who had no response to therapy or in patients with disease progression. American Association for Cancer Research press release; April 15, 2014

Much criticism has been aimed at drug companies in recent years related to the common practice of withholding unfavorable or undesirable data from clinical trials to protect their newly developed products. Responding to this trend and in an effort to promote progress in medical research, Boehringer Ingelheim has announced that it is engaged in a program to make clinical study data and other clinical study–related documents more widely accessible for drugs and other therapies approved by regulatory agencies after the approval of or termination of a drug development program.

“The free exchange of scientific information is the basis for innovation in medicine. Boehringer Ingelheim as a research-driven pharmaceutical company is committed to the registration of all clinical studies prior to initiation and to disclosing all study results independent of outcome. Going beyond applicable regulatory and legal requirements, we at Boehringer Ingelheim feel it is the right approach and hope it will benefit science,” said Dr Christopher Corsico, Global Head of Clinical Development, Medicine and Regulatory at Boehringer Ingelheim.

Boehringer Ingelheim will register protocol information for all types of clinical studies on www.ClinicalTrials.gov, including phase 1 clinical trials in healthy volunteers, and uncontrolled and noninterventional studies for all prescription and nonprescription drugs performed worldwide. The company is committed to providing information related to studies started in 1998 or later. Starting with studies completing in 2014, the company will also post study results on ClinicalTrials.gov for products approved outside of the United States only and from terminated drug development programs.

Furthermore, clinical study reports and other clinical documents can be requested via the company’s website, accessible under trials.boehringeringelheim.com/trial_results.html. This website will also enable researchers to request access to deidentified patient level study data that form the basis of clinical trial findings. The company made these commitments in 2013, but they are now being implemented. Boehringer Ingelheim press release; May 12, 2014

Skin Cancer Awareness Month in May Prompts Donations to Melanoma Research Foundation

Low-Value Services, Including in Oncology, Cost Medicare Billions of Dollars

May, the skin cancer awareness month, served as the impetus for MoleSafe USA—a program that provides melanoma screening and surveillance via total body photography, digital dermoscopy, and digital serial monitoring—to partner with the Melanoma Research Foundation to support the foundation’s efforts in raising awareness of melanoma, promoting education, and encouraging early detection through melanoma screening programs and monthly self-skin examinations.

MoleSafe, with locations in the United States, Australia, and New Zealand, is donating $10 to the Melanoma Research Foundation for every screening it conducts in the month of May to promote skin health and to encourage research and screening related to melanoma, where early detection can have a significant impact on clinical outcomes. Despite the significant reductions in the number of new cases of cancer, melanoma remains the cancer with the fastest growing incidence rate. In 2014, approximately 76,000 Americans are expected to be diagnosed with melanoma, leading to approximately 10,000 deaths, according to the American Cancer Society.

“The Melanoma Research Foundation is leading the melanoma community to transform melanoma from one of the deadliest cancers to one of the most treatable through research, education and advocacy,” said Richard Bezozo, MD, President of MoleSafe. “While there currently isn’t a cure for melanoma…when caught early, the five-year survival rate can near 99 percent.” Being aware of the warning signs of melanoma, including the appearance of a new bump or nodule, color spreading into the surrounding skin, redness or swelling beyond the mole, pain, tenderness, skin itching, and/or bleeding can expedite detection and improve outcomes. Monitoring for changes in skin moles and lesions is important. MoleSafe, Inc press release; May 1, 2014

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Drug Maker Releasing Detailed Clinical Trials Data to the Medical Community

VALUE-BASED CANCER CARE

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A new study investigating the efficiency of care under Medicare using 2009 data shows that much of the care provided to Medicare beneficiaries is not cost-effective and cost Medicare $8.5 billion that year in inefficient services (Schwartz AL, et al. JAMA Intern Med; 2014 May 12. Epub ahead of print). This translates to $310 per beneficiary on services determined in this study to be low-value care.

The study is based on insurance claims for >1.3 million Medicare beneficiaries, showing that between 25% and 42% of beneficiaries received low-value services that provided little or no benefit to patients.

The investigators reviewed 26 procedures that were deemed to be of low value based on the Choosing Wisely program; these included cervical cancer screening for women aged ≥65 years, computed tomography scanning of the sinuses for uncomplicated acute rhinosinusitis, preoperative stress testing, and back imaging for patients with lower back pain. The total cost for these services amounted to $8.5 billion.

“There are hundreds of other low-value services,” said coinvestigator J. Michael McWilliams, MD, PhD, Associate Professor of Health Care Policy, Harvard Medical School. “We suspect this is just the tip of the iceberg.”

“We were surprised that these wasteful services were so prevalent,” said lead author Aaron Schwartz, MD, PhD, student of Health Care Policy, Harvard Medical School. “Even just looking at a fraction of wasteful services and using our narrowest definitions of waste, we found that one-quarter of Medicare beneficiaries undergo procedures or tests that don’t tend to help them get better.”

The researchers suggest that using claims-based measures of low-value services could help to develop programs to reduce unnecessary, wasteful care, as well as to identify specific cases of overuse of care among the most efficient providers. Kaiser Health News; May 12, 2014

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Economics of Cancer Care

Challenges Facing US Cancer Care in 2014... shortages, rapidly rising costs, imbalances in access to care, and an unstable practice environment.

“To overcome these challenges, it will be essential for policymakers to recommit to the fight against cancer and make sustained investments in cancer research and care programs,” said ASCO President Clifford A. Hudis, MD, FACP. “It will also be necessary for cancer care professionals to be even more nimble and creative as we seek to bring valuable cancer advances to a growing number of patients.”

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Table Key Recommendations to Address Current Challenges in Oncology Oncology workforce • Identify creative strategies for leveraging the oncology workforce • Leverage technology and innovative practice models • Monitor and address physician burnout • Monitor and address the size and diversity of the oncology workforce State of oncology practice • Payers should align payment systems with the goal of delivering high-value, patient-centered care, and provide funding and support to help struggling practices make the transition to value-driven payment models • Test a range of promising cancer care delivery models that address the unique challenges of treating the disease • Reduce instability in federal payment systems Quality of cancer care • Build on existing investments made by the oncology community in quality monitoring and information technology • Advance “learning health systems” • Remove disparities in access to cancer care • Establish a common understanding of how to define and measure value in oncology care

Photo courtesy of ASCO

Current and Future Challenges in Cancer Care Although the delivery system of cancer care in the United States is among the best in the world, significant challenges will impede the nation’s ability to meet the growing demands of the needs of patients with cancer. Key challenges are highlighted in the report.

Rapid growth in the demand for cancer prevention, screening, and treatment. ASCO projects that by 2030, the number of new cancer cases in the United States will increase by 45%—from 1.6 million to 2.3 million annually—and cancer will become the nation’s leading cause of death, driven mainly by the nation’s rapidly aging population. Simultaneously, the number of cancer survivors, now at 13.7 million, will continue to grow. It is estimated that by 2022, there will be almost 18 million cancer survivors— a more than 35% increase from today.

Disparities in access to quality cancer care. Millions of people with cancer lack access to quality medical care, and African Americans and Latinos have disproportionally lower rates of access to care. Although the Congressional Budget Office has projected that the Patient Protection and Affordable Care Act (ACA) will provide insurance coverage to an additional 29 million Americans by 2017, the ACA alone may not solve the disparities in cancer care—in part because it places considerable emphasis on expanding Medicaid coverage, which has been linked with poor outcomes for patients with cancer.

The economic burden has created an urgent need to improve the value of patient care. The economic burden is especially critical in cancer care. The US annual costs of cancer care are projected to rise from $104 billion in 2006 to more than $173 billion in 2020. “This increase is a result of many factors, including the cost of many new cancer therapies. Access to high-quality cancer care will be sustained and expanded only if we address these rising

costs, including the use of unnecessary or ineffective tests and treatments,” the report states.

A potential workforce shortage will have a far-reaching impact. The authors of the ASCO report estimate that by 2025, the demand for oncology services will grow by 42%, whereas the supply of oncologists will grow by only 28%, leaving a projected deficit of 1487 physicians over the next decade. Given that an oncologist sees an average of 300 new patients annually, nearly 450,000 new patients are likely to face obstacles in accessing cancer care. ASCO reports that the projected shortfall is driven in part by an aging oncology workforce and an impending wave of physician retirements.

Continued from the cover

“To overcome these challenges, it will be essential for policymakers to recommit to the fight against cancer and make sustained investments in cancer research and care programs. It will also be necessary for cancer care professionals to be even more nimble and creative.”

—Clifford A. Hudis, MD, FACP

Currently, 1 in 5 cancer specialists is aged >64 years. Furthermore, there is an inadequate number of oncologists in many rural communities. Only 3% of oncologists are based in rural areas, where 20% of Americans live.

The financial viability of small and mid-sized practices is a growing concern. Further complicating the supply of cancer care services is a growing concern about the survival of smaller, independent practices. Small (1 or 2 physicians) and mid-sized (<7 physicians) local oncology practices serve more than 33% of new patients in the United States, according to the 2013

ASCO National Oncology Census.

Nevertheless, nearly 66% of small oncology practices reported that they are likely to merge, sell, or close in the next year because of financial pressures.

The number of private community practices represented in the census fell by approximately 25% between 2012 and 2013 (from 335 to 253), according to the ASCO report.

A Call to Action to Oncology Stakeholders The report includes a call to action with specific recommendations in 3 critical areas—the oncology workforce, the state of oncology practices, and the quality of cancer care (Table).

These recommendations focus on preserving patient access to care, while improving the quality of care and controlling or slowing the projected rise in costs.

Policymakers Are Key to the Solutions The report makes clear that action by Congress and other policymakers, including payers and hospitals, is crucial to head off impending threats in the state of cancer care in the United States.

ASCO has outlined several actions for federal policymakers that would help to support its mission of continued quality of care. These include: 1. Develop and test new healthcare delivery and payment models that preserve the viability of small community practices while encouraging high-quality care

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2. End persistent financial threats to community practices caused by sequester-related cuts in Medicare physician payments, and by the sustainable growth rate formula

“This first annual report to the nation on the state of cancer care in America offers insight into many issues raised by the IOM and provides recommendations for action.”

—American Society of Clinical Oncology 3. Embrace and support physician-led initiatives, such as ASCO’s established Quality Oncology Practice Initiative, and CancerLinQ learning health system currently under development.

“This first annual report to the nation on the state of cancer care in America offers insight into many issues raised by the IOM [Institute of Medicine] and provides recommendations for action. By taking these steps, the cancer community will be able to move beyond crisis mode to achieve a high-functioning, rapid learning system that promotes progress and delivers patient-centered, high-value care for every individual with cancer,” concluded the report. n

www.ValueBasedCancerCare.com

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Economics of Cancer Care

Frequent Mammography Screening for Breast Cancer Adds Billions to Cost

See also Breast Cancer, page 25

By Rosemary Frei, MSc

T

he total annual cost of mammography screening for women aged 40 to 85 years in the United States is estimated to be $7.8 billion, according to a new analysis (O’Donoghue C, et al. Ann Intern Med. 2014;160:145-153). That is $4.3 billion more than the cost would be if mammography intervals were lowered to fall in line with the recommendations of the US Preventive Services Task Force (USPSTF), the study researchers calculated.

Lead investigator Cristina O’Donoghue, MD, MPH, Resident in the Department of Surgery, University of Illinois at Chicago, and colleagues conducted the analysis to highlight the true aggregate cost to the US healthcare system of too-frequent mammography screening, in light of the many conflicting guidelines that have been published in the past few years and the ongoing debate on this topic.

“I’ve heard respected academics saying, ‘It’s only about $100 for a mammogram, it’s not expensive.’ But if it’s more than $4 billion more for the current screening approach compared with screening intervals recommended by the USPSTF, that’s a lot of money,” said Dr O’Donoghue. “If you had that money in your pocket, would you decide to screen annually, or do other things, such as make sure every woman has a breast cancer risk assessment?”

Dr O’Donoghue conducted the study with Laura J. Esserman, MD, MBA, Coleader, Breast Oncology Program, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, and 2 other academics. The study was funded by the University of California, San Francisco, and the Safeway Foundation.

at a glance ➤ Mammographies for women aged 40 to 85 years cost an estimated $7.8 billion in the United States, $4.3 billion more than if screening intervals were lowered to match the recommended guidelines ➤ Following mammography guidelines will save billions that can be invested in personalized risk-based screening and prevention strategies

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Study Details The investigators created a simulation model of the cost of mammography at the rates that American women underwent breast cancer screening in 2010. They then compared the model to their estimates of the cost of 3 other screening-rate strategies, including (1) an annual screening starting at age 40 years and ending at age 84 years, as

“I’ve heard respected academics saying, ‘It’s only about $100 for a mammogram, it’s not expensive.’ But if it’s more than $4 billion more for the current screening approach compared with screening intervals recommended by the USPSTF, that’s a lot of money.”

—Cristina O’Donoghue, MD, MPH

recommended by the American Cancer Society, the American College of Radiology, and other organizations; (2) biennial screening of women aged 50 to 70 years, which is the European approach; and (3) the current USPSTF recommendations, which comprise risk-based screening for women aged 40 to 49 years and those aged between 75 and 85 years with ≤2 comorbid conditions, and biennial mammograms for women aged 50 to 75 years.

The investigators included in the total cost of mammography the cost of the procedure itself, recalls, biopsies, and computer-aided detection.

The data for the study came from

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the Behavioral Risk Factor Surveillance System (BRFSS) 2010 survey, conducted by the Centers for Disease Control and Prevention, to calculate the cost of the current screening approach in the United States. The investigators corrected for bias inherent in such telephone surveys, and excluded women aged <40 years, those aged >85 years, and women with a recent history of breast cancer.

In addition, the researchers used 2001 to 2007 data from the Breast Cancer Surveillance Consortium to calculate the percentage of women who would be recalled for repeated mammograms. They calculated the recall costs from the Digital Mammographic Imaging Screening Trial results of workup costs, and adjusted them for use of digital versus film mammography in 2010. They also adjusted all costs to 2010 US dollars.

They then estimated the number of women who would have undergone screening mammography in any given year—in this case 2010—based on previously reported frequency of mammography screening in the United States.

For example, 20% of women who are screened every 5 years were assumed to have had a screening mammogram, and 50% of those screened every 2 years were assumed to have done so in 2010. Based on the BRFSS data, it was estimated that 61% of women aged 40 to 75 years and 75% of women aged 65 to 70 years would have a screening mammogram in 2010 using their regular screening interval.

The investigators also determined that 85% of women would be compliant with biennial, annual, or USPSTFbased screening. Furthermore, for the simulated screening strategies of annual, biennial, and USPSTF guidelines, the researchers assumed that 85% of women would receive mammography screening.

For the estimate of screening costs using the USPSTF recommendations, the investigators assumed that 20% of women aged 40 to 50 years would be high-risk, and therefore would be screened once every 2 years. They also determined, based on Medicare reports, that approximately 50% to 75% of women aged 70 to 85 years have ≤2 chronic conditions.

The team also found that besides screening frequency, the other largest contributors to cost were variation of

the percentage of women screened, percent of film versus digital mammography, cost of individual mammograms, number of recalls, and cost of recalls.

Based on all these data, the total aggregate cost of actual mammography screening in 2010 was estimated to be approximately $7.8 billion. The total aggregate cost for annual screening would be $10.1 billion; by contrast, that cost would be $3.5 billion for screening based on the recent USPSTF recommendations, and $2.6 billion for biennial screening.

“It is unsustainable to remain ignorant of the costs associated with any health intervention, even breast cancer screening.”

—Joann G. Elmore, MD, MPH, and Cary P. Gross, MD

Better Use of Limited Resources?

In an accompanying editorial, Joann G. Elmore, MD, MPH, Professor, Department of Medicine, School of Medicine, and Adjunct Professor of Epidemiology, School of Public Health, University of Washington, Seattle, and Cary P. Gross, MD, Director, Cancer Outcomes, Public Policy and Effectiveness Research Center, Yale School of Medicine, New Haven, CT, applaud the study (Elmore JG, Gross CP. Ann Intern Med. 2014; 160:203-204).

Dr Elmore and Dr Gross call for more consideration of cost in the conversations about optimizing breast cancer screening in the United States, from the individual physician–patient interaction to conversations among policymakers.

“It is unsustainable to remain ignorant of the costs associated with any health intervention, even breast cancer screening,” Dr Elmore and Dr Gross wrote.

“Following mammography screening guidelines, such as those from the USPSTF, that optimize frequency on the basis of best available evidence will put us in a position to improve screening and save billions of dollars that can be invested in personalized risk-based screening and prevention strategies,” Dr O’Donoghue and colleagues concluded. n

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Metastatic Cancer...

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Oncologist. 2012; 17:801-812. 2. Pentheroudakis G, Pavlidis N, Fountzilas G, et al. Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary. Mol Cancer. 2013;12:57.

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RG- 24.0.0.15 Rev2 1/14

4th Conference

AVBCC Fourth Conference: Optimizing Value and Stakeholder Integration...

Continued from the cover

President, Gary Owens Associates, Ocean View, DE, and Grant D. Lawless, RPh, MD, Associate Professor of Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, Los Angeles.

The topics at this year’s conference centered around challenges facing all stakeholders in optimizing value in cancer care, and defining the barriers associated with cost, quality, and access to care.

“Balancing the cost–quality equation is one of the major themes we try to tackle in the Association for ValueBased Cancer Care,” said Dr Owens.

The total cost of cancer care continues to grow, posing challenges to all oncology stakeholders, including patients, providers, payers, and manufacturers (Table).

Themes in day 1 included proving the value of oncology therapy using comparative effectiveness research, methods and tools for optimal reimbursement for new and emerging technologies, the impact of changing risk models (ie, accountable care organizations, oncology medical homes) on reimbursement of cancer care and traditional pharmaceutical relationships, the use of competitive intelli-

Table Total Cost Is Growing • Based on growth and aging of the US population, medical expenditures for cancer in the year 2020 are projected to reach at least $158 billion (in 2010 dollars) • This represents an increase of 27% over 2010 • If newly developed tools for cancer diagnosis, treatment, and follow-up continue to be more expensive, medical expenditures for cancer could reach as high as $207 billion

“Balancing the cost–quality equation is one of the major themes we try to tackle in the Association for Value-Based Cancer Care.”

—Gary M. Owens, MD gence to maintain coverage and access, and delivering value and access across multiple regions and nations.

Over the 4 conference days, experts in various areas of cancer care presented data and considered new options for improving patient care and outcomes, including new therapies, a renewed focus on patient-centered care, and new approaches to physician reimbursement.

The marketplace for the pharmaceutical industry is changing, and it represents a changing opportunity, said Dr Lawless. “We’ve seen an evolution among pharma and biotech. We went from the time of the blockbuster model that was all about volume, to the market model where it was having a mix and a matrix of different products… to where we are now, which I call the payer model,” Dr Lawless said.

“It’s not just government payers; it’s really that whole payer mix. And the payer mix is changing as well. It’s everything from hospital health systems to countries to regions.” The payer model is patient-centric, and value in this model is based on improv­­ ing outcomes and health technology assessment.

Looking Globally for Solutions Innovation in the pharmaceutical industry is becoming more expensive, and the recovery of investment is becoming more challenging, said Dr Lawless. In the past, margins were high for a number of years. Over time, margins have become narrower over a shorter period of time. “What we’re facing is a challenge of efficiency,” he said. “Oncology is going to be one of the most impacted areas of all. We’re going to look across the globe.”

The response to payer challenges varies by country, and the United States can learn from different models to assess reimbursement and to lower healthcare costs. The US response to these challenges has been healthcare reform, formularies and preferred drug lists, and clinical pathways. In Germany, free market pricing is established for 1 year, after which pricing is negotiated based on cost-effectiveness.

“How we look at measuring value at different points in the continuum of care will be an interesting change.”

—Grant D. Lawless, RPh, MD

Italy has a government medicine agency that operates autonomously and according to cost-effectiveness criteria in managing the value and cost of medicines. In France, the main determinant of a drug’s reimbursement level is its

efficacy, and this method has led to substantial government savings. In the United Kingdom, pricing is based on the current National Institute for Health and Care Excellence assessment value.

“China, Japan, South Korea, and other areas that are emerging are also coming up with some unique payment models as well, so the world is changing, and we’re part of it,” Dr Lawless said. “How we look at measuring value at different points in the continuum of care will be an interesting change. One of the things we hear over and over is that it’s fine to have a great and a needy population, but at the point of delivery, does it make a difference and change the outcome?”

Drug review methods generally rely on comparative effectiveness research and cost-utility analyses, but the choice of comparator differs between countries. In Germany, the appropriate comparator for this type of research is suggested by the manufacturer, but is chosen by the government. In the United Kingdom, the comparator is the current best alternative or routine treatment. In the United States, all alternatives are considered using the available data.

In going from regulation to coverage reimbursement decisions, said Dr Lawless, the 4 questions being asked by organizations and government agencies are: 1. Can it work (is it safe as well as efficacious)?

2. Does it work (is it effective)?

3. Does it work better than others (comparative effectiveness among different technologies)?

4. Is it worth it (outcomes measures at different points in the delivery of care)? n

Payers Facing Multiple Challenges in Ensuring Access to Cancer Care Value of new technologies, payment reform top concerns

By Wayne Kuznar Los Angeles, CA—The cost of cancer care is a major cost driver for payers, who are actively engaging in the management of this complex disease state.

Payer approaches to cancer care continue to evolve, with new reimbursement methodologies key to maintaining affordability, said Gary M. Owens, MD,

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President, Gary Owens Associates, Ocean View, DE, and John Fox, MD, MHA, Senior Medical Director and Associate Vice President of Medical Affairs, Priority Health, Grand Rapids, MI, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

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Cost and Value Based on growth in spending and the aging of the US population, medical expenditures for cancer in the year 2020 are projected by the National Institutes of Health to reach at least $158 billion (in 2010 dollars), representing a 27% increase from 2010.

“That number could be as high as $207 billion if other new and unanticipated changes in medical technology occur, or if cancer patients continue to live longer and require more treatment,” said Dr Owens.

Cancer drugs are a portion of the 27% increase in cancer expenditures Continued on page 11

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Payers Facing Multiple Challenges... since 2010, and therefore represent a component of cancer care that payers are looking to actively manage, Dr Owens noted.

Healthcare is consuming more of the workers’ pay as workers’ contributions to health insurance premiums are increasing at a much more rapid rate than are inflation and wages. The result is a gap in the affordability of care. “Payers are challenged to balance access to care with responsible stewardship of their customers’ financial resources,” Dr Owens pointed out.

Payers are also challenged with the difficult task of assessing the value of new technology, including drug therapy, diagnostics, surgical treatments, advances in radiation therapy, and others. Robotic surgery is one such treatment that requires assessment of its value, as do the molecular and genetic diagnostics that are sprouting up, he said.

Other challenges to payers are consolidation of practices under hospital systems, creating shifts in the sites of care and its associated cost consequences. “The same care you got yesterday can cost 2 to 3 times as much

“The same care you got yesterday can cost 2 to 3 times as much tomorrow.”

—Gary M. Owens, MD

tomorrow,” said Dr Owens. “That’s a direct factor in the way healthcare services are contracted for under payers, but, nevertheless, it’s the cold reality that payers are dealing with.”

Payers are also looking at new methods of reimbursement, such as reimbursement for following guidelines

Table 1 Priority Health’s Oncology Medical Home Model Payment reform • Plan pays acquisition cost for drugs • Care management fee for patients on oral/intravenous chemotherapy Payment enhancements • Annual $1500 per-physician per-year infrastructure development fee • Payment for treatment planning and advance care planning • Share savings for reductions in emergency department visits and hospitalizations Care reform • Implementation of preferred therapeutic regimens • Standardized care management programs • Patient engagement programs with a “call-me-first” policy • Enhanced access to same-day and next-day care

Table 2 Michigan’s Oncology Medical Home: Performance Metrics Domain: end of life • Percentage of cancer patients admitted to the hospital in the last 4 weeks of life • Percentage of patients prescribed chemotherapy in the last 2 weeks of life • Percentage enrolled in hospice within 3 days of death • Percentage of new patients with ACP discussions within 60 days of first chemotherapy dose • Percentage of patients with an advanced directive in the medical record within 60 days of starting chemotherapy Domain: office triage, care access, case management • Number of calls per symptom type with disposition (home, same-day visit, nextday visit, emergency department, direct admit, other) • ECOG performance status or Karnofsky score at each chemotherapy contact • Nonelective hospital admissions per 100 patient chemotherapy months • Emergency department visits per 100 patient chemotherapy months Domain: office chemotherapy • Percentage compliance with preferred regimen for first- and second-line chemotherapy Domain: patient satisfaction • Community Oncology Alliance patient satisfaction tool, annually ACP indicates advance care planning; ECOG, Eastern Cooperative Oncology Group; NCCN, National Comprehensive Cancer Network.

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Continued from page 10

or pathways, reimbursement on a riskbased model, or the use of accountable care organizations. “It’s a huge living laboratory out there right now, and we’re trying a number of models,” he said. The addition of new healthcare consumers through the Affordable Care Act has also created an uncertain landscape of the health insurance marketplace.

Expect some limitations on access to some types of care, Dr Owens advised, and enhanced consideration of comparative effectiveness research and the cost-effectiveness of treatments in deciding this access.

Payer–Provider Collaboration and Payment Reform Dr Fox discussed the challenges of payer and provider partnerships, using Priority Health’s oncology medical home initiative as the example for a new approach to cancer care and the changes occurring in access to oncology care as a result of mergers, acquisitions, and facility closures.

Priority Health’s oncology medical home initiative has instituted payment reform, so that the plan pays community-based oncologists the acquisition cost for drugs and a flat care management fee independent of the stage and type of cancer, for patients receiving oral or intravenous chemotherapy (Table 1). Its fee recognizes a larger number of nurses, pharmacists, social workers, and financial planners in oncology practices than in other physician practices, Dr Fox said.

The plan also pays a $1500 annual infrastructure development fee, as well as a fee for treatment planning and advance care planning. There are also shared savings for reductions in emergency department visits and hospitalizations.

“We also agreed that there were elements that were important for high-quality care, and those included implementation of preferred therapeutic regimens,” said Dr Fox. “We agreed that we were going to have standardized care management programs, including nurse navigators, and patient engagement programs with a ‘callme-first’ policy instead of calling their primary care physician or cardiologist.

Finally, a critical element to providing high-quality care was enhanced access to same-day and next-day services.”

A number of performance metrics were also agreed on. End-of-life care was a critical domain for which measurements were established, such as the percentage of patients with cancer admitted to the hospital during the

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“We agreed that we were going to have standardized care management programs, including nurse navigators, and patient engagement programs with a ‘call-me-first’ policy instead of calling their primary care physician or cardiologist. Finally, a critical element to providing highquality care was enhanced access to same-day and nextday services.”

—John Fox, MD, MHA last 4 weeks of life, and the percentage prescribed chemotherapy in the last 2 weeks of life. Other performance domains agreed on were office triage, care access, and case management measurements; how to measure compliance with preferred regimens for first- and second-line chemotherapy; and patient satisfaction (Table 2).

“We’re in the third year of this program, and all of the practices have agreed to continue participation, because there was good collaboration and it was consistent with the way they wanted to practice,” said Dr Fox. The downside is the difficulty that practices have to comply with multiple payer strategies.

Statewide eligibility criteria for oncology medical home accreditation have been developed in Michigan. To be accredited, the practice must use a certified electronic medical record, its leadership must have oriented the staff on the importance and significance of the oncology medical home, the practice must be willing to share practice and aggregate patient data, and the practice must administer the Community Oncology Alliance patient satisfaction survey at least every 6 months. n

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AACR Meeting Highlights

Potential New Approach to Melanoma

By Phoebe Starr

San Diego, CA—Preliminary results suggest that an investigational antibody-drug conjugate called DEDN6526A (Seattle Genetics, Genentech) has activity against melanoma, including cutaneous, mucosal, and ocular melanoma, which is considered difficult to treat. The new drug comes on

“DEDN6526A is well-tolerated and, more important, benefits a substantial proportion of patients. It is particularly promising to see clinical activity in patients with mucosal...melanoma.”

—Jeffrey R. Infante, MD

the heels of trastuzumab emtansine, the first antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of breast cancer. The conjugate links an antibody to a toxic chemotherapy that remains inactive until the antibody recognizes a protein on the surface of cancer cells and releases its toxic “payload” into the cancer cells.

This is one of the first clinical trials to test an antibody-drug conjugate for the treatment of melanoma, explained Jeffrey R. Infante, MD, Director, Drug Development Program, Sarah Cannon Research Institute, Nashville, TN. “We are encouraged by the initial responses. DEDN6526A is well-tolerated and, more important, benefits a substantial proportion of patients. It is particularly promising to see clinical activity in patients with mucosal, as well as ocular, melanoma, and we hope that patients who enroll in the ongoing expansion phase of the trial gain similar benefit,” Dr Infante told attendees at the 2014 American Association for Cancer Research annual meeting.

At the meeting, Dr Infante present-

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ed the results of the dose-escalation phase of the first-in-human phase 1 trial of this new therapy. The antibody recognizes the endothelin B receptor (ETBR), which Dr Infante estimates is elevated in approximately 50% of melanomas; the toxic chemotherapy is monomethyl auristatin E (MMAE).

When DEDN6526A is administered to a patient, the antibody attaches to ETBR on the cancer cell surface, and MMAE is released to kill the melanoma cells. Dr Infante said that he and his coinvestigators are still working on a reliable assay to measure ETBR levels to get a more precise handle on how this drug works.

“We need a companion diagnostic to go along with this drug to identify patients who express ETBR. We are working on it,” Dr Infante noted.

The dose-escalation phase included 28 patients with metastatic or unresectable melanoma (17 with cutaneous melanoma, 8 with ocular melanoma, and 3 with mucosal melanoma). Patients were given DEDN6526A every 3 weeks; the maximum tolerated dose was determined as 2.4 mg/kg every 3 weeks, and this is the dose being tested in the expansion phase of the trial.

Adverse events thought to be drug-related included fatigue, chills, alopecia, sensory neuropathy, decreased appetite, headache, nausea, and vomiting. Neutropenia was the most frequent grade 3 adverse event.

Infusion-related reactions were also observed, but these were reduced with steroid premedication.

Among 19 patients in the dose-esca-

lation phase who received ≥1.8 mg/kg of DEDN6526A, clinical benefit was observed in 12 patients; 2 patients with cutaneous melanoma and 2 with mucosal melanoma had confirmed partial responses. Of the remaining 8 patients, 5 with cutaneous melanoma, 2 with

“These are exciting results because there are not that many examples of antibodydrug conjugates that work.

The demonstration of clinical response is important.”

—Thomas J. Lynch, Jr, MD

ocular melanoma, and 1 with mucosal melanoma had stable disease for 6 months or longer. In some cases, disease was stable for a prolonged period.

Dr Infante said that 1 patient has been stable and in the study for 2 years.

Dr Infante emphasized that this was

at a glance ➤ A new antibody-drug conjugate, DEDN6526A, has activity against melanoma, including cutaneous, mucosal, and ocular melanoma, which is considered difficult to treat ➤ Among 19 patients in the dose-escalation phase who received ≥1.8 mg/kg of DEDN6526A, clinical benefit was observed in 12 patients ➤ A companion diagnostic is needed to identify the many patients with elevated expression of ETBR an unselected population. Responses may be even better once a companion diagnostic can identify patients with elevated expression of ETBR. An expansion cohort of 24 additional patients with melanoma is now being studied.

Thomas J. Lynch, Jr, MD, Director, Yale Cancer Center, New Haven, CT, commented on this study. “These are exciting results because there are not that many examples of antibody-drug conjugates that work. The demonstration of clinical response is important.

This was not an enriched population and we still don’t know the biomarker, but if a test is developed to identify responders, then this may turn out to be a new approach to treatment of patients with melanoma,” Dr Lynch stated. n

Highest Response in Metastatic Renal-Cell Carcinoma with Pazopanib, Third-Line VEGF Inhibitor

By Charles Bankhead

San Diego, CA—Almost 50% of patients with metastatic renal-cell carcinoma (mRCC) had objective responses to third-line treatment with the angiogenesis inhibitor pazopanib, according to the results of a small clinical trial reported at the 2014 American Association for Cancer Research annual meeting.

Overall, 12 of 28 patients achieved objective responses (including 1 complete response), and another patient

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had an unconfirmed partial response.

In the subgroup of responding patients, the duration of response to pazopanib exceeded the duration of previous responses in a majority of cases.

The cohort had a median progression-free survival of 16.5 months, a “remarkable” clinical outcome for such a heavily pretreated group of patients, said principal investigator Sumanta K. Pal, MD, Assistant Pro-

fessor of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA. “This is the highest objective response rate observed to date in a trial of third-line therapy for metastatic renal-cell carcinoma,” said Dr Pal. “Equally unprecedented is the median progression-free survival, which is remarkable for this group of patients.”

Pazopanib, a multitargeted tyro-

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AACR Meeting Highlights

AG-221 Achieved Excellent Responses...

AG-221 achieved CR in 5 of 7 respondents in a cohort of patients with AML/MDS in a phase 1 trial.

“This is the first clinical trial of an inhibitor of mutated IDH, and while the primary objectives of this study are to determine the safety and tolerability of AG-221, we were also able to demonstrate promising clinical activity, including multiple complete remissions, in patients whose blood cancers carried an IDH2 mutation, even at the lowest tested dose,” said lead investigator Eytan M. Stein, MD, Assistant Attending Physician, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York.

In a separate interview, Dr Stein explained that patients like those in the study typically receive chemotherapy, even though it is extremely toxic and does not provide much benefit.

AG-221 is far less toxic and does not compromise the immune system, he explained.

AG-221 (developed by Agios) is an orally available, selective potent inhibitor of the gene mutation in the IDH metabolic enzyme. “Our study validates the concept of blocking mutated IDH2. The drug blocks mutated IDH2, dramatically decreasing the oncometabolite 2HG, an abnormal substance produced by mutated IDH2, allowing leukemia cells to mature into healthy infection-fighting cells,”

“This is the first clinical trial of an inhibitor of mutated IDH, and while the primary objectives of this study are to determine the safety and tolerability of AG-221, we were also able to demonstrate promising clinical activity, including multiple complete remissions, in patients whose blood cancers carried an IDH2 mutation, even at the lowest tested dose.”

—Eytan M. Stein, MD

Continued from the cover

Dr Stein explained.

The phase 1 dose-escalation study enrolled 22 patients with AML or MDS whose cancers harbored mutated IDH2.

Patient cohorts were treated with AG221 administered in 28-day cycles as 30 mg twice daily, 50 mg twice daily, 75 mg twice daily, or 100 mg daily.

The cutoff date for data presentation was March 2014. The doses of 75 mg twice daily and 100 mg daily are still being evaluated and will continue to be escalated until a maximum tolerated dose is identified, Dr Stein said.

The data presented at AACR were based on 10 patients from the 30-mg and 50-mg cohorts. Patients had progressive or refractory disease after 1 to 4 previous therapies; 1 patient had undergone bone marrow transplantation. The median age was 62.5 years, and all patients had documented IDH2 mutations. Of the 10 patients, 7 were evaluable for efficacy.

Of 7 patients, 6 had objective responses as assessed by the investigator, including 3 CRs and 2 CRs with an incomplete platelet recovery.

Responding patients are continuing to receive the drug.

Thus far, the treatment has been well-tolerated. In all, 2 patients had severe adverse events: 1 patient had an elevated white blood cell count, and 1 had confusion and respiratory failure resulting from disease-related

at a glance ➤ AG-221 can induce complete remissions in patients with relapsed, refractory AML and MDS who harbor mutated IDH2 ➤ AG-221 is less toxic than typical chemotherapy and patients are less immunocompromised ➤ AG-221 showed favorable clinical activity, including multiple complete remissions, in patients with blood cancers and an IDH2 mutation, even at the lowest dose ➤ Laboratory tests showed a >90% reduction in plasma 2HG levels with AG-221, as well as cellular differentiation and normalization of bone marrow and blood cell counts infection. A total of 4 patients died within 30 days of study drug termination, all as a result of disease-related sepsis occurring in cycle 1.

Laboratory tests showed a >90% reduction in plasma 2HG levels with treatment, as well as evidence of cellular differentiation and normalization of cell counts in bone marrow and blood. n

Highest Response in Metastatic Renal-Cell Carcinoma... sine kinase inhibitor, is approved for the treatment of advanced RCC. Previous studies of the agent included a phase 3 trial of patients who were refractory to cytokine therapy or were treatment-naïve. No previous trial had determined pazopanib’s activity in the third-line setting or examined temporal changes in molecular profile during therapy.

Study Details Dr Pal and colleagues evaluated pazopanib’s third-line potential for mRCC in a well-defined group of previously treated patients. They performed a phase 2, single-arm trial involving patients whose disease had progressed after 2 previous systemic regimens, 1 of which had to be an inhibitor of vascular endothelial growth factor (VEGF). Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0

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to 2, and clear-cell histology.

The primary outcome was response rate, and the trial was statistically powered to detect a 23% overall response rate, defined as “clinically encouraging.” Investigators also examined immunologic markers associated with treatment failure or success.

Patients received pazopanib 800 mg daily on 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or death.

None of the patients enrolled in the study had good-risk characteristics.

Approximately 60% had intermediate-risk features, and approximately 40% had poor-risk features.

Overall, 23 of the 28 patients received anti-VEGF therapy as first-line treatment, and the most frequently used therapy in second-line was the mammalian target of rapamycin inhibitor class. Some of the patients received anti-VEGF therapy as first-

and second-line therapy. The median duration of previous anti-VEGF therapy was 4 months.

“This is the highest objective response rate observed to date in a trial of thirdline therapy for metastatic renal cell carcinoma. Equally unprecedented is the median progression-free survival, which is remarkable for this group of patients.”

—Sumanta K. Pal, MD

In addition to the 13 patients who had responses (including the 1 uncon-

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firmed response), 9 had stable disease, resulting in a clinical benefit rate of 78%. After a median follow-up of 17.1 months, the median overall survival had yet to be reached.

Biomarker analysis showed that response was associated with lower levels of hepatocyte growth factor, VEGF, interleukin (IL)-8, IL-6, and soluble IL-2 receptor (P <.05 for all analyses).

The most frequently reported adverse event was hypertension (93%, all grades), which was grade 3/4 in 50% of the cases. Blood pressure was manageable with antihypertensive medications, and no patient stopped treatment because of uncontrolled blood pressure.

In addition, 14% of patients had grade 3 proteinuria. The most frequently reported laboratory abnormalities were hyponatremia and elevated creatinine. n

www.ValueBasedCancerCare.com

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AACR Meeting Highlights

CDK 4/6 Inhibitor Slows Progression of Metastatic Breast...

Continued from the cover

for patients who received letrozole alone as first-line therapy. The positive outcome owes to a combination of better patient selection and better therapy, said Richard S. Finn, MD, Assistant Professor of Medicine, University of California, Los Angeles, at the 2014 American Association for Cancer Research meeting.

“Two prominent reasons for this success are that we identified a subtype of breast cancer—hormone receptor-positive, HER2-negative— most likely to respond to the therapy, and we had a much-improved second-generation inhibitor of CDK 4/6,” said Dr Finn. “Palbociclib is very specific and efficient in block­ing CDK 4/6, which results in less toxicity.”

The outcome of the randomized, phase 2 trial left a major question unanswered: why patients chosen on the basis of estrogen receptor (ER) positivity had better PFS with palbociclib than those selected for ER positivity and CDK 4/6 expression.

Invited discussant José Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan Kettering Cancer Center, New York, said that confirmation of the “strikingly positive” results in phase 3 studies could make palbociclib a new therapeutic standard for patients with advanced ER-positive breast cancer. Dr Baselga also cautioned that positive phase 2 results do not always translate into positive phase 3 trials, singling out the PARP (poly[ADP-ri-

bose] polymerase) inhibitor iniparib as a prime example.

Dr Finn reported findings from a trial conducted in 2 phases involving biomarker-selected patients. In­ vestigators in the multicenter trial first evaluated the combination of palbociclib and letrozole in patients with ER-positive breast cancer. During the second phase, patients were chosen on the basis of having ER-positive tumors that also expressed CDK 4/6.

Study Details The trial involved a total of 165 women with previously untreated metastatic breast cancer. During the first phase, 66 patients with ERpositive breast cancer were randomized to receive letrozole with or without palbociclib. During the second phase, investigators randomized 99 patients with ER-positive, CDK 4/6– positive breast cancer to the same 2 treatment regimens.

The primary end point was PFS, and the 10-month differential in favor of the palbociclib regimen resulted from combining the PFS results from the 2 phases. During the first phase, the combination led to a median PFS of 26.7 months compared with 5.8 months with letrozole alone. In the second part of the trial, patients chosen on the basis of both biomarkers had a median PFS of 18.1 months with letrozole plus the PARP inhibitor palbociclib compared with 11.1

“Two prominent reasons for this success are that we identified a subtype of breast cancer—hormone receptorpositive, HER2-negative— most likely to respond to the therapy, and we had a much-improved secondgeneration inhibitor of CDK 4/6. Palbociclib is very specific and efficient in blocking CDK 4/6, which results in less toxicity.”

—Richard S. Finn, MD

months for letrozole alone.

The reason for the apparent disconnect between PFS benefit and bio-

marker status was not clear, said Dr Finn. He noted that patient selection could have focused on other potential biomarkers. Preclinical studies showed that response to palbociclib in ER-positive breast cancer was associated with overexpression of cyclin D1 and retinoblastoma protein, as well as downregulation of p16. The use of a different biomarker or biomarker profile to select patients might have led to different results.

Another possible explanation is that ER positivity is the key factor in response to the CDK 4/6 inhibitor, Dr Finn added.

Overall survival did not differ significantly between the treatment groups: 37.5 months with palbociclib and 33.3 months with letrozole alone.

However, Dr Finn pointed out that survival data are immature and will continue to be analyzed.

In general, palbociclib was tolerated.

The most frequently reported adverse events in patients treated with letrozole plus palbociclib were neutropenia, leukopenia, fatigue, and anemia. Adverse events were mostly grade 1/2 in severity, with the exception of grade 3/4 neutropenia, which occurred in more than 50% of patients who received palbociclib (grade 3 in 48% of patients).

Phase 3 trials of palbociclib have already begun, one of which is evaluating the CDK 4/6 inhibitor with letrozole and the other in combination with fulvestrant. n

Multitargeted Kinase Inhibitor Shows Promise for Breast Cancer Subgroup HER2+/HR– breast cancer identified as biomarker signature for neratinib use

By Charles Bankhead San Diego, CA—A multitargeted kinase inhibitor met criteria for a phase 3 clinical trial in breast cancer after statistical modeling of clinical data showed a high probability of success versus standard therapy for patients with HER2-positive/hormone receptor (HR)-negative (HER2+/HR–) disease.

Neoadjuvant treatment with pac­ litaxel plus neratinib (followed by doxorubicin plus cyclophosphamide) led to an estimated pathologic complete response (pCR) rate of 56% compared with 33% for paclitaxel paired with trastuzumab and followed by

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doxorubicin plus cyclophosphamide.

Statistical modeling showed that the neratinib combination had a 95% probability of demonstrating superiority to paclitaxel plus trastuzumab, and a 79% likelihood of success in a phase 3 clinical trial of patients with HER2+/ HR– breast cancer, as reported at the 2014 American Association for Cancer Research meeting.

“The adaptive trial identified a biomarker signature for neratinib, and neratinib has graduated in the HER2+/ HR– signature,” said John W. Park, MD, Professor of Clinical Medicine,

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University of California, San Francisco Helen Diller Family Comprehensive Cancer Center. “Based on these results, neratinib is under consideration for phase 3 testing in the neoadjuvant population.”

The results came from the ongoing Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) 2 trial, which uses a combination of adaptive randomization and Bayesian modeling to match a breast cancer therapy with the subgroup of patients most likely to benefit. The

strategy is designed to provide results in a short period of time, and with as few patients as possible.

Neratinib is an irreversible panErbB/HER2 inhibitor. According to Dr Park, I-SPY 2 has 6 experimental regimens under investigation.

The HER2+/HR– breast cancer subtype was 1 of 10 biomarker signatures evaluated in the trial. The signatures are derived from combinations of HER2 status, HR status, and results of the MammaPrint gene-expression assay. Patients with early breast cancer are randomized to the experimental Continued on page 17

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Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX 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 colonystimulating 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 treatment-emergent 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 Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40178 February 2014.

In the Literature ALK-Positive NSCLC Responds to Ceritinib Treatment

Non–small-cell lung cancer (NSC LC) harboring anaplastic lymphoma kinase (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib (Xalkori). Despite initial responses to crizotinib, resistance ultimately oc-

curs. In preclinical studies, ceritinib (Zykadia), a novel, oral adenosine triphosphate–competitive inhibitor of the ALK tyrosine kinase, has shown greater antitumor potency than crizotinib.

In a phase 1 study, researchers sought to determine the safety, maximum tolerated dose, and antitumor activity of ceritinib in patients with advanced

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. 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.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 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.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

ALK-rearranged NSCLC. The results demonstrated that ceritinib produced a highly active response rate in this patient population, including patients with previous crizotinib treatment and irrespective of the presence of ALK resistance mutations (Shaw AT, et al.

N Engl J Med. 2014;370:1189-1197).

The trial consisted of 2 phases and

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

included 130 patients. In the doseescalation phase, 59 patients with tumors harboring ALK alterations were treated with ceritinib at doses of 50 mg to 750 mg once daily in 21-day cycles.

In an expansion phase, 71 patients were treated at the maximum tolerated dose of 750 mg daily. Among the 130 patients enrolled, 122 had advanced NSCLC and had previously received cytotoxic chemotherapy. Of the 122 patients with advanced NSCLC, 68% had previously received crizotinib.

The most common adverse events (AEs) were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%), and elevated alanine aminotransferase (ALT; 35%) levels. The most common grade 3 or 4 drug-related AEs were increased ALT levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%), and increased lipid lipase levels (7%), all of which were reversible on discontinuation of treatment. Of 130 patients, 66 (51%) required at least 1 dose reduction. In 8 (6%) of the 130 patients, ceritinib was permanently discontinued. No treatment-related deaths occurred.

Among the 114 patients with NSCLC who received ≥400 mg of ceritinib daily, the overall response rate was 58%, which included 1 (1%) confirmed complete response and 65 (57%) partial responses. The overall response rate was 56% among 80 patients previously receiving crizotinib, and 62% among the 34 crizotinib-naïve patients.

Among 114 patients receiving ≥400 mg daily, the median progression-free survival was 7 months, which was similar at 6.9 months in the crizotinib relapse group and was 10.4 months in crizotinib-naïve patients.

Because ceritinib has been shown to induce substantial and durable responses in a majority of cases, these findings suggest that ceritinib can be an alternative treatment to crizotinib.

On April 29, 2014, the US Food and Drug Administration granted accelerated approval for ceritinib for patients with metastatic ALK-positive NSCLC (see FDA Update, page 4).

Chemotherapy Better Option for Patients with Lung Cancer without EGFR Mutations

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred treatment option for patients with advanced non– small-cell lung cancer (NSCLC) who have tested positive for EGFR mutations, because of better outcomes than conventional chemotherapy.

However, it is unclear if EGFR TKIs are as efficacious as chemotherapy in patients without EGFR mutations (known as EGFR wild-type), which Continued on page 23

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AACR Meeting Highlights

FGFR Inhibitor Shows Promising Anticancer Activity

By Phoebe Starr

San Diego, CA—Inhibition of fibroblast growth factor receptors (FGFRs) 1, 2, 3, and 4 is showing promise in the treatment of cancers driven by FGFR alterations, especially bladder cancer and lung cancer, according to phase 1 studies presented at the 2014 American Association for Cancer Research annual meeting.

A phase 1 study, singled out for attention at an official press conference, showed that the investigational panFGFR inhibitor BGJ398 (Novartis) had activity against different types of solid tumors, including bladder cancer. The most notable side effect of this drug is hyperphosphatemia, an on-target effect that is manageable by dose interruptions, schedule adjustments, and phosphate-lowering medications.

“The primary purpose of this firstin-human clinical trial of BGJ398 was to look at tolerability. However, we restricted enrollment only to patients with FGFR genetic alterations in their tumors, because we believed that these patients would have the greatest chance of benefiting from the drug,” said Lecia V. Sequist, MD, MPH, Associate Professor of Medicine, Harvard Medical School, and Assistant Physician, Massachusetts General Hospital, Boston.

Dr Sequist said that she and her colleagues were especially encouraged by the activity seen in bladder cancer, “for which there are few treatment options.”

“This study clearly demonstrates

“This study clearly demonstrates the value of a personalized approach to cancer therapy with a targeted agent by showing that patients with FGFR genetic abnormalities can respond to an FGFR inhibitor.”

—Lecia V. Sequist, MD, MPH the value of a personalized approach to cancer therapy with a targeted agent by showing that patients with FGFR genetic abnormalities can respond to an FGFR inhibitor,” Dr Sequist said.

The study enrolled 107 patients with lung cancer, breast cancer, cholangiocarcinoma, or urothelial-cell/bladder cancer. Of those patients, 43 were treated in the dose-escalation phase of

the trial. There were 3 groups treated in the expansion phase: squamous-cell lung cancer treated daily, and 2 other groups with various cancers (one group was treated continuously daily, and the other group was treated for 3 weeks on and 1 week off).

The 125-mg daily dose was identified as the maximum tolerated dose.

The 3-weeks-on and 1-week-off schedule demonstrated an improved safety profile, and is the schedule that will go forward for phase 2 testing.

Tumor shrinkage was observed in patients treated at doses of ≥100 mg daily in the dose-escalation phase, as well as among patients in all 3 expansion arms. Tumor shrinkage was observed in various cancer types, most notably in 5 of 6 patients with bladder cancer who had an FGFR3 mutation.

Anticancer activity was also observed in patients with squamous-cell lung cancer, squamous-cell head and neck cancer, breast cancer, and cholangiocarcinoma. Dr Sequist said that the lung cancer data will be presented at the 2014 American Society of Clinical Oncology meeting.

Lessons learned from this phase 1 study and others include the need for proactive management to reduce hyperphosphatemia. A number of phase 2 studies are ongoing or are planned, and correlative studies of specific FGFR genetic alterations will be included.

Another abstract presented at the meeting focused on a similar drug

at a glance ➤ Inhibition of FGFRs is promising in the treatment of cancers driven by FGFR alterations, especially bladder cancer and lung cancer ➤ The pan-FGFR inhibitor BGJ398 had activity against different types of solid tumors, including bladder cancer ➤ Tumor shrinkage was observed in patients treated at doses of ≥100 mg daily in the dose-escalation phase, as well as among patients in all 3 expansion arms ➤ BGJ398’s most notable adverse effect is hyperphosphatemia, which is managed by dose interruptions, schedule adjustments, and phosphate-lowering medications ➤ Phase 2 studies are ongoing or are planned, and correlative studies of specific FGFR genetic alterations will be included under development by Johnson & Johnson—a pan-FGFR inhibitor called JNJ-42756493. The study had a similar design, similar responses, and similar adverse events—mainly hyperphosphatemia. The 9-mg daily dose was identified as the maximum tolerated dose going forward in phase 2 trials. n

Multitargeted Kinase Inhibitor Shows Promise... or control arm. Response data are incorporated into the statistical model, which “learns” from the information and narrows the biomarker signature to patients most likely to respond to the experimental arm.

As tumor signatures unlikely to benefit from the experimental therapy are excluded, randomization continues in the remaining signatures, a process known as adaptive randomization. Because of confounding by the randomization process, estimated response rates are calculated for each signature, said Dr Park.

The phase 2 clinical trial has 3 principal end points: estimated pCR, probability that the experimental regimen is superior to the current standard, and predicted probability of success. To receive consideration for phase 3 evalua-

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tion, a treatment regimen must achieve a 95% probability of superiority and an 85% probability of success versus standard care in a trial of 300 patients

patients treated with neratinib and 78 patients receiving standard care. On the basis of the results, the statistical model yielded an estimated pCR of

“The adaptive trial identified a biomarker signature for neratinib, and neratinib has graduated in the HER2+/HR– signature. Based on these results, neratinib is under consideration for phase 3 testing in the neoadjuvant population.”

—John W. Park, MD

whose breast cancer has the signature identified in the phase 2 trial.

Dr Park reported data from 115

56% for the neratinib regimen and 33% for the standard regimen. The regimen met the 85% probability threshold for

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a phase 3 trial, but the recent addition of new data decreased the probability to 79%, said Dr Park.

The principal toxicity issue with neratinib was severe diarrhea (grade 3/4), which occurred in 39% of patients who received the drug compared with 4% of patients in the control arm. Early in the trial, investigators modified supportive care for diarrhea and initiated the prophylactic use of loperamide.

The changes appeared to reduce problem diarrhea, said Dr Park. Cardiac toxicity was not a problem in the neratinib arm or in the control arm.

Discontinuation resulting from toxicity occurred more often with neratinib, whereas disease progression was a more common cause of discontinuation in the control arm. n

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Personalized Medicine

PD-L1 Expression Potential Biomarker for Response to Immunotherapy with MK-3475 Patients with melanoma or with NSCLC investigated in 2 studies

By Phoebe Starr San Diego, CA—Two studies, one in melanoma and one in non–small-cell lung cancer (NSCLC), presented at the 2014 American Association for Can­ cer Research meeting attempted to correlate response to the anti–programmed cell death (PD)-1 inhibitor MK-3475 with the biomarker PD-L1.

The hope is that the level of PD-L1 expression will be a biomarker for the selection of patients for treatment with this new agent.

The first study suggests that PD-L1 expression may become a marker for determining which patients with melanoma will best benefit from MK-3475, and the second study indicates that PD-L1 is a robust predictor of response and outcomes in patients with NSCLC treated with this drug. Ongoing studies are looking for additional evidence.

“We found a major difference in the response rates between patients with PD-L1–positive and PD-L1–negative tumors treated with MK-3475. This is the largest data set yet, to my knowledge, looking at PD-L1 expression in tumors from melanoma patients treated with PD-1 inhibitors.”

—Adil I. Daud, MD

MK-3475 is an investigational potent antibody that inhibits PD-1. This immunotherapy is designed to restore the ability of the immune system to recognize and target cancer cells by selectively achieving dual blockade of 2 ligands of the PD-1 protein: PD-L1 and PD-L2.

Melanoma Results The first study involved patients with melanoma, and the results were presented by lead investigator Adil I. Daud, MD, Codirector of the Melanoma Center at the University of California, San Francisco (UCSF) and Director of melanoma clinical research at the

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UCSF Helen Diller Family Comprehensive Cancer Center.

“We found a major difference in the response rates between patients with PD-L1–positive and PD-L1–negative tumors treated with MK-3475,” said Dr Daud. “This is the largest data set yet, to my knowledge, looking at PD-L1 expression in tumors from melanoma patients treated with PD-1 inhibitors.”

In this study, 195 patients with advanced melanoma had a mandatory biopsy and were then treated with 1 of 3 doses of MK-3475 for 12 weeks when response was assessed; responders continued receiving treatment until disease progression, and nonresponders discontinued the study. Patients treated previously with ipilimumab had no restriction on previous therapies; those who were ipilimumabnaïve could have had up to 2 previous therapies. Among 125 patients who were evaluable for PD-L1 expression, PD-L1 expression was positive in 89 tumors (71%), and 36 patients were PD-L1–negative.

In unselected patients, the response rate was 40%. Among PD-L1–positive patients, the response rate was 49% versus 13% among PD-L1–negative patients (P = .007). The responses were durable in PD-L1–positive and PD-L1– negative patients, Dr Daud said.

Progression-free survival (PFS) curves also showed major differences between PD-L1–positive and PD-L1– negative patients. The median PFS was 10.6 months in PD-L1–positive patients versus 2.9 months in PD-L1– negative patients (P = .051). The overall survival data are not mature.

Among patients with melanoma who received MK-3475, those whose tumors expressed PD-L1 had an overall response rate (ORR) of 46% compared with 17% ORR in patients without PD-L1 expression. After 6 months of therapy with MK-3475, 64% of the patients whose tumors were PD-L1– positive had no disease progression, compared with 34% of those whose tumors were PD-L1–negative.

Similarly, 86% of the patients whose tumors were PD-L1–positive were alive after 12 months compared with 72% of patients whose tumors were PD-L1–negative.

When discussing the study at a press briefing, Dr Daud emphasized that these were preliminary results and more data are needed to verify the

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utility of MK-3475 as a biomarker for patients with advanced melanoma, saying, “Because we saw durable responses in PD-L1–negative patients,

“PFS was markedly improved in those with strong PD-L1 staining, and responses were durable. We expect that these median and final PFS may change over time.

As with melanoma, there is no statistically significant difference in survival at this point, but we do see a trend favoring PD-L1 positivity.”

—Leena Gandhi, MD, PhD

the clinical utility of selecting patients for treatment with MK-3475 based on PD-L1 expression is not clear in advanced melanoma.”

Data from ongoing studies may indeed provide additional information on the relationship between PD-L1 expression and response to MK-3475.

The US Food and Drug Administration (FDA) has assigned a priority review for the manufacturer’s application for the licensing of MK-3475 (now known as pembrolizumab) for the treatment of patients with advanced melanoma, with a final FDA decision expected in October 2014.

NSCLC Results A second presentation from an early-phase study showed that PD-L1 expression of >50% was predictive of response to MK-3475 in patients with NSCLC. These findings were also based on an analysis of a training set of 146 patients from the ongoing phase 1 study, and were reported by Leena Gandhi, MD, PhD, Thoracic Oncologist, Dana-Farber Cancer Institute, Boston.

The ORR for PD-L1–positive and PD-L1–negative groups was 19%.

However, strong positivity (>50% expression) clearly differentiated re-

at a glance ➤ MK-3475 is a potent immunotherapy that targets cancer cells and inhibits PD-1 ➤ PD-L1 expression is associated with a response to MK-3475 in patients with melanoma and is a robust predictor of response and outcomes in patients with NSCLC ➤ In patients with melanoma, the response to MK-3475 therapy was 49% among PD-L1– positive patients versus 13% among PD-L1–negative patients (P = .007) ➤ PD-L1 expression of >50% was predictive of response to MK-3475 in patients with NSCLC sponders from nonresponders. Approximately 25% of the cohort was PD-L1–positive using this cutoff.

The median PFS was 14.1 weeks in the PD-L1–positive patients versus 9.3 weeks in the PD-L1 weakly positive or negative patients. Overall survival times were 9.3 months versus 7.3 months, respectively, which were not statistically significant.

“PFS was markedly improved in those with strong PD-L1 staining, and responses were durable. We expect that these median and final PFS may change over time. As with melanoma, there is no statistically significant difference in survival at this point, but we do see a trend favoring PD-L1 positivity,” Dr Gandhi said.

Ongoing studies will analyze more patients in the phase 1 study, and there is an ongoing randomized study of 2-mg/kg MK-3475 versus 10-mg docetaxel in patients with NSCLC. MK-3475 is also being evaluated as a single agent and in combination with other drugs in patients with multiple solid tumors and hematologic malignancies.

A major problem with this effort is that the tests for PD-L1 expression are not standardized. Several tests for PD-L1 expression are being developed by pharmaceutical companies, and they differ in many aspects, including set points for positivity and reagents. n

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Personalized Medicine

Simple Blood Test Predicts Response to Enzalutamide in Patients with Prostate Cancer

See also Prostate Cancer, page 34

By Phoebe Starr

San Diego, CA—A preliminary study from a highly respected group of researchers suggests that a simple blood test for the androgen receptor splice variant-7 (AR-V7) in the AR gene can identify men with castrate-resistant prostate cancer (CRPC) who will not respond to enzalutamide (Xtandi). If these results are confirmed in a larger population, the test could help to differentiate among patients who could and could not benefit from this drug, avoid unnecessary costs, and allow the patient to move on to an effective drug.

The data were presented for the first time at the 2014 American Association for Cancer Research annual meeting.

“AR-V7 is detectable in circulating T-cells in a subset of CRPC patients, and seems to predict resistance to enzalutamide. We believe these data have immediate clinical implications, in that we can steer patients who test positive for this splice variant away from enzalutamide and offer them chemotherapy and radiation,” said Emmanuel S. Antonarakis, MD, Associate Professor of Oncology, Johns

Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. “Further, the availability of a blood biomarker for AR-V7 could fuel the development of novel AR therapies,” Dr Antonarakis added.

The use of enzalutamide for CRPC in the predocetaxel space is off-label.

However, approval for this indication may be forthcoming. Currently, 3 other therapies are approved for this indication, which include abiraterone (Zytiga) plus prednisone, radium-223 (Alpharadin), and sipuleucel-T (Provenge).

“Even though enzalutamide is considered a very effective drug for some patients, about 20% of patients do not respond,” Dr Antonarakis said.

He noted that many potential reasons for resistance to the drug have been proposed, but he and his team have focused on splice variants of the AR gene. “Our studies suggest that AR-V7 is the most important variant related to resistance to enzalutamide,” Dr Antonarakis said.

A 2-part assay was used to detect AR-V7 in circulating T-cells: the Dana

Test Prostate Cancer Select and the AdnaTest ProstateCancer Select kits.

The study enrolled 31 men with CRPC who were planning to initiate treatment with enzalutamide. Circulating

“AR-V7 is detectable in circulating T-cells in a subset of CRPC patients, and seems to predict resistance to enzalutamide. Even though enzalutamide is considered a very effective drug for some patients, about 20% of patients do not respond.”

—Emmanuel S. Antonarakis, MD

T-cell samples were provided at baseline, time of response, and time of resistance. The data that Dr Antonarakis presented were derived from baseline circulating T-cell samples.

Of the 31 patients, 12 (39%) had detectable AR-V7 in their circulating T-cells, and 19 (61%) did not. Among patients who were previously treated with abiraterone, the risk of detectable AR-V7 increased to 55%, whereas it was detectable in only 9% of patients who were abiraterone-naïve.

According to the Response Evaluation Criteria in Solid Tumors (RECIST), no tumor shrinkage was seen in any patient with detectable AR-V7.

Every patient who had a prostate-specific antigen (PSA) response was wildtype for AR-V7, whereas only 1 of the patients with detectable AR-V7 had a PSA response. The presence of detectable AR-V7 was associated with a 7fold risk of PSA progression and an 8.5-fold risk of clinical progression.

A multivariate analysis identified 3 factors associated with lack of response, including detectable AR-V7, baseline PSA level, and previous abir­ aterone treatment. The 2 factors associated with progression-free survival included the presence of AR-V7 and previous treatment with abiraterone. n

Multigene Testing for Breast Cancer May Be Beneficial BRCA1/2 testing leaves out 4 mutations

See also Breast Cancer, page 25

By Rosemary Frei, MSc Las Vegas, NV—Researchers are making a compelling case for screening women at high risk for breast cancer for more than BRCA mutations. In fact, 4 genetic mutations are well recognized in genetic-based breast cancer, including CDH1, PTEN, STK11, and TP53.

At the 2014 National Consortium of Breast Centers meeting, a team from Ambry Genetics presented their study results, showing that among 4323 women with inherited breast cancer who were tested for gene mutations, more than 50% of those with nonBRCA mutations had no indication they were carrying these mutations.

Testing positive for these women can have a direct impact on the medical management.

Overall, 202 (4.7%) women had gene mutations; of these women, 27 (13.4%) had non-BRCA mutations. Although the majority of the women had BRCA1 mutation (44.5%) or BRCA2 (42%), the others were TP53 (9.4%), PTEN (2.5%), CDH1 (1%), and STK11 (0.5%). Of

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those with non-BRCA mutations, 56% did not meet the clinical criteria that are used to suggest the presence of these mutations.

“A lot of physicians are only ordering BRCA testing....But in fact, in many cases it’s beneficial to test for all these genes at once.”

—Steven Keiles, MS

“A lot of physicians are only ordering BRCA testing, because they only know 1 lab that tests for breast cancer mutations, and that lab only tests for BRCA, or they think the other mutations are so rare they’re not worth

testing for,” said Steven Keiles, MS, Director of Clinical Affairs, Ambry Genetics Corporation, Aliso Viejo, CA, who led the study. “But in fact, in many cases it’s beneficial to test for all these genes at once.”

Mr Keiles also pointed out that the testing criteria have been broadened recently—for example, in 2013, the National Comprehensive Cancer Network (NCCN) increased the range of women who are appropriate for TP53 testing to a maximum of 35 years from the previous 30-year upper age limit.

CDH1 is associated with hereditary diffuse gastric cancer. PTEN is associated with Cowden syndrome, TP53 with Li-Fraumeni syndrome, and STK11 with Peutz-Jeghers syndrome.

All of these conditions also confer an elevated risk for breast cancer.

Mr Keiles and his colleagues reviewed the results from 4323 women who underwent genetic testing with the 6-gene panel between June 17, 2013, and January 17, 2014. The investigators also examined the proportion

MAY 2014

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of patients who were found to have a mutation and who did or did not meet the syndrome-based testing criteria defined by the NCCN. Furthermore, 44% of women who tested positive did not meet clinical criteria for one of the diseases that the mutations are classically associated with. These included women who would not normally routinely be tested for the non-BRCA gene mutations, according to Mr Keiles. “But for these women, it was worth doing the testing, because more than 13% of the women who ended up testing positive were positive for genes other than BRCA1 and BRCA2,” he said, adding that the team has now reviewed the results of approximately 5000 women, and the numbers are similar for this larger group.

Mr Keiles noted that Myriad charges $4000 for BRCA1 and BRCA2 testing, whereas his company’s price is $2200, and $3300 for the 6-gene panel. The BRCAplus panel uses next-generation and Sanger sequencing. n

www.ValueBasedCancerCare.com

19

Health Policy

Recent HHS Reports Highlight Need to Address Drug Shortages

By John Warren, JD; James Cohen, JD; and Michael Ryan, JD

Mr Warren is Senior Director, McDermott+Consulting; Mr Cohen is Partner, Head, FDA Practice, McDermott Will & Emery; and Mr Ryan is Associate, Health Industry Advisory Practice Group, McDermott Will & Emery, Washington, DC

I

n recent years, an increasing number of drug shortages have threatened public health by reducing—if not eliminating—patient access to critical pharmaceuticals. As such, drug shortages have been the subject of considerable federal activity, including an October 31, 2011, executive order (ie, Executive Order 13588) that directed the US Food and Drug Administration (FDA) to “take steps that will help to prevent and reduce current and future disruptions in the supply of lifesaving medicines” (eg, requiring broader reporting of manufacturing discontinuances and expediting regulatory reviews),1 and a December 2011 interim final rule issued by the FDA that amended the FDA’s early notification requirements.2 FDA Safety and Innovation Act Perhaps most important, however, is that the FDA Safety and Innovation Act (FDASIA) significantly enhances the FDA’s ability to identify and mitigate the effects of drug shortages, by 3: • Requiring all manufacturers of all covered prescription drugs (ie, drugs that are life-supporting, life-sustaining, or are intended for use in the prevention or treatment of debilitating disease or condition, including any such drug used in emergency medical care or during surgery [except for radiopharmaceuticals and other products designated by the Secretary of the US Department of Health & Human Services (HHS)]) to notify the FDA of permanent discontinuation or temporary interruption in manufacturing (before the FDASIA, this requirement applied only to sole product manufacturers) • Authorizing the FDA to require (by regulation) that biologic product manufacturers provide notice of permanent discontinuation or temporary interruption (previous law excluded all biologics from the reporting requirements) • Requiring the FDA to send a noncompliance letter to companies that fail to provide the required notice of permanent discontinuation or temporary interruption • Expressly permitting the FDA to continue expediting reviews and inspections that may mitigate a shortage • Requiring the improvement of inter-

20

nal and external communications by the FDA regarding shortages • Mandating the development and implementation of a strategic plan to help the FDA mitigate and respond to shortages • Triggering the initiation of a new rulemaking process (which will replace the December 2011 interim final rule) to incorporate the new requirements set forth in FDASIA.

Two recently released reports from the HHS and the US Government Accountability Office focus on the impact of prescription drug shortages.

The FDASIA also requires the HHS to submit an annual report regarding drug shortages to the Congressional Committees of Jurisdiction. On February 5, 2014, the FDA submitted its first annual report, in which it discussed actions it has taken to identify and prevent or mitigate prescription drug shortages, and described the impact drug shortages have on the healthcare system—particularly on patients and healthcare providers.4 With respect to the efficacy of the agency’s activities, the report stated that the total number of actual drug shortages decreased from 250 in 2011 to 117 in 2012, with 280 other drug shortages prevented in 2012. The FDA attributes these results to the above-described presidential, congressional, and agency activities, which have resulted in manufacturers providing the FDA with earlier notice of potential shortages, and the agency having additional time to work with sponsors and other groups to maintain patient access to critical medication.

The report also highlighted the mitigation efforts that the FDA can implement when faced with a potential shortage. Mitigation efforts may include allowing other manufacturers to increase production to make up for the shortfall; expediting reviews and inspections relating to manufacturers attempting to restore production, competing manufacturers interested in starting new production, and competing manufacturers interested in in-

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creasing the existing production of products in shortage; and exercising the temporary enforcement discretion for new sources of drugs. The FDA also noted that it exercised its regulatory flexibility in order to prevent 140 drug shortages in the first 9 months of 2013.

GAO Report The FDASIA also requires the US Government Accountability Office (GAO) to issue a report that examines the causes of drug shortages, and formulates recommendations to prevent or minimize them. On February 10, 2014, the GAO released this analysis.5 To create this report, the GAO reviewed data, interviewed stakeholders, and performed a meta-analysis of 20 different studies and FDA data.

The GAO found that, despite the efforts of the FDA, the number of drug shortages remained high. The GAO report noted that 44% of the shortages were sterile injectable generic drugs, 17% were sterile injectable brandname drugs, and the remainder were oral drugs. Even more disturbing, the GAO found that during the period from 2007 to 2012, nearly 50% of the reported shortages were for drugs that were in shortage multiple times.

According to the report, 4 categories of drugs—anesthetics, anti-infectives, cardiovascular agents, and nutritive drugs—accounted for 53% of critical drug shortages.5 The GAO’s analysis indicates that the majority of drug shortages (70%) are related to manufacturing quality, delays, or capacity issues. Although the report identified additional underlying factors, such as payer-related issues, particularly Medicare Part B pricing, and market-based price competition, the report did not present any of these factors as being significant causes of shortages.5 Providers indicated to the GAO that drug shortages can affect patient care beyond just the inability to access drugs in short supply. Provider groups highlighted the risks stemming from the inability to find suitable and effective alternative drugs, rationing care when drugs have limited availability, and the increased cost of short-supply drugs.

Provider groups also noted that their practices were required to devote additional staff and provider time and costs on managing drug inventory instead of

on providing direct patient care.5 The GAO report lauded the FDA’s efforts to identify and mitigate drug shortages. However, it noted that many contributing factors are beyond the FDA’s control. The GAO recommends that the FDA streamline its existing processes by better and more consistently using the information it collects to further enhance its ability to identify, track, and prevent drug shortages.5 Implications Patients, providers, manufacturers, and payers alike will be encouraged by the FDA’s report of reductions in and the prevention of drug shortages.

Nevertheless, the GAO’s report and remaining shortage concerns suggest that significant progress remains to be made. Therefore, where required to more fully address shortage-related issues, the FDA’s regulatory policy may evolve over time—at least to the extent required and permitted under the FDASIA. For example, as mentioned above, the FDA intends to replace the 2011 interim final rule with regulations consistent with the FDASIA’s requirements. The comment period for the proposed replacement rule closed in early January 2014, so the FDA could promulgate the final regulations as soon as later in 2014. Therefore, interested entities—especially manufacturers—should carefully monitor communications regarding the final rule from the FDA, as well as other FDA activities under its drug shortage program. n References

1. US Food and Drug Administration. Executive Order 13588—reducing prescription drug shortages.

October 31, 2011. www.whitehouse.gov/the-pressoffice/2011/10/31/executive-order-reducingprescription-drug-shortages. Accessed May 5, 2014.

2. US Department of Health & Human Services.

Applications for Food and Drug Administration approval to market a new drug; revision of postmarketing reporting requirements—discontinuance. Fed Regist. 2011;76:78530-78540.

3. Food and Drug Administration Safety and Innovation Act, Pub L No 112-144, 126 Stat 993. www.gpo. gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW112publ144.pdf. Accessed May 5, 2014.

4. US Food and Drug Administration. First annual report on drug shortages for calendar year 2013.

Report to Congress. February 5, 2014. www.fda.gov/ downloads/Drugs/DrugSafety/DrugShortages/ UCM384892.pdf. Accessed May 5, 2014.

5. US Government Accountability Office. Drug shortages: public health threat continues, despite efforts to help ensure product availability. Report to Congressional Addressees. GAO-14-194. February 2014. www.gao.gov/assets/670/660785. Accessed May 5, 2014.

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1st oral kinase inhibitor for previously treated CLL

NOW APPROVED NEW

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

1 daily dose

FOR PREVIOUSLY TREATED CLL

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE).

Monitor patients for fever and infections and evaluate promptly.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels.

Maintain hydration.

Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 02/14

PRC-00287

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA™. 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.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%). *Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), ADVERSE REACTIONS – atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), MCL: The most commonly occurring adverse reactions dehydration (6.4%), and musculoskeletal pain (6%). (≥20%) in the clinical trial were thrombocytopenia*, diarrhea Treatment-emergent Grade 3 or 4 cytopenias were reported (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal in 35% of patients. pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), Five patients (10%) discontinued treatment due to adverse constipation (25%), rash (25%), abdominal pain (24%), vomiting reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas.

(23%), and decreased appetite (21%).

Adverse reactions leading to dose reduction occurred in 13% *Treatment-emergent decreases (all grades) of platelets (57%), of patients. neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS The most common Grade 3 or 4 non-hematological adverse CYP3A Inhibitors - Avoid concomitant administration with reactions (≥5%) were pneumonia (7%), abdominal pain (5%), strong or moderate inhibitors of CYP3A. If a moderate CYP3A atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin inhibitor must be used, reduce the IMBRUVICA™ dose. infections (5%). Treatment-emergent Grade 3 or 4 cytopenias CYP3A Inducers - Avoid co-administration with strong CYP3A were reported in 41% of patients. Ten patients (9%) discontinued inducers. treatment due to adverse reactions in the trial (N=111).

SPECIAL POPULATIONS - Hepatic Impairment - Avoid use in The most frequent adverse reaction leading to treatment patients with baseline hepatic impairment. discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICATM (ibrutinib) capsules

INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy.

Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 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].

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Gastrointestinal disorders

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

57

17

Neutrophils Decreased

47

29

Hemoglobin Decreased

41

9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48) All Grades Grade 3 or 4 System Organ Class Preferred Term (%) (%) 4 63 Gastrointestinal disorders Diarrhea 2 23 Constipation 2 21 Nausea 0 21 Stomatitis 2 19 Vomiting 0 15 Abdominal pain 0 13 Dyspepsia Infections and infestations Upper respiratory 2 48 tract infection 6 21 Sinusitis 6 17 Skin infection 8 10 Pneumonia 0 10 Urinary tract infection 4 31 General disorders and administrative Fatigue 2 25 site conditions Pyrexia 0 23 Peripheral edema 4 13 Asthenia 0 13 Chills 2 54 Skin and subcutaneous tissue disorders Bruising 0 27 Rash 0 17 Petechiae 0 19 Respiratory, thoracic and mediastinal Cough 0 15 disorders Oropharyngeal pain 0 10 Dyspnea 6 27 Musculoskeletal and connective tissue Musculoskeletal pain 0 23 disorders Arthralgia 2 19 Muscle spasms 0 21 Nervous system disorders Dizziness 2 19 Headache 0 10 Peripheral neuropathy Metabolism and nutrition disorders Decreased appetite 17 2 Neoplasms benign, malignant, Second 10* 0 unspecified malignancies* Injury, poisoning and procedural Laceration 10 2 complications Psychiatric disorders Anxiety 10 0 Insomnia 10 0 Vascular disorders Hypertension 17 8 *One patient death due to histiocytic sarcoma.

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) Percent of Patients (N=48) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

71

10

Neutrophils Decreased

54

27

Hemoglobin Decreased

44

0

* Based on laboratory measurements per IWCLL criteria and adverse reactions Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

IMBRUVICATM (ibrutinib) capsules Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 PRC-00339

EML4-ALK Fusion Testing and Crizotinib Are Not Cost-Effective in NSCLC

Studies with the tyrosine kinase inhibitor crizotinib (Xalkori) have shown significant improvement in clinical outcomes for the treatment of echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4ALK) fusion-positive non–small-cell lung cancer (NSCLC), but researchers recently questioned its cost-effectiveness. In the study, researchers evaluated the cost-effectiveness of EML4-ALK fusion testing and first-line therapy with crizotinib for patients with advanced ALK-fusion–positive NSCLC, from the perspective of the Canadian public healthcare system (Djalalov S, et al. J Clin Oncol.

2014;32:1012-1019).

Researchers used a Markov model to compare the cost-effectiveness of 2 treatment approaches for patients with stage IV nonsquamous NSCLC. The first approach consisted of molecular screening and targeted therapy with crizotinib.

The second approach consisted of standard of care, which included platinum doublet (cisplatin and gemcitabine) as first-line therapy, second-line pemetrexed (Alimta), and third-line erlotinib (Tarceva). The transition probabilities and mortality rates included in the model were calculated from the Ontario Cancer Registry and the Cancer Care Ontario New Drug Funding Program (CCO NDFP). The costs were obtained from the Ontario Case Costing Initiative, CCO NDFP, University Health Network, and from literature.

Overall, the results showed that targeted crizotinib therapy using EML4-ALK fusion testing resulted in 0.011 quality-adjusted life-years (QALYs), but cost $2725 (Canadian dollars) more per patient. Fusion testing accounted for $60 of those costs. Researchers then calculated an incremental cost-effectiveness ratio (ICER) of $255,970 per QALY gained compared with standard of care with no testing and no crizotinib treatment. Among EML4-ALK fusion-positive patients, first-line crizotinib resulted in 0.379 QALYs; cost an additional $95,043; and produced an ICER of $250,632 per QALY gained compared with standard of care.

The major driver of crizotinib’s cost-effectiveness was drug price.

For this strategy to be more economically feasible, the researchers concluded that lower drug costs, more targeted molecular therapy, or improved effectiveness would be required. They noted that the results are preliminary, because they are based on noncomparative data; therefore, future head-to-head clinical trials will provide better insight into the optimal treatment of advanced NSCLC, which accounts for 85% of all lung cancers. n

Issued: February 2014

MAY 2014

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Active ingredient made in China.

account for the majority of patients with advanced NSCLC. To determine the association between the first-generation EGFR TKI (erlotinib [Tarceva] and gefitinib [Iressa]) treatment versus chemotherapy and survival in patients with advanced NSCLC harboring wild-type EGFR, researchers conducted a systematic review and meta-analysis of randomized controlled trials (Lee JK, et al. JAMA. 2014;311:1430-1437).

Researchers identified 11 randomized controlled trials, with 1605 patients with wild-type EGFR (N = 811 in the TKI group, and N = 794 in the chemotherapy group). In all, 4 trials were performed in the first-line setting, 4 in second-line, and 3 in second-line or later settings. All 11 trials used TKIs in their standard dosing and schedule (erlotinib 150 mg daily, gefitinib 250 mg daily). The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate and overall survival (OS).

The pooled analysis showed that chemotherapy was associated with longer PFS compared with EGFR TKI in patients with wild-type tumors (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.1-1.81). For a median PFS of 6.4 months in patients treated with standard chemotherapy, the corresponding reduction in PFS with the EGFR TKI would be 1.9 months. In a subgroup analysis of 4 trials using more sensitive platforms, conventional chemotherapy demonstrated a longer PFS compared with TKI (HR, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy improvement in PFS was also significant in 6 second-line or later trials (HR, 1.34; 95% CI, 1.09-1.65). The higher objective response rate (including complete and partial responses) of chemotherapy also supported the longer PFS in patients with wild-type EGFR tumors compared with TKI (16.8% vs 7.2%, respectively). However, OS did not differ between the groups.

The apparent discrepancy between the PFS/objective response rate and OS can be explained by the large crossover rates of the included trials. Therefore, the findings suggest that in patients with wild-type EGFR tumors, conventional chemotherapy could be the preferred treatment option over EGFR TKI. The investigators cautioned that this recommendation cannot be conclusive, because overall comparisons were based on randomization. Toxicity outcomes were also not assessed.

B:14.25”

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions].

• Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists.

Chemotherapy Better Option for Patients... Continued from page 16

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USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients).

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

In the Literature

Health Policy

Up Next for the Center for Medicare and Medicaid Innovation: Cancer

By Ross D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPH

Mr Margulies is an Associate, Foley Hoag, LLP, and Mr Slotnik is a Partner, Health Policy Strategies, LLC

I

n passing the Affordable Care Act (ACA) in 2010, Congress had as one of its central goals the creation of new, innovative ways of paying for and delivering healthcare services.

With this goal in mind, the ACA established the Center for Medicare and Medicaid Innovation (CMMI), which is tasked with developing new payment and service delivery models to “demo” and, if successful, to eventually roll out nationwide. Since 2010, CMMI has focused the vast majority of its efforts on several high-profile demonstrations, including the Pioneer Accountable Care Organization program, and the several initiatives focused on improving care and savings costs for individuals enrolled in Medicare and Medicaid (the “dual-eligible”).

Until now, reforming the way we pay for and deliver cancer care has been on the back burner for CMMI. In late 2013, however, as part of CMMI’s interest in testing new models of care that will focus on specific diseases and patient populations in the outpatient setting (“Specialty Practitioner Payment Model”), CMMI announced a new partnership with the MITRE Corporation to assess specialty payment model opportunities, conduct model simulations, and to ultimately support the development of alternative payment models.

In cooperation with the Brookings Institution and the RAND Corpora-

at a glance ➤ CMMI will assess specialty payment models and promote the development of alternative payment models ➤ The target is to move from traditional FFS payment models to volume-based reimbursement, while aligning physician payments with high-quality care ➤ Medical home models are very likely to transition from FFS toward full bundled or sharedsavings approaches ➤ For oncologists, paying close attention to innovation in reimbursement structures and delivery models is critical

24

Ross D. Margulies

Jayson Slotnik

The panel’s overall goal is a transition from volume-based reimbursement to payment for episodes of care, with a focus on aligning physician payments with the delivery of highquality care....The panel considered a number of models that move away from the traditional fee-for-service payment model toward a more coordinated, high-quality cancer care regimen. tion, in late 2013, MITRE announced that oncology care was selected as the first specialty analysis in the demonstration because of the high disease burden and high healthcare costs associated with the disease state. In November, MITRE convened an oncology technical expert panel to review alternative payment reform models that are focused on increasing quality and lowering costs in the cancer care space. For the value-based cancer community, a review of the models under consideration by the panel is a rare and helpful insight into the future of cancer care.

The panel’s overall goal is a transition from volume-based reimbursement to payment for episodes of care, with a focus on aligning physician payments with the delivery of high-quality care.

With this broad framework in mind, the panel considered a number of models that move away from the traditional fee-for-service (FFS) payment model toward a more coordinated, high-quality cancer care regimen.

there was wide consensus that clinical pathways should only be viewed as a component of another model, because the model alone does not alter the existing FFS payments, and the model lacks a patient-centered focus and a potential for continued savings over time.

Alternative 1: Clinical Pathways The first model the panelists considered was the clinical pathways model, which uses an add-on case payment to encourage adherence to predefined, evidence-based chemotherapy regimens. Although there was little negative said of this model,

Alternative 3: Bundled Payments All of the panelists agreed that some type of bundled payment for oncology is likely in the future, but that a larger, global bundle in oncology would be very challenging to implement as a first step for the Centers for Medicare & Medicaid Services’ (CMS) payment

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Alternative 2: Patient-Centered Oncology Medical Home The medical home model, which supports changes in processes of care resulting in high-quality care delivery, was viewed by all of the panelists as a likely model to use to transition from the FFS approach toward full-bundled or shared-savings approaches. Members noted that many providers already incorporate elements of this model into their practice, and that although it has the potential to dramatically improve the patient experience, the potential for long-term cost-savings associated with a more bundled or episode-based approach is much less associated with the medical home model.

reform. Instead, the panelists recommended the use of narrowly defined bundles for only the most common cancers. The panelists were in general agreement that narrower bundles for common cancers, such as breast cancer and colon cancer, were more likely to succeed, because the diseases contain more discrete treatment regimens with more known costs. The panelists all agreed that there was an immediate need for additional testing of bundled payments in oncology to better build the existing knowledge database.

Alternative 4: Oncology Accountable Care Organizations One of CMMI’s major focuses, the number of primary care accountable care organizations (ACOs) has surged in recent years. However, improving care for patients with cancer as part of an ACO has proved more difficult because of its reliance on specialized providers and high expense. Few panelists believed that an oncology-specific ACO model would be a good model for CMS to pilot. Instead, panelists in-

For the broader oncology community, paying close attention to what is happening at the highest level of innovation is critical.

dicated interest in participating in accountable cancer care elements as part of a broader ACO framework.

For the broader oncology community, paying close attention to what is happening at the highest level of innovation is critical. The basic goal behind CMMI is to pilot programs through demonstrations and, if successful, roll them out on a much larger national basis.

Staying informed on what CMMI is thinking on oncology care ensures that the oncology community is apprised of what is coming down the pipeline and, most important, has a voice at the table. If you would like to submit comments, MITRE welcomes comments on the ongoing efforts at specialtypaymentreform@brook ings.edu. n

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New Guidelines Expand Pool of Patients Eligible for Sentinel Node Biopsy

See also Economics of Cancer Care, page 8

By Alice Goodman

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he American Society of Clinical Oncology (ASCO) has issued new guidelines for the use of sentinel node biopsy (SNB) in patients with early-stage breast cancer (Lyman GH, et al. J Clin Oncol. 2014;32:13651383. The newer version expands the use of SNB to a larger group of patients, based on evidence from 9 randomized trials and 13 cohort studies conducted since 2005, when the first SNB guidelines were published.

By expanding these guidelines, more women with early-stage breast cancer will be spared the more invasive procedure, axillary lymph node dissection (ALND), which is associated with increased morbidity.

“The updated guidelines broaden the indications for use of SNB for staging patients with early-stage breast cancer based on recent clinical trials and greater experience in a range of clinical settings. As in the previous guidelines, routine complete ALND is not recommended in patients with negative SNB,” Gary H. Lyman, MD, MPH, FASCO, Codirector, Hutchinson Institute for Cancer Outcomes Research, Seattle, WA, told Value-Based Cancer Care. “However…, it is now considered safe for most patients with only 102 positive lymph nodes on SNB to avoid complete lymph node biopsy if they will undergo breast-sparing surgery followed by locoregional radiation therapy,” he said. Dr Lyman was Cochair of the ASCO Expert Panel that updated the guideline.

ALND entails removal of most of the lymph nodes in the axilla on the same side as the breast tumor, and analyzing the nodes for cancer positivity. This procedure can cause long-term adverse events, including pain, numbness, and lymphedema, which is associated with

compromised quality of life.

SNB was hailed as a breakthrough when it was first introduced, because it promised to spare many women from having to undergo ALND. SNB involves removing a few lymph nodes and analyzing them for signs of cancer. If the SNBs are cancer-free, this usually means that the cancer has not spread to the other lymph nodes. SNB does have side effects, but these are fewer and less severe than those associated with ALND.

“It is now considered safe for most patients with only 102 positive lymph nodes on SNB to avoid complete lymph node biopsy if they will undergo breastsparing surgery followed by locoregional radiation.”

—Gary H. Lyman, MD, MPH, FASCO

The Updated Guidelines Based on 9 randomized controlled trials, the updated guidelines include

3 new recommendations: 1. Women without SNB metastases should not receive ALND 2. Most women with 1 or 2 metastatic SNBs planning to receive breast-conserving surgery and whole-breast irradiation should not undergo ALND 3. Women with SNB metastases who will be treated with mastectomy may be offered ALND. In addition, 2 groups of recommendations were updated based on cohort studies and/or informed consensus, stating that: • Women with operable breast cancer and multicentric tumors, and/or ductal carcinoma in situ (DCIS) who are planning to have mastectomy and/or had previous breast and axillary surgery, and/or had preoperative neoadjuvant systemic therapy, may be offered SNB • Women who have large or locally advanced invasive breast cancer (tumor size, T3/T4), and/or inflammatory breast cancer, and/or DCIS, when breast-conserving surgery is planned, and/or are pregnant, should not have SNB. Finally, the Expert Panel that updated the guidelines had insufficient evidence on chronologic age, body mass index and body surface area, and some other factors to change some of the previous recommendations.

Patient–Physician Communication As in all decision-making processes, appropriate communication between patient and clinician is a critical component for optimizing patient compliance and outcome, the Expert Panel noted. “We strongly encourage patients to talk with their surgeon and other members of their multidisciplinary team to understand their op-

tions and make sure everybody’s on the same page,” Dr Lyman said upon the release of the guidelines. “The most critical determinant of breast cancer prognosis is still the presence and extent of lymph node involvement and, therefore, the lymph nodes need to be evaluated so we can understand the extent of the disease.”

“The most critical determinant of breast cancer prognosis is still the presence and extent of lymph node involvement.”

—Gary H. Lyman, MD, MPH, FASCO

The discussions should consider the patient’s perspective, set realistic expectations by discussing potential benefits and harms of SNB, explain potential outcomes, and take the time to understand what quality of life means to each individual patient.

“Certainly, improving patient quality of life is an important reason for avoiding unnecessary full lymph node dissection. However, it is important to note that it is essential that patients discuss with their surgeon and oncologist whether they are appropriate candidates for SNB, and what the possible outcomes and subsequent management is likely to look like. It is impor­ tant to place the decision of local regional surgery in the context of the entire patient clinical setting and other therapies likely to be administered, including radiation, chemotherapy, and hormonal therapy,” Dr Lyman told Value-Based Cancer Care. n

Reports from ASCO MAY 30 - JUNE 3, 2014

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FOR YOUR ONCOLOGY PRACTICE NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer recommendations for abiraterone acetate (ZYTIGA®) plus prednisone1: Category 1* Asymptomatic pre-docetaxel mCRPC Symptomatic post-docetaxel mCRPC

FOR PATIENTS WITH mCRPC WHO HAVE PROGRESSED ON ADT† LOCAL‡

THERAPY

ADT

§

ZYTIGA PLUS PREDNISONE

®

For more information, please visit www.zytigahcp.com.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women.

ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress.

Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia,

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ZYTIGA Next ®

5.2 5 .

2 Months 5.2-month difference in median overall survival vs placebo plus prednisone (median OS: 35.3 months vs 30.1 months, respectively)

57% reduction in risk of radiographic progression or death vs placebo plus prednisone (median rPFS not reached vs 8.28 months, respectively)

Significantly increased median time to initiation of chemotherapy vs placebo plus prednisone (25.2 months vs 16.8 months, respectively)¶

Significantly increased median time to opiate use for prostate cancer pain vs placebo plus prednisone (not reached vs 23.7 months, respectively)¶

Hazard ratio (HR) = 0.792; 95% CI: 0.655, 0.956; P = 0.0151; prespecified value for statistical significance not reached.

HR = 0.425; 95% CI: 0.347, 0.522; P < 0.0001.

HR = 0.580; 95% CI: 0.487, 0.691; P < 0.0001.

HR = 0.686; 95% CI: 0.566, 0.833; P = 0.0001.

*Evidence and consensus level rating. †Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a Phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N = 1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH)

agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. ‡Local therapy = radiation and/or surgery. § For many patients with mCRPC, gonadotropin-releasing hormone (GnRH)agonist therapy typically continues throughout the disease course, and is used concomitantly with other mCRPC treatments, including ZYTIGA®. This illustration is not intended to suggest that ZYTIGA® is the only treatment option following androgen-deprivation therapy (ADT).

Primary endpoint. ¶ Secondary endpoint.

Reference: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.4.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed August 2, 2013. For the detailed recommendations, view the most recent and complete version of the Guideline on NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 003307-130924

hypercholesterolemia,hyperglycemia,elevatedAST,hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the coadministration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8.

Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 10/13 003686-131001

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency.

Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

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 clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot flush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) All Grades1 Grade 3-4 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

0

7.6

0

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

0

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal

discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema all fractures with the exception of pathological fracture terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

4 Includes 5 Includes 6 Includes

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) All Grades Grade 3-4 Laboratory Abnormality (%) (%) Hypertriglyceridemia 62.5 0.4 High AST 30.6 2.1 Hypokalemia 28.3 5.3 Hypophosphatemia 23.8 7.2 High ALT 11.1 1.4 High Total Bilirubin 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N = 542) Placebo (N = 540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo.

There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms.

There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA 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 ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, 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 ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves.

Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: September 2013 003185-130920

Breast Cancer

Benefits and Risks of Mammography Explored in New Analyses

By Rosemary Frei, MSc

A

ccording to a new systematic review of the risks and benefits of breast cancer screening, regular mammography is associated with a 19% reduction in breast cancer mortality, but it is also associated with a 61% cumulative risk of a false-positive result, and approximately 19% of the cases are, in fact, considered overdiagnoses (Pace LE, Keating NL. JAMA. 2014;311:1327-1335).

The Mammography Conundrum “We are hopeful that our review will help physicians and patients understand the limitations of mammography and really engage in shared decisions about when to start and how often to have mammograms,” Nancy L. Keating, MD, MPH, Associate Professor of Medicine and of Health Care Policy, Harvard Medical School, and Associate Physician, Brigham and Women’s Hospital, Boston, told ValueBased Cancer Care.

“It’s unfortunate that we don’t have

at a glance ➤ Regular mammography use is associated with a 19% reduction in breast cancer mortality in all age-groups, as well as a 61% cumulative risk for false-positive results ➤ However, approximately 19% of the cancers diagnosed are considered overdiagnoses, the most concerning potential harm of mammography screening ➤ The benefit-harm ratio of screening mammography may improve with raising the thresholds for recall and biopsy after mammography, reduced screening frequency, and using frequent screenings for high-risk women only ➤ Unlike the United States, where mammography is recommended starting at age 40 years, most other countries begin screening at age 50 years ➤ Although the harms from breast cancer treatment are greater in older women, it is unknown if mammography decreases the mortality risk in women aged ≥75 years

30

a better test to screen for breast cancer.

We need to acknowledge the limitations of mammography and the importance of individualizing these decisions,” said Dr Keating, who shares this view with her colleague, Lydia E. Pace, MD, MPH, Research Fellow in Medicine at Brigham and Women’s Hospital.

Lydia E. Pace, MD, MPH

“It’s unfortunate that we don’t have a better test to screen for breast cancer. We need to acknowledge the limitations of mammography and the importance of individualizing these decisions.”

—Nancy L. Keating, MD, MPH In an accompanying editorial, Joann G. Elmore, MD, MPH, University of Washington School of Medicine, Seattle, and Barnett S. Kramer, MD, MPH, Director, Division of Cancer Prevention, National Cancer Institute, noted that “the United States apparently is distinct in having so many groups actively encouraging annual screening starting at age 40 years. Most other countries recommend beginning screening later (eg, age 50) and at less frequent intervals (eg, every 2 to 3 years)” (JAMA. 2014;311:1298-1299).

Dr Elmore and Dr Kramer added that “raising the thresholds for recall and biopsy after mammography, reducing the frequency of screening examinations, and focusing on frequent screenings for only high-risk populations may improve the benefit-harm ratio of screening mammography.”

Screening in Older Women A review article by Louise C. Wal-

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ter, MD, Chief of Geriatrics, University of California, San Francisco, and Mara A. Schonberg, MD, MPH, Harvard Medical School, Boston (JAMA. 2014;311:1336-1347), focused on the literature related to women aged ≥75 years, who have largely been excluded from randomized controlled trials of screening mammography.

The authors noted that retrospective cohort and case-controlled studies indicate that routine mammography lowers breast cancer mortality in older women. In women aged >80 years, the sensitivity of mammography is 86% and the specificity is 94% compared with 73% and 92%, respectively, in women aged 50 years.

However, just as in younger women, there are significant harms from mammography for older women; in fact, the harms from breast cancer treatment are greater in older women and those with limited life expectancy, according to data cited by Dr Walter and Dr Schonberg. They cited a 2004 study that showed that 97.5% of women in the United States diagnosed with ductal carcinoma in situ undergo surgery.

Dr Walter and Dr Schonberg suggest that physicians explain to older women that “it is not known if mammography decreases the risk of dying from breast cancer in women aged 75 years and older and a choice should be made whether to continue screening.

Clinicians should explain this choice in the context of potential benefits and harms related to screening.”

Risk Reduction, Overdiagnosis Dr Keating and Dr Pace noted that based on a 2011 and a 2013 meta-analysis, the risk ratio for breast cancer mortality reduction with mammography screening in all age-groups is 0.81. This is equal to a 19% mortality

reduction. Furthermore, they cited other studies showing a 61.3% 10-year cumulative risk of having at least 1 false-positive result for women undergoing annual mammograms starting at age 40 or 50 years, and a 49.7% false-positive risk for women starting annual mammography at age 66 to 74 years.

And a 2013 meta-analysis of 3 randomized trials—which did not offer screening to the control group— showed that 19% of cancers diagnosed during the screening period were overdiagnoses that comprised ductal carcinoma in situ and some invasive

“It is not known if mammography decreases the risk of dying from breast cancer in women aged 75 years and older.”

—Louise C. Walter, MD, and Mara A. Schonberg, MD, MPH

cancer diagnoses. Both types are now considered overdiagnoses, according to Dr Keating and Dr Pace, because their treatment would cause more harm to the patient, without any benefit, because “the tumor would not have caused problems if undetected,” they wrote. “Many authors now describe overdiagnosis as the most concerning potential harm of mammography screening,” they added.

They underlined the need to discuss the “risks, benefits, uncertainties, alternatives, and patient preferences” when discussing mammography intervals with patients.

“It’s important to consider a woman’s risk of breast cancer, because women at higher risk will have greater benefit from mammography,” Dr Keating told Value-Based Cancer Care.

She and Dr Pace believe that decision aids show great promise, noting that a study among American women aged ≥75 years showed that those who received a decision aid knew more about the benefits and risks of screening than women who had not received such an aid. These women also are less likely to have a mammogram in the next 2 years. Dr Keating and Dr Pace expect decision aids to become more widely available in the future. n

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Society of Gynecologic Oncology

Preventive Oophorectomy May Not Eliminate Risk for BRCA1-Related Uterine Cancer

By Charles Bankhead

Tampa, FL—Prophylactic salpingooophorectomy did not eliminate the risk for a rare but aggressive form of uterine cancer in women with BRCA1 mutations, according to a study reported at the 2014 Society of Gynecologic Oncology meeting.

Of 296 women who underwent the risk-reducing surgery, 4 subsequently developed high-risk uterine cancer.

That number translates into an incidence rate 26 times higher than would have been expected in the general population.

The uterine cancer risk was limited to patients with BRCA1 mutations and did not involve women with BRCA2 mutations.

“While the absolute risk is still relatively low, it is much higher than we would have expected for these aggressive uterine cancers,” said Noah D. Kauff, MD, Director, Ovarian Cancer Screening and Prevention, Memorial Sloan Kettering Cancer Center, New York.

“Doctors should let their patients with BRCA1 mutations know that this report suggests they may be at risk for rare types of aggressive uterine cancer.

However, whether or not a woman decides to have a hysterectomy at the time of risk-reducing salpingo-oophorectomy may depend on her age, prior cancer history and other risk factors.”

Prophylactic oophorectomy has be-

“Doctors should let their patients with BRCA1 mutations know that this report suggests they may be at risk for rare types of aggressive uterine cancer.

However, whether or not a woman decides to have a hysterectomy at the time of risk-reducing salpingooophorectomy may depend on her age, prior cancer history and other risk factors.”

—Noah D. Kauff, MD

come standard practice for women with BRCA mutations. The need for concomitant hysterectomy has remained controversial because of uncertainty about uterine cancer’s involvement in the BRCA-associated tumor spectrum, said Catherine A. Shu, MD, Gynecologic Oncology Fellow, Memorial Sloan Kettering Cancer Center, who reported the findings.

To examine uterine cancer risk in BRCA mutation carriers, Dr Shu and colleagues searched medical records of women who underwent BRCA testing from mid-1995 through the end of 2011 and subsequently underwent prophylactic oophorectomy. The researchers identified 525 patients with BRCA mutations, including 296 with BRCA1 and 229 with BRCA2.

After a median follow-up of almost 6 years, 4 patients were diagnosed with uterine cancer. Dr Shu said that 2.23 uterine cancers would have been expected.

All 4 uterine cancers occurred in patients with BRCA1 mutations, and all 4 cancers were high-risk—2 cases of serous cancer, and 1 each of carcinosarcoma and leiomyosarcoma. By contrast, less than 1 high-risk case (0.28) would have been predicted (P <.001).

An analysis of the results by tamoxifen use showed that 2 high-risk cases each occurred in tamoxifen users (0.092 expected; P = .004) and in

women without a history of tamoxifen exposure (0.184; P = .015).

The National Comprehensive Cancer Network guidelines recommend prophylactic salpingo-oophorectomy for BRCA1 mutation carriers to reduce the risk for ovarian cancer and breast cancer. The recommendation does not include hysterectomy, which involves

“It also was believed that uterine cancers that do develop following risk-reducing salpingooophorectomy were likely to be low risk. The new study suggests that may not be the case.”

—Catherine A. Shu, MD, and colleagues

increased risks for bleeding, infection, and possibly long-term problems with bladder, bowel, or sexual function.

“It also was believed that uterine cancers that do develop following riskreducing salpingo-oophorectomy were likely to be low risk. The new study suggests that may not be the case,” Dr Shu and colleagues concluded. n

Large Study Supports Regionalization of Gynecologic Cancer Care

By Charles Bankhead

Tampa, FL—Women with gynecologic cancers had significantly better survival when treated at high-volume centers, according to a review of 863,000 cases reported at the 2014 Society of Gynecologic Oncology meeting.

Patients treated at the highest-volume centers had a median survival of more than 1 year longer than that of patients treated at centers with the lowest annual procedural volume (122.7 vs 110.0 months, respectively).

An analysis of individual types of gynecologic cancers yielded significantly better survival at high-volume centers for all but uterine cancer.

“Regionalization of care is already

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ongoing,” Jeff F. Lin, MD, Gynecologic Oncology Fellow, Magee-Womens Hospital of the University of Pittsburgh Medical Center, PA, and colleagues, concluded in a poster presentation. “Treatment at high-volume centers is associated with improved outcomes even when controlled for age, stage, and comorbidities,” noted Dr Lin and colleagues.

“These data support regionalization of gynecologic cancer care and identify patients who may benefit from transfer to high-volume centers.”

The findings add to existing evidence supporting favorable associations between procedural volume and

clinical outcomes. The associations have added implications in light of policy discussions about potential regionalization of healthcare services at specialized centers.

Dr Lin and colleagues sought to determine the characteristics and outcomes of centers that provide care for high volumes of patients with gynecologic cancers. The investigators queried the National Cancer Data Base to identify patients treated for cervical, uterine, ovarian, vaginal, and vulvar cancer from 1998 through 2011. Case volumes were calculated for centers, which were divided into quartiles according to volume.

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The principal outcome of interest was estimated overall survival (OS).

Univariate and multivariate analyses were performed to identify charac­ teristics associated with procedural volume.

A Large Sample The analysis comprised 863,156 patients and 1666 centers. Uterine cancer accounted for 427,473 cases, followed by ovarian cancer (215,877), cervical cancer (142,518), vulvar cancer (63,641), and vaginal cancer (13,647).

Dr Lin reported that 64 centers accounted for the highest-volume quartile, followed by 120 in the second

Continued on page 32

www.ValueBasedCancerCare.com

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Pancreatic Cancer

Emerging Targeted Therapies for Advanced Pancreatic Cancer Show Promise

By Wayne Kuznar

San Francisco, CA—New cytotoxic combinations introduced over the past several years for the treatment of advanced pancreatic adenocarcinoma now constitute the standard of care for the treatment of all stages of the disease. Eileen M. O’Reilly, MD, Gastrointestinal Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, reviewed emerging treatments at the 2014 Gastrointestinal Cancers Symposium.

“There are new opportunities for building on these cytotoxic combinations by the addition of molecularly targeted agents, and there is renewed interest in evaluating a range of immunotherapeutic approaches in pancreas adenocarcinoma,” Dr O’Reilly said.

In 2010, the FOLFIRINOX (leucovorin/fluorouracil/irinotecan/oxaliplatin) regimen was established as a standard treatment option for patients with metastatic pancreatic adenocarcinoma in a randomized phase 3 trial, said Dr O’Reilly.

However, enthusiasm for the FOL­ FIRINOX regimen has been tempered by the increased gastrointestinal (vomiting, diarrhea), neurologic (peripheral

neuropathy), hematologic (thrombocytopenia, febrile neutropenia), and constitutional adverse events compared with gemcitabine, Dr O’Reilly said, in addition to the need for growth factor support.

“There are new opportunities for building on these cytotoxic combinations by the addition of molecularly targeted agents, and there is renewed interest in evaluating a range of immunotherapeutic approaches in pancreas adenocarcinoma.”

—Eileen M. O’Reilly, MD

The regimen of nab-paclitaxel plus gemcitabine recently received approval from the US Food and Drug Administration for the first-line management of metastatic pancreatic adenocarcino-

ma based on findings from a randomized phase 3 trial comparing it with single-agent gemcitabine. The nabpac­litaxel plus gemcitabine combination demonstrated an improved overall survival (OS; 8.5 vs 6.7 months, respectively; P = .015), progression-free survival (5.5 vs 3.7 months, respectively; P = .024), and tumor response (23% vs 7%, respectively). It was also superior on the end point of OS in patients with poor-risk features (ie, Karnofsky performance status of 70-80). This combination, therefore, may be suitable for a broader number of patients than FOLFIRINOX, noted Dr O’Reilly.

New Therapies, Immunotherapies Multiple targeted-type approaches are being evaluated in pancreatic adenocarcinoma, said Dr O’Reilly. Interfering with hyaluronan in the stroma with the use of pegylated recombinant human hyaluronidase PH20 (PEGPH20) as a stromal degradation agent that facilitates drug delivery is showing promise. PEGPH20 may augment the effects of cytotoxic agents, and has led to late-phase trials of its use in combination with nab-

paclitaxel plus gemcitabine or with FOLFIRINOX. The poly(ADP-ribose) polymerase (PARP) inhibitor veliparib may have benefit in patients with pancreatic adenocarcinoma and BRCA/PALB2 mutation. Early-phase trials have been completed to establish a dosing strategy; veliparib is now being evaluated in a phase 2 study in combination with cisplatin and gemcitabine.

Janus kinase (JAK) inhibition is another potential avenue. Ruxolitinib, a JAK1 and JAK2 inhibitor, combined with capecitabine improved 6-month survival compared with capecitabine and placebo in patients with previously treated pancreatic adenocarcinoma.

Immunotherapeutic approaches include: • Combining a Listeria-based vaccine, CRS-207, with a GVAX vaccine, which improved OS in a randomized phase 2 trial • Anti-CD40–targeted agents • Anti–PD-1, anti–PD-L1, and antiCTL4–targeted agents • Adoptive transfer of chimeric-antigen receptor approaches against mesothelin. n

Society of Gynecologic Oncology

Large Study Supports Regionalization of... quartile, 235 in the third, and 1247 centers in the lowest-volume quartile.

Results Overall, patients treated at the lowest-volume centers had a 10% greater mortality risk compared with patients treated at the highest-volume centers (odds ratio [OR], 1.10; P <.005). Centers in the second and third quartiles also had a higher mortality risk compared with the centers that cared for the most gynecologic oncology patients (OR, 1.02, P = .039; OR, 1.3, P = .009).

In absolute terms, the difference in median OS between the highest and lowest quartiles ranged from 2.3 months for vulvar cancer (136.4 vs 134.1 months) to 34.1 months for vaginal cancer (72.2 vs 38.1 months).

Median OS for patients with cervical cancer was 117.8 months for the highest-volume centers, followed by 114.1, 111.5, and 102.4 months for quartiles 2

32

through 4 (P <.005).

Patients with ovarian cancer had a median OS of 49.4 months at centers in the top quartile, decreasing to 45.4, 42.7, and 32.5 months as centers’ volume decreased (P <.005).

Survival for patients with uterine cancer varied the least, ranging from 159.7 months in the first quartile to 157.9, 156.0, and 156.2 months in the other quartiles.

For vaginal cancer, the median survival values were 72.2, 69.8, 60.7, and 38.1 months (P <.005). Median survival in patients with vulvar cancer was 136.4 months in the first quartile, 125.6 months in the second, 130.4 months in the third, and 134.1 months in the fourth (P <.005).

Analysis of factors associated with high volume showed that centers in the top quartile were more likely to be academic or research centers. No community oncology program reached the

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Continued from page 31

top 2 volume-based quartiles. Higher volume was also associated with pa-

“Treatment at high-volume centers is associated with improved outcomes....These data support regionalization of gynecologic cancer care and identify patients who may benefit from transfer to high-volume centers.”

—Jeff F. Lin, MD, and colleagues

tient residence in metropolitan areas, location in the South, and location more than 30 miles from patients.

Patients at the lowest-volume centers were older, lived in higher-income

at a glance ➤ Patients treated at the highest-volume centers had a median survival of >1 year longer than patients treated at centers with the lowest volume ➤ High-volume centers in the top quartile were more likely to be academic or research centers ➤ No community oncology program reached the top 2 volume-based quartiles ➤ Patients at the lowest-volume centers were older, lived in higher-income areas, and were more likely to have advanced disease areas, and were more likely to have advanced disease. n

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Survivorship

Survivorship Care Plan Use Lagging

By Rosemary Frei, MSc

C

ancer centers are ramping up their efforts to create survivorship care plans (SCPs) for all of their patients. However, according to a new survey conducted in 2013, they still have far to go before January 1, 2015, when the American College of Surgeons Commission on Cancer (CoC) accreditation requirement of creating SCPs for all patients comes into effect (Birken SA, et al. J Cancer Educ.

2014 April 6. Epub ahead of print).

Of the 81 cancer centers that responded to the survey, approximately 51% indicated that they were not yet using SCPs but that they plan to use them. In addition, approximately 58% indicated that only 0% to 25% of their providers use SCPs, and approximately 47% noted that providers develop SCPs for 0% to 25% of the cancer survivors. The most common reason cited for implementing or using SCPs was the desire to comply with the CoC requirements.

“The question is, why develop a survivorship care plan if you don’t deliver it?” queried lead investigator Sarah A. Birken, PhD, MSPH, a postdoctoral fellow, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. She noted several ways to interpret the survey results, “one is that because

the CoC won’t audit survivors and PCPs [primary care providers], as long as the SCP is in the record, that is enough to meet the requirement. Another possibility is that cancer centers were just beginning to get ready for

“The question is, why develop a survivorship care plan if you don’t deliver it?”

—Sarah A. Birken, PhD, MSPH the January 2015 deadline when we conducted the survey, and if we repeated it now, we may find cancer programs are phasing in implementation, and many more are developing SCPs and delivering them to survivors and their providers.”

Approximately 45% of responders said that their centers were already using SCPs; however, 30% of them reported only an occasional use of the program and only 15% reported regular use of these plans. Membership in the National Cancer Institute’s Com-

Table Implementation of Survivorship Care Plan in Cancer Centers Sample questions Responses Frequency, % Which option best describes SCP use in your cancer program?

SCPs are not used, but we are planning to use them

51.25

What percentage of providers in your cancer program has used SCPs?

0%-25%

58.33

SCPs are developed for what percentage of all survivors in your center?

0%-25% 26%-50%

47.22 22.22

What percentage of SCPs are delivered to survivors in your center?

0%-25% 76%-100%

45.71 22.86

What percentage of SCPs are delivered to survivors’ primary care providers?

0%-25% 76%-100%

52.78 19.44

For which tumor groups are SCPs used/will be used?

Breast Colorectal Prostate

81.58 55.26 38.16

SCP indicates survivorship care plan.

Adapted from Birken SA, et al. J Cancer Educ. 2014 April 6. Epub ahead of print. munity Cancer Centers Program was associated with SCP use: members receive support to develop SCPs. Centers in academic programs also were more likely to use SCPs. Other significant results are shown in the Table.

“Taken together, our results suggest that support specifically intended to facilitate SCP use may promote SCP use more effectively than the nonspecific resources (eg, time, staff, training, money) that are commonly cited as

determinants of SCP use,” concluded the investigators.

The team also conducted a subanalysis that confirmed the inconsistent use of SCPs across American cancer programs.

Dr Birken recently interviewed clinicians to determine what specific factors motivate them to use SCPs. She and her colleagues hope to use the results to develop programs to more effectively promote the use of SCPs. n

Updated NCCN Survivorship Guidelines

By Wayne Kuznar

Hollywood, FL—Cancer survivorship guidelines have been expanded to include the management of neuropathic pain and cancer-associated cognitive dysfunction, said speakers at the 2014 National Comprehensive Cancer Network (NCCN) meeting.

Between 20% and 40% of patients with cancer have neuropathic pain, said Susan G. Urba, MD, Professor of Medical Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, and it “is one of the most common reasons that cancer patients stop their treatment early.”

The NCCN guidelines call for universal screening for pain in all patients with cancer, and if pain is present, a comprehensive pain assessment to identify the etiology and to determine patient goals for comfort and function.

Neuropathic Pain For cancer-related neuropathic pain,

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antidepressants and anticonvulsants, such as gabapentin (Neurontin) and pregabalin (Lyrica), are first-line adjuvant analgesics. These can be used alone or in conjunction with opioids, said Dr Urba.

“Analgesic effectiveness is not dependent on antidepressant activity,” said Dr Urba, and, therefore, the analgesic dose [of antidepressants] may be lower than that used for the treatment of depression. Start with a low dose, she advised, and increase the dosage every 3 to 5 days if tolerated.

Duloxetine (Cymbalta) was tested specifically in patients with chemotherapy-induced neuropathy, and was found to significantly decrease the level of pain interference with daily function and to improve quality of life compared with placebo. Venlafaxine (Effexor) was also significantly superior to placebo on the outcomes of complete relief of neuropathy and a

>50% relief of neuropathy in patients with oxaliplatin (Eloxatin)-induced neuropathy.

Topical agents, which work best when combined with an opioid, antidepressant, or anticonvulsant, are now included in the NCCN guidelines.

Neuropathic pain “is one of the most common reasons that cancer patients stop their treatment early.”

—Susan G. Urba, MD

Cognitive Impairment Cancer-associated cognitive change is now being recognized in NCCN survivorship guidelines, which address the management of patients who do

MAY 2014

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not receive central nervous system (CNS)-directed treatments, but who may be experiencing cognitive change.

“For a subset of patients, cancer and cancer treatment disrupt ‘normal’ cognitive functions,” said Elizabeth A. Kvale, MD, Director, Supportive Care and Survivorship Outpatient Clinic, University of Alabama at Birmingham Comprehensive Cancer Center. The effect precedes cancer treatment in some patients: as many as 30% of patients experience cognitive impairment before adjuvant therapy.

“Chemobrain” has been the common vernacular for cancer-associated cognitive impairment, but this label ignores the many contributors to cognitive changes, said Dr Kvale. The mechanisms thought to contribute to cancer-associated cognitive dysfunction include direct toxicity of chemotherapy to neurons, microvascular damage that contributes to white matContinued on page 39

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Prostate Cancer

Advances in the Treatment of Patients with Castration-Resistant Prostate Cancer Use disease state as the guide

By Wayne Kuznar Hollywood, FL—The treatment options for patients with castration-resistant prostate cancer (CRPC) have increased over the past few years.

Understanding the clinical disease states is essential when choosing therapy for this patient population, according to Celestia S. Higano, MD, Professor of Medicine and Urology, University of Washington, Seattle, who described the recent additions to the therapeutic armamentarium at the 2014 National Comprehensive Cancer Network Conference.

In terms of treatment, patients with CRPC can be divided into 2 groups— those with metastatic disease and those without metastatic disease. Dr Higano focused on the current therapeutic options for patients with metastatic CRPC, which can be further categorized into asymptomatic or symptomatic disease and pre- or postchemotherapy.

Immunotherapy Sipuleucel-T (Provenge) is the only immunotherapy agent approved by the US Food and Drug Administration for the treatment of patients with metastatic CRPC and is indicated for use in asymptomatic or minimally symptomatic patients. Its approval was based on a significant survival advantage compared with placebo in the phase 3 trial known as IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment), said Dr Higano.

The median survival benefit with sipuleucel-T in IMPACT was 4.1 months, similar to the benefit achieved in 2 smaller phase 3 trials conducted in identical patient populations using the same trial design. “It’s consistent across all 3 trials,” Dr Higano said. “I do believe the data.”

In IMPACT, the placebo and sipuleucel-T survival curves overlapped for the first 6 months, which is likely because “immunotherapy does not kick in right away like we see with chemotherapy or even hormonal therapy,” Dr Higano said. “It takes time to actually make a difference.”

Prostate-specific antigen (PSA) levels do not decline with the use of sipuleucel-T, and it has no effect on progression-free survival (PFS), even though all 3 trials demonstrated significant survival benefit, she said. Sipuleucel-T is very well tolerated, with mild toxicities.

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The current challenge is to determine when to prescribe sipuleucel-T. “My own belief is that it should happen early in the course of metastatic

“Immunotherapy does not kick in right away like we see with chemotherapy or even hormonal therapy. It takes time to actually make a difference. My own belief is that [prescribing it] should happen early in the course of metastatic castration resistance.”

—Celestia S. Higano, MD

castration resistance,” Dr Higano said. Ideally, it should occur before the initiation of several second-line hormonal manipulations, before corticosteroid use, with chemotherapy

and/or with abiraterone, at a time when the immune system is more robust and patients are less likely to have symptoms, rapid progression, or liver metastases.

When prescribing sipuleucel-T, educate patients and their families not to expect a decline in PSA, and the lack of ability to predict benefit in individual patients, Dr Higano said. Patients should be evaluated monthly for symptomatic progression. Imaging should be obtained at baseline and again at 3 months to monitor disease.

Hormonal Therapy The 2 newest hormonal options are abiraterone (Zytiga) or enzalutamide (Xtandi). Abiraterone is an oral CYP17 inhibitor that is recommended to be taken on an empty stomach in combination with prednisone. Enzalutamide is an oral pure antiandrogen that does not require prednisone.

It is contra­indicated in patients with a history of seizures or those who take drugs that lower the threshold for seizures. Both hormonal agents result in a decline in PSA levels.

In the pre- and postdocetaxel setting, abiraterone and enzalutamide show improvements in median overall survival compared with placebo, and a delay in radiographic PFS, said Dr Higano.

Radium-223 Radium Ra 223 dichloride (Radium-223; Xofigo) is an alpha particle– emitting radioisotope that is indicated for patients with prostate cancer who

have symptoms in the postdocetaxel setting (or who are unfit for docetaxel), a population that derived significant survival benefit and a delay to a first skeletal event with radium-223 in the ALSYMPCA phase 3 study.

Dosing in ALSYMPCA was monthly for 6 months. Radium-223 is also a calcium mimetic that targets new bone growth in and around metastases; thus, skeletal-related events may become a new end point in future trials of this agent, Dr Higano said.

Although radium-223 must be administered by a specialist in nuclear medicine, there are no restrictions on patient contact with other people.

Chemotherapy Docetaxel (Doxil) and cabazitaxel (Jevtana) are the only chemotherapy options to demonstrate a survival benefit in the setting of metastatic CRPC, according to Dr Higano. Docetaxel is a first-line chemotherapy option for patients who are symptomatic or who have rapidly progressing disease.

Cabazitaxel is a semisynthetic taxoid derivative. It has poor affinity for P-glycoprotein and therefore may be active in docetaxel-refractory disease.

Cabazitaxel is approved for use with prednisone, and is indicated for patients with metastatic CRPC previously treated with docetaxel.

Dr Higano offered practical advice for the use of cabazitaxel: reduce the initial dose to 20 mg/m2, use growth factor in all patients, and appreciate that a lack of pain progression does not mean a lack of clinical benefit. n

Contrast-Enhanced Ultrasound a Promising, Inexpensive Diagnostic Tool for Prostate Cancer

By Rosemary Frei, MSc

Stockholm, Sweden—An inexpensive, noninvasive imaging modality is proving successful for verifying the presence of prostate cancer.

Preliminary results on 24 men, presented at the 2014 European Association of Urology Congress, showed that the method—called contrast-ultrasound dispersion imaging

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(CUDI)—has a 77.9% sensitivity and a 82.4% specificity. The technique could significantly reduce the need for invasive, painful, and costly biopsies if confirmed in larger studies.

CUDI involves giving a boost to normal ultrasound with a 2.4-mL injection of contrast medium containing microbubbles (SonoVue; Bracco,

Milan); these highlight the significant concentration of blood vessels around tumors. The only extra costs, besides that for standard ultrasonography, are approximately $60 (US dollars) for the microbubble solution, plus the cost of the software to decipher the resulting images once it is on the market.

Based on this successful pilot trial Continued on page 36

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COMING SOON A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to discuss the most recent available data concerning improvements in cost of care, safety profiles, and patient preferences as they pertain to the use of emerging agents used in the treatment of patients with MM. IN MULTIPLE MYELOMA

Value-BasedCare

™

November 2013 u 8th IN A SERIES

Cost-Effective Use of Imaging Modalities for Diagnosis and Monitoring in Multiple Myeloma

Topics include: • Effective Treatment of Newly

Diagnosed and Relapsed/ Refractory Patients with MM: Utilizing Optimal Dosing Regimens • Appropriate Duration of Therapy

for MM in a Value-Based Care Plan • Improving the Standard of Care

in MM: Interpreting Overall Survival Data and Assessing the Cost of a Complete Response • Establishing a Value-Based

Paradigm for the Management of Patients with MM: A Pharmacoeconomic Analysis of Treatment Options

Introduction Identification, characterization, and management of osteolytic bone lesions are key aspects of care in multiple myeloma (MM).1 A comprehensive, chart-based study from the Mayo Clinic, published in 2003, revealed that 84% of patients with myeloma developed skeletal lesions at some time during the course of their disease.2 Based on conventional radiography at the time of diagnosis, 79% of patients presented with at least one type of skeletal abnormality (Figure 1).2 In the decade since the publication of this influential study, these high estimates of skeletal-related events have held constant.1 What has changed, however, are the options available to clinicians for imaging the skeleton. Although radiographic skeletal survey remains the fundamental imaging study at both the initial workup and follow-up of the patient with MM, additional newer technologies can be utilized. These include magnetic resonance imaging (MRI), computed tomography (CT) scan, and positron emission tomography (PET) scan, which may be combined with CT scan (PET-CT). Bone densitometry is another imaging technology with application in the disease.3 These technologies may provide helpful diagnostic and follow-up information on the patient, but despite evidence-based guidelines on imaging in MM, there is currently no standard for their appropriate clinical use.3-7 Individual providers, institutions, and payers are tasked with the decision to deploy or to forego MRI, CT, and PET on a case-by-case basis. The choice to utilize these sophisticated imaging methods ultimately affects the value of myeloma care: overuse or inappropriate use of such technologies results in unnecessary utilization costs; failure to use the technologies when prudent may result in a lower quality of care.

This article will explore the current clinical evidence base for the use of various imaging methods in MM. It will also present expert consensus on the approach to imaging in selected patients.

These data and opinions are useful in making rational decisions to employ and to reimburse imaging in the patient with myeloma.

The most recent of the guidelines, from the National Comprehensive Cancer Network (NCCN), recommends radiographic skeletal survey for all patients at initial workup and for the follow-up of every patient annually or when symptoms are present.3 The NCCN makes provisional recommendations for MRI, CT, and PET scans, which are described as “useful under some circumstances” in initial workup and may be used “as clinically indicated” for follow-up surveillance.3 When is additional testing “useful” and “indicated”? Different organizations and experts have given various answers to this question. According to the NCCN, PET-CT scanning and MRI scans provide greater sensitivity than did conventional radiography.3 Therefore, during an initial workup in a patient who presents with bone pain, weakness, or other symptoms in

OVERVIEW The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to provide readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care.

Each supplement will discuss a specific topic to be considered when developing value-based strategies. In this final newsletter, we discuss strategies for ensuring value-based care as it is related to the use of imaging modalities in myeloma.

STAKEHOLDER’S PERSPECTIVE Assessing the Optimal Use of Imaging Modalities in Patients with Myeloma ...........................5

Imaging Options in MM: Evidence-Based Guidelines and Expert Consensus Since 2007, 5 different sets of clinical practice guidelines have been issued on the use of imaging technologies in MM (Table).3-7 These guidelines provide a good starting point for individual providers, institutions, and payers seeking to evaluate these modalities.

This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

AVBCC100-8.indd 1

James R. Berenson, MD Institute for Myeloma & Bone Cancer Research West Hollywood, CA

An official publication of

11/15/13 9:58 AM

VIEW THE SERIES ONLINE AT:

www.ValueBasedCancer.com/myeloma VBCMM_AVBCC127cs_Ksize13114

Lung Cancer

Treatment Paradigm for Lung Cancer Shifting Toward Targeted Therapies, Immunotherapy Driver mutations guide drug development for NSCLCs

By Wayne Kuznar Hollywood, FL—Driver mutations, most frequently KRAS and EGFR, account for approximately 50% of non– small-cell lung cancer (NSCLC), and this recognition is shifting the NSCLC treatment paradigm toward targeted therapy when possible, said Leora Horn, MD, MSc, Assistant Professor of Medicine, Division of Hematology/ Oncology, Vanderbilt University, Nashville, TN, at the 2014 National Comprehensive Cancer Network Conference.

In the future, immunotherapy may play a significant role in the NSCLC treatment armamentarium.

Chemotherapy hit a plateau in the treatment of metastatic NSCLC, with little difference in survival between the most frequently used regimens.

Platinum-based doublet therapy as first-line therapy is associated with overall survival (OS) of approximately 1 year in NSCLC, said Dr Horn. “There is still the option of delaying and careful observation of patients’ use of erlotinib, docetaxel, pemetrexed, or gemcitabine at the time of progression,” Dr Horn said.

Targeted Therapy Leading the Way “What’s driving lung cancer these days and what’s happening, which is really exciting, is defining these multiple molecular subsets of NSCLC patients,” Dr Horn said. “About 55% of patients with lung cancer will have a driver mutation that we’re able to

identify. That’s not necessarily a driver mutation for which we have a targeted therapy at this time.”

The most common molecular subtype is a KRAS mutation, observed in 15% to 25% of patients with NSCLC, followed by an EGFR mutation in 10% to 35%.

First-line treatment of patients with NSCLC and EGFR mutations with a tyrosine kinase inhibitor (TKI), such as gefitinib, erlotinib, or afatinib, outperformed chemotherapy on median progression-free survival, Dr Horn said.

“What they’ve also shown us is that there is no significant difference in overall survival, and that’s because in the majority of these trials, 80% of patients or more were crossing over to a TKI at the time of progression on chemotherapy,” she said.

A common mechanism of acquired resistance to an EGFR-related TKI therapy is a second-site mutation, most often the T790M mutation, which is seen in approximately 50% of patients.

Disease progression, or rapid acceleration of disease resulting in hospitalization or death, occurs in approximately 20% of patients who discontinue TKI therapy. Patients with disease progression who resume their TKI therapy “can once again get control of these tumors, because we know that they are oncogene addicted,” Dr Horn said. Another treatment regimen that can control disease progression in pa-

Contrast-Enhanced Ultrasound... at 3 hospitals, the researchers have patented the technique and are expanding their research network.

“More and more hospitals are asking to join our studies. Therefore, in 2015, I expect at least 5 Dutch hospitals will be involved. We should be able to take targeted biopsies by CUDI in large trials in 2016,” said lead investigator Massimo Mischi, PhD, MSc, Head, Biomedical Diagnostics Research Lab, Eindhoven University of Technology, the Netherlands. “The US is somewhat behind Europe in contrast enhanced ultrasound imaging due to FDA restrictions,” he said.

Dr Mischi noted that this is about to change, thanks to the involvement of the International Contrast Ultrasound Society “in promoting research on

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tients with acquired resistance to a TKI is the combination of afatinib and cetuximab, she said.

Encouraging data in acquired drug resistance have been obtained with the third-generation TKI, AZD9291. Of the first 35 evaluable patients in a clinical trial, 15 patients have had a partial response, including 9 of 18 with the T790M mutation.

“About 55% of patients with lung cancer will have a driver mutation that we’re able to identify.”

—Leora Horn, MD, MSc

CO-1686 is another agent being explored for the treatment of patients with the T790M mutation and acquired resistance to TKIs in clinical trials in the United States; the response rate was 67% in 9 evaluable patients.

In patients with anaplastic lymphoma kinase (ALK)-positive NSCLC, single-agent crizotinib more than doubled the median PFS compared with chemotherapy.

In patients with ALK-positive NSCLC with acquired resistance to crizotinib, as well as in crizotinib-naïve patients, the second-generation ALK inhibitor LDK378 has produced im-

—Massimo Mischi, PhD, MSc

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Immunotherapy in Development Programmed death (PD)-1 and PD-L1 antibodies are being looked at as targets in lung cancer. “There appears to be a reaction between PD-1 and its ligands that promote an immunosuppressive tumor microenvironment,” said Dr Horn. PD-L1 is broadly expressed in patients with NSCLC with adenocarcinoma and squamouscell carcinoma.

Nivolumab, a PD-1 inhibitor, is an immunoglobulin G4 monoclonal antibody that was associated with an overall response rate as high as 24%, and a median OS of 14.9 months in heavily pretreated patients with NSCLC. The anti–PD-L1 monoclonal antibody MPDL3280A is being explored in NSCLC. In a phase 1 study, “what we saw was rapid and durable responses in both squamous and nonsquamous NSCLC patients,” said Dr Horn. A majority of patients respond by 12 to 21 weeks of therapy at the time of their first computed tomography scan. When responses were examined by PD-L1 immunohistochemistry (IHC) status, a higher response rate (83%) was observed in tumors with an IHC score of 3 compared with an IHC score of 2 or 1.

Some patients with PD-L1–negative tumors also exhibited a response. n

Continued from page 34

“More and more hospitals are asking to join our studies.

Therefore, in 2015, I expect at least 5 Dutch hospitals will be involved.

We should be able to take targeted biopsies by CUDI in large trials in 2016.”

contrast-enhanced ultrasound and disseminating the results.”

The pilot trial included 19 patients from the Academic Medical Center University Hospital, Amsterdam, the Netherlands, and 5 patients from

pressive response rates, said Dr Horn, including in patients with central nervous system disease.

Jeroen Bosch Hospital, ‘s-Hertogenbosch, the Netherlands. The investigators analyzed the estimated intravascular dispersion of the ultrasound contrast agent, which reflects the angiogenic changes to the microvascular

architecture caused by cancer growth.

The researchers then compared the results to the histologic results gathered after the patients’ prostates were removed by radical prostatectomy.

The investigators focused on two 0.5-cm2 regions in each prostate— one with benign tissue and the other with cancerous tissue—to determine CUDI’s accuracy. The results revealed that the contrast agent’s dispersion pattern had a high sensitivity and specificity for determining the location and size of the tumors.

Other CUDI parameters analyzed, such as the area under the time-intensity curve formed as the ultrasound probe passed across the surface of the prostate, were not as sensitive or specific for tumor tissue. n

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Drug Update

Imbruvica (Ibrutinib) the First Bruton’s Tyrosine Kinase Inhibitor Approved for Treatment of Patients with Relapsed Chronic Lymphocytic Leukemia

By Lisa A. Raedler, PhD, RPh, Medical Writer

C

hronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is a cancer of B-cell lymphocytes, which originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing an immune response.1,2 In CLL, excess B-cells accumulate in the bone marrow and blood, where they crowd out healthy blood cells.2 The Leukemia & Lymphoma Society has estimated that more than 15,500 Americans were diagnosed with CLL in 2013.3 The incidence of CLL increases significantly among people aged ≥50 years; only a small fraction of adults are diagnosed in their 30s or 40s.3 The majority of patients who are diagnosed with CLL are asymptomatic, and the diagnosis is made as a result of a routine blood test that shows a high white blood cell count.4 As it advances, CLL can cause swollen lymph nodes, an enlarged spleen, anemia, and infections.2 The prognosis for patients with CLL varies significantly based on their disease subtype and risk status, with survival duration ranging from approximately 1 year to more than 20 years.5 According to the American Society of Clinical Oncology, the 5-year overall survival rate for patients with CLL of all stages is approximately 79%.5 Early-stage CLL is typically not treated, whereas patients with symptomatic intermediate- or high-risk CLL are usually receiving chemotherapy combined with a targeted monoclonal antibody drug, either rituximab or another CD-20 targeted agent.6 Studies comparing treatment with chemotherapy, such as fludarabine or the combination of fludarabine and cyclophosphamide, with chemoimmunotherapy (fludarabine and rituximab) have shown that rituximab-containing combinations significantly improve complete response rates, remission duration, and overall survival of previously untreated patients with CLL.7 In November 2013, the US Food and Drug Administration (FDA) approved obinutuzumab (Gazyva) in combination with chlorambucil for the treatment of patients with previously untreated CLL.8 Obinutuzumab is a humanized monoclonal antibody that targets CD20 on the surface of CLL cells.9

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There is no consensus regarding the management of patients with relapsed and refractory CLL. Treatment decisions are based on several factors, including the timing of relapse, the patient’s age, disease extent, overall health status, and previous therapies.10 Agents that are frequently used (either alone or in combination) in the relapsed and/or refractory CLL setting include alemtuzumab, bendamustine, chlorambucil, fludarabine, ofatumu­ mab, and rituximab.11 As a chronic illness, the cost burden associated with CLL is significant. A recent published cost analysis was conducted in Germany using both the direct and indirect costs of CLL.12 European investigators found that the total per-patient cost for patients with CLL was €9753 (approximately $13,500) annually compared with €4807 (approximately $6600) annually

“Rarely does a drug come along with so much potential to help CLL patients….I have been impressed with the promising and durable response rates we have seen in patients.”

—John C. Byrd, MD

for individuals in the control group with the same age and sex. In this study, the economic burden associated with CLL was primarily driven by inpatient and pharmaceutical costs.

From a societal perspective, productivity loss was the highest cost driver associated with a diagnosis of CLL.12 Ibrutinib for Previously Treated Patients with CLL On February 12, 2014, the FDA accelerated the approval of an expanded indication for ibrutinib (Imbruvica; Pharmacyclics) for patients with CLL who have received at least 1 previous therapy.13 A few months earlier (in November 2013), the FDA accelerated its approval of ibrutinib for the treatment of patients with mantle-cell lymphoma who had received at least 1 previous therapy.13 Ibrutinib is the first

Table 1 Ibrutinib for CLL Dose Modifications for Adverse Reactions Nonhematologic Dose modification postrecovery in patients toxicity event with CLL, starting dose, 420 mg First

Restart at 420 mg daily

Second

Restart at 280 mg daily

Third

Restart at 140 mg daily

Fourth

Discontinue ibrutinib therapy

CLL indicates chronic lymphocytic leukemia.

Source: Imbruvica (ibrutinib) prescribing information; 2014.

FDA-approved drug designed to target Bruton’s tyrosine kinase (BTK), a protein necessary for the growth and survival of B-cells.14 The FDA’s accelerated approval of ibrutinib for CLL was based on a multicenter, single-arm study of 48 patients with previously treated CLL.13,15 The primary end point of this trial was overall response rate.13,15 (The analysis used for the approval of ibrutinib for CLL excluded data for an additional 34 patients in the trial who received ibrutinib 840 mg daily and 3 patients with small lymphocytic lymphoma.16) John C. Byrd, MD, Director of the Division of Hematology at the Ohio State University Comprehensive Cancer Center in Columbus, and a prin­cipal investigator in the ibrutinib CLL trial, stated, “Rarely does a drug come along with so much potential to help CLL patients….I have been impressed with the promising and durable response rates we have seen in patients.”16 Mechanism of Action Ibrutinib is a small-molecule inhibitor of BTK, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.15 As an irreversible covalent inhibitor, ibrutinib continues to inhibit BTK even after the drug is metabolized.17 Preclinical studies have demonstrated that ibrutinib prevents the activation of downstream pathways affected by BTK, promotes cancer-cell apoptosis, and inhibits cell proliferation.18 Dosing and Administration In patients with CLL who have received at least 1 previous therapy, the recommended dose and schedule for ibrutinib is 420 mg orally once daily.

Ibrutinib should be administered at the same time each day, and should be

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swallowed whole with water. The capsules should not be opened, broken, or chewed.15 Table 1 summarizes ibrutinib dose modification guidelines for patients with any grade ≥3 nonhematologic toxicity, grade ≥3 neutropenia with infection or fever, or grade 4 hematologic toxicities. Ibrutinib may be reinitiated at the starting dose after symptoms of toxicity have resolved to grade 1 or to baseline.15 Because ibrutinib is primarily metabolized by the cytochrome (CY) P450 enzyme 3A, it should not be coadministered with strong or moderate CYP3A inhibitors. The concomitant use of strong CYP3A inhibitors that are taken on a long-term basis (eg, rit­ onavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended.15 Increased drug exposure is also expected in patients with hepatic impairment; however, there are insufficient data to recommend a dose of ibrutinib in patients with baseline hepatic impairment.15 Less than 1% of the ibrutinib dose is excreted renally.15 Exposure to ibrutinib is not altered in patients with creatinine clearance (CrCl) of >25 mL/ min. No data exist for patients with severe renal impairment (CrCl <25 mL/min) or for patients on dialysis.15 Clinical Trials

Pivotal Phase 2 Study

The safety and efficacy of ibrutinib for the treatment of patients with CLL were demonstrated in a phase 1b/2 open-label, multicenter trial. This trial included 48 patients with CLL who had previously received multiple therapies.15 In this study, ibrutinib was given orally, 420 mg daily, in continuous 28day cycles until disease progression.15 The primary end point of this phase 2 Continued on page 38

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Drug Update

Imbruvica (Ibrutinib) the First Bruton’s Tyrosine... study was overall response rate, which was defined as partial response and complete response. Tumor response was evaluated by an Independent Review Committee using a modified version of the International Workshop on CLL criteria.15

Patient population

The median age of the 48 patients with CLL evaluated for this trial was 67 years (range, 37-82 years).15 Most patients were male (71%) and Caucasian (94%). All of the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ median time since the diagnosis of CLL exceeded 6 years (80 months). These patients had received 1 to 12 (median, 4) previous therapies for CLL.15

Efficacy

In this phase 2 study of ibrutinib in patients with relapsed CLL, the overall response rate was 58.3% (95% confidence interval, 43.2%-72.4%).15 All were partial responses. The duration of response for these patients with CLL ranged from 5.6 months to 24.2+ months. The median duration of response was not reached at the time of the FDA’s approval of the drug for CLL.15 An increase in lymphocyte counts, defined as a ≥50% increase from baseline and above absolute lymphocyte count of 5000/mcL, was observed in 77% of patients with CLL who received ibrutinib in this phase 2 study.

Isolated lymphocytosis occurred during the first 4 weeks of ibrutinib therapy and resolved after a median of 23 weeks (range, 1-104+ weeks).15

RESONATE: Phase 3 Study

As a condition for the accelerated approval of ibrutinib for patients with

CLL, the FDA instructed the drug manufacturer to submit the results of phase 3 randomized clinical trials to the FDA. In January 2014, the manufacturer of the drug notified the FDA that based on the favorable results of a planned interim analysis, the phase 3 RESONATE clinical trial that compared ibrutinib and ofatumumab for patients with CLL was ended early.16,19 This phase 3 clinical trial randomized patients with previously treated CLL or with small lymphocytic lymphoma who were not considered candidates for treatment with purine analog-based treatments to receive either ibrutinib or the anti-CD20 monoclonal antibody ofatumumab.19 The results of this interim analysis showed significant improvements in progression-free survival and overall survival with ibrutinib compared with ofatumumab for patients with previously treated CLL in this phase 3 trial.16,19 Adverse Events The 48 previously treated CLL patients who received ibrutinib in the phase 2 clinical trial received 420 mg daily for a median of 15.6 months.15 Adverse reactions that occurred at a frequency of ≥20% included thrombocytopenia (71%, all grades), diarrhea (63%), bruising (54%), neutropenia (54%), upper respiratory tract infection (48%), anemia (44%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%).15 The most common grade 3 or grade 4 nonhematologic adverse reactions were pneumonia (8%), hypertension (8%), atrial fibrillation (6%), sinusitis (6%), skin infection (6%), dehydration

Table 2 Selected Adverse Events of Patients with CLL Receiving Ibrutinib System organ class/ All grades, % Grade 3 or 4, % adverse events (N = 48) (N = 48) Blood disorders Thrombocytopenia 71 10 Neutropenia 54 27 Infections/infestations Sinusitis 21 6 Skin infection 17 6 Pneumonia 10 8 Vascular disorders Hypertension 17 8 Musculoskeletal/connective tissue disorders Musculoskeletal pain 27 6 CLL indicates chronic lymphocytic leukemia.

Source: Imbruvica (ibrutinib) prescribing information; 2014.

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(6%), and musculoskeletal pain (6%; Table 2).15,16 Of the 48 patients with CLL, 5 discontinued ibrutinib as a result of adverse reactions in the phase 2 trial: 3 patients with infections and 2 patients with subdural hematomas.15 Of the patients with CLL who received ibrutinib, 13% experienced adverse reactions that led to dose reduction. In 38% of patients, uric acid levels shifted from normal to elevated during the study, including 4% of patients with values >10 mg/dL.15 Warnings and Precautions Ibrutinib has no contraindications.15 Hemorrhage. Bleeding events, including bruising of any grade, were observed in 63% of patients with CLL who received 420 mg of ibrutinib daily.15 Of the patients with CLL, 6% had grade ≥3 bleeding events, including subdural hematoma, gastrointestinal bleeding, and hematuria. Clinicians should consider the benefit-risk of ibrutinib in patients who require antiplatelet or anticoagulant therapies, and the benefit-risk of withholding ibrutinib for at least 3 to 7 days before and after surgery depending on the procedure and the risk of bleeding.15 Infections. Fatal and nonfatal infections occurred in the clinical trial of ibrutinib in patients with CLL.15 At least 35% of patients with CLL had grade ≥3 infections. Clinicians should regularly monitor patients who are receiving ibrutinib for signs of fever and infections and should evaluate the patients promptly.15 Myelosuppression. Grade 3 or 4 cytopenias, including neutropenia (27%) and thrombocytopenia (10%; Table 2), were reported in the patients with CLL receiving ibrutinib.15 Patients should undergo monthly complete blood cell counts while taking ibrutinib.15 Renal toxicity. Serious and even fatal cases of renal failure have occurred with ibrutinib.15 Increases in creatinine levels up to 1.5 times the upper limit of normal (ULN) occurred in 23% of patients with CLL receiving ibrutinib and from 1.5 to 3 times the ULN in 4% of patients with CLL. Patients receiving ibrutinib should undergo periodic creatinine level monitoring and should maintain hydration.15 Secondary primary malignancies.

Other malignancies, including skin cancers (8%) and other types of carcinomas (2%), have been observed in patients with CLL who have received ibrutinib.15 Embryo-fetal toxicity. Based on animal studies, ibrutinib can cause fetal

Continued from page 37

harm when administered during pregnancy. Women should be advised to avoid becoming pregnant while taking ibrutinib.15 Specific Populations Pregnant women. Ibrutinib has been assigned Pregnancy Category D. Based on animal data, ibrutinib can cause fetal harm when administered to a pregnant woman.15 Nursing mothers. Ibrutinib has not been studied in nursing mothers. It is not known whether this agent is excreted in human breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse events with ibrutinib, a decision should be made to discontinue nursing or to discontinue taking ibrutinib, with the importance of the drug to the mother kept in mind.15 Pediatric patients. The safety and efficacy of ibrutinib in pediatric patients have not been established.

Older patients. In the clinical trial of ibrutinib for the treatment of patients with CLL, 52% of patients were aged ≥65 years. When older and younger patients were compared, no overall differences in efficacy were observed.

However, a higher number of adverse events were reported in older patients (aged ≥65 years). Specifically, grade ≥3 adverse events occurred more often among older patients compared with among younger patients (80% vs 61%, respectively).15 Conclusion Ibrutinib, the first FDA-approved BTK inhibitor, offers clinicians and previously treated patients with CLL an effective and safe treatment option.

This once-daily oral agent has demonstrated a high response rate, as well as a favorable toxicity profile, in patients with relapsed CLL. Because ibrutinib has a favorable therapeutic index, its use in combination with other agents for the treatment of patients with CLL and other hematologic malignancies is currently being explored.16,20 Examples include an ongoing study combining ibrutinib with bendamustine and ri­ tuximab for patients with relapsed or refractory CLL and a study combining ibrutinib with rituximab for patients with relapsed or refractory mantle-cell lymphoma.21 n References

1. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. www.lls.org/#/diseaseinformation/leuke mia/chroniclymphocyticleukemia/. Accessed March 3, 2014.

2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: causes and risk factors. www.lls.org/ diseaseinformation/leukemia/chroniclymphocyticleu kemia/causesriskfactors/. Accessed March 3, 2014.

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Imbruvica (Ibrutinib) the First Bruton’s Tyrosine...

11, 2014.

15. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics; February 2014.

16. Inman S. FDA approves ibrutinib for chronic lymphocytic leukemia. OncLive. February 12, 2014. www.onclive.com/web-exclusives/FDA-ApprovesIbrutinib-for-CLL#sthash.bNUKV3Wo.dpuf. Accessed March 11, 2014.

17. Woyach J. BTK inhibition and the mechanism of

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action of ibrutinib. Targeted Oncology. August 20, 2013. www.targetedonc.com/targeted-communications/ Dr-Woyach-on-BTK-Inhibition-and-the-Mechanismof-Action-of-Ibrutinib. Accessed December 16, 2013.

18. Akinleye A, Chen Y, Mukhi N, et al. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6:59.

19. US Food and Drug Administration. Ibrutinib (Imbruvica). Updated February 13, 2014. www.fda.

Navigation and 5 Survivorship Conference YEAR

A N N I V E R S A RY

September 18-21, 2014 Walt Disney World Dolphin Hotel • Orlando, Florida

TO DATE, THE CONFERENCE HAS HAD MORE THAN:

1,700

107

Total Attendees

Thank you again for a wonderful conference

ter changes, and inflammatory mediators that are toxic to neurons and that impair CNS function.

There are currently no brief sensitive tools to screen for the disorder, but neuropsychologic testing can substantiate the patient’s experience.

Neuroimaging confirms structural and functional changes in the brain of patients with cancer-associated cognitive impairment, but is not helpful in diagnosis.

“Current management strategies are patient-centered, supportive, and nonspecific,” Dr Kvale said. “Reassurance and watchful waiting are not unreasonable strategies for patients exhibiting symptoms of cancer-associated cognitive dysfunction. For most patients these symptoms will resolve on their own over the course of time.

Reassuring them that this is not a progressive dementing condition is a perfectly reasonable thing to do.” n

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Expert Speakers

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(only missed your first year). I submit a report year to help me get funding for the following

Continued from page 33

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Abstracts

on the conference to my administration each

Updated NCCN Survivorship...

gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm385878.htm. Accessed March 11, 2014.

20. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.

21. ClinicalTrials.gov. Ibrutinib combination. Search results. http://clinicaltrials.gov/ct2/results?term= ibrutinib+combination+&Search=Search. Accessed March 11, 2014.

FIFTH ANNUAL

Abstracts Submitted

3. Leukemia & Lymphoma Society. Incidence: how common is CLL? www.lls.org/#/diseaseinformation/ leukemia/chroniclymphocyticleukemia/incidence/.

Accessed March 3, 2014.

4. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: signs and symptoms. www.lls.org/ diseaseinformation/leukemia/chroniclymphocyticleu kemia/signssymptoms/. Accessed March 3, 2014.

5. Cancer.net. Leukemia–chronic lymphocytic–CLL: statistics. Updated February 18, 2014. www.cancer. net/cancer-types/leukemia-chronic-lymphocytic-cll/ statistics. Accessed March 4, 2014.

6. Cancer.net. Leukemia–chronic lymphocytic–CLL: treatment options. www.cancer.net/cancer-types/ leukemia-chronic-lymphocytic-cll/treatment-options.

Accessed March 4, 2014.

7. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: clinical trials. www.lls.org/diseasein formation/leukemia/chroniclymphocyticleukemia/ clinicaltrials/. Accessed March 3, 2014.

8. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release.

November 1, 2013. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm373209.htm. Ac­cessed November 29, 2013.

9. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; November 2013.

10. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: before treatment. www.lls.org/#/ diseaseinformation/leukemia/chroniclymphocyticleu kemia/beforetreatment/. Accessed March 3, 2014.

11. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: chemotherapy and drug therapy. www.lls.org/#/diseaseinformation/leukemia/chron iclymphocyticleukemia/treatment/chemotherapy drugtherapy/. Accessed March 3, 2014.

12. Blankart CR, Koch T, Linder R, et al. Cost of illness and economic burden of chronic lymphocytic leukemia. Orphanet J Rare Dis. 2013;8:32.

13. US Food and Drug Administration. FDA approves Imbruvica to treat chronic lymphocytic leukemia.

Press release. February 12, 2014. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm385764.htm. Accessed March 14, 2014.

14. Lymphoma Research Foundation. Breakthrough therapy ibrutinib effective in CLL and MCL lymphomas. August 2013. www.lymphoma.org/site/pp.asp ?c=bkLTKaOQLmK8E&b=8756085. Accessed March

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year and so far...so good. I attend various national conferences throughout the year and stand amazed at your ability to continue

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2010

2011

2012

2013

Year of Submission

– 2013 Conference Attendee

93%

23

9

10 0

to provide new and motivating presentations.

20

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93% of 2013 conference attendees said they intended to change their practice as a result of participating in the AONN+ Conference

“WOW! I am so impressed with the growth of AONN. Lillie, Sharon, and their team are awesome. The speakers were knowledgeable about their subject matter and all the presentations were relevant to my practice. I will use the pearls of wisdom shared by the speakers to my team at

97%

97% of 2013 conference attendees rated the AONN+ Conference as Above Average or Excellent when compared with other continuing education activities

home. I arrived feeling we have a pretty good program and I am leaving with ideas to share to make it even better!”

– Donna Moore Wilson, BSN, RN, CBCN Oncology Nurse Navigator Bon Secours Cancer Institute Richmond, Virginia AONN+ A-SIZE_22414

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